Clinical trial NCT03382561
Conditions: Extensive Stage Lung Small Cell Carcinoma Recurrent Lung Small Cell Carcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2018-05-21; Completion date: 2025-01-31
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II clinical trial studies whether the addition of nivolumab to cisplatin (or carboplatin) and etoposide will improve outcomes when treating patients with extensive stage small cell lung cancer. Chemotherapy drugs, such as cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cisplatin/carboplatin and etoposide together with nivolumab may work better in treating patients with extensive stage small cell lung cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the progression-free survival (PFS) of patients with extensive stage small cell lung cancer (ED-SCLC) treated with cisplatin/carboplatin and etoposide (CE) or CE with nivolumab (CEN) as front-line treatment.

SECONDARY OBJECTIVES:

I. To estimate overall survival of patients with ED-SCLC treated with cisplatin/carboplatin and etoposide (CE) or CE with nivolumab (CEN) as front-line treatment.

II. To assess best overall response rate after treatment with CE with or without nivolumab as first line treatment.

III. To evaluate the toxicity profile of nivolumab with CE.

EXPLORATORY OBJECTIVES:

I. To evaluate immune biomarkers and biomarkers correlatives. II. To evaluate serial circulating tumor deoxyribonucleic acid (DNA) and explore whether clinical outcome is associated with fluctuations in DNA levels following the administration of therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1, carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients continue to receive nivolumab IV over 30 minutes every 2 weeks for up to 2 years.

ARM B: Patients receive carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months if the patient is less than 2 years from registration, every 6 months if the patient is 2-3 years from registration, and yearly for up to 5 years from study enrollment.

Arms: arm 1: Patients receive nivolumab IV over 30 minutes on day 1, carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients continue to receive nivolumab IV over 30 minutes every 2 weeks for up to 2 years. arm 2: Patients receive carboplatin IV over 30-60 minutes on day 1 or cisplatin IV over 60-120 minutes on day 1, and etoposide IV over 60-120 minutes on days 1-3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Carboplatin intervention 2: Cisplatin intervention 3: Etoposide intervention 4: Nivolumab
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
i
28 State Street, Suite 1100, Boston, MA 02109
p: 857.504.2900
f:617. 589.0914
ecog-acrin.org
February 17, 2020
Martha Kruhm, MS RAC
Head, Protocol and Information Office
Quality Assurance Section
CTEP, DCT, NCI
6130 Executive Blvd, EPN Room 7000
Bethesda, MD   20892
Dear Ms. Kruhm:
Enclosed is Addendum #5 to EA5161, Randomized Phase II Clinical Trial of 
Cisplatin/Carboplatin and Etoposide (CE) Alone or in Combination with Nivolumab as Frontline 
Therapy for Extensive Stage Small Cell Lung Cancer (ED-SCLC)
This addendum is in response to a nivolumab rapid request for amendment from Dr. Jeffrey 
Moscow dated January 28, 2021.
No updates to the case report forms in Medidata Rave are planned as a result of this 
amendment.
Please replace your current copy of the protocol and Informed Consent document with these 
updated versions.  We recommend that each institution maintain a file containing the original 
protocol, Informed Consent, and all subsequent revisions/versions.
IRB Review Requirements:
A) Full IRB review of this addendum is recommended, however, ECOG-ACRIN will accept the 
method of review determined by the standard operating procedures for the IRB of record for 
this protocol.
Sites using the CIRB as their IRB of record: The protocol and/or informed consent form 
changes have been approved by the CIRB and must be activated within 30 days of the CIRB 
posting of this notice.
Sites not using the NCI CIRB: Per CTMB Guidelines, the protocol updates and/or informed 
consent changes must be approved by local IRBs within 90 days of distribution of this notice. If 
your local IRB has different SOPs, they must be available at future E-A audit.
The following revisions to EA5161 protocol have been made in this addendum:
Section
Change
1.
Cover Page
Updated Version Date and added Addendum #5.
2.
Section 5.3
Updated CAEPR to Version 2.4, December 2, 2020.


ii 
The following revisions to EA5161 Informed Consent Document have been made in this 
addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated Version Date. 
2. 
“What possible risks 
can I expect from 
taking part in this 
study?” 
Updated Risk List for nivolumab to version 2.4, December, 2020. 
If you have any questions regarding this addendum, please contact Jack Fraulini at 
jfraulini@ecog-acrin.org or 857-504-2900. 
We request review and approval of this addendum to EA5161 so ECOG-ACRIN may activate it 
promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director, Protocol Development 
 


 
EA5161 
1 
Randomized Phase II Clinical Trial of 
Cisplatin/Carboplatin and Etoposide (CE) Alone or in 
Combination with Nivolumab as Frontline Therapy for 
Extensive Stage Small Cell Lung Cancer (ED-SCLC) 
STUDY CHAIR: Ticiana Leal, MD 
STUDY CO-CHAIR: Afshin Dowlati, MD  
STUDY STATISTICIAN: Suzanne Dahlberg, PhD  
THORACIC COMMITTEE CHAIR: Suresh Ramalingam, MD 
LABORATORY CO-CHAIR Afshin Dowlati, MD 
Version Date:  February 17, 2021 
 
STUDY PARTICIPANTS 
 
AMENDMENTS 
ALLIANCE / Alliance for Clinical Trials in 
Oncology 
 
Addendum #1 
Addendum #2 
NRG / NRG Oncology 
 
Addendum #3 
SWOG / SWOG 
 
Addendum #4 
 
 
Addendum #5 
US Only   
 
 
 
 
 
 
 
Agents 
IND# 
NSC# 
Supply 
Nivolumab 
 
748726 
NCI 
Cisplatin 
 
119875 
Commercial 
Carboplatin 
 
241240 
Commercial 
Etoposide  
 
141540 
Commercial 
 


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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Small Cell Lung Cancer (SCLC) ................................................................... 7 
1.2 
PD-1 inhibition .......................................................................................... 7 
1.3 
Immunotherapy in SCLC .......................................................................... 14 
1.4 
Rationale for the combination ................................................................ 16 
1.5 
Correlatives Background ......................................................................... 17 
2. Objectives ......................................................................................................... 18 
2.1 
Primary Endpoints ................................................................................... 18 
2.2 
Secondary Endpoints ............................................................................... 18 
2.3 
Exploratory objectives ............................................................................. 18 
3. Selection of Patients ......................................................................................... 19 
3.1 
Eligibility Criteria ..................................................................................... 19 
4. Registration and Randomization Procedures ................................................... 23 
4.1 
Protocol Number ..................................................................................... 26 
4.2 
Investigator Identification ....................................................................... 26 
4.3 
Patient Identification .............................................................................. 26 
4.4 
Eligibility Verification .............................................................................. 26 
4.5 
Stratification Factors ............................................................................... 26 
4.6 
Additional Requirements ........................................................................ 26 
4.7 
Instructions for Patients who Do Not Start Assigned Protocol Treatment27 
5. Treatment Plan ................................................................................................. 28 
5.1 
Agent Administration .............................................................................. 28 
5.2 
Adverse Event Reporting Requirements ................................................. 29 
5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for BMS-
936558 (Nivolumab, MDX-1106, NSC 748726) ....................................... 44 
5.4 
Dose Modifications ................................................................................. 49 
5.5 
Supportive Care ....................................................................................... 59 
5.6 
Duration of Therapy ................................................................................ 61 
5.7 
Duration of Follow-up ............................................................................. 62 
6. Measurement of Effect ..................................................................................... 63 
6.1 
Antitumor Effect – Solid Tumors ............................................................. 63 
7. Study Parameters .............................................................................................. 71 
7.1 
Therapeutic Parameters .......................................................................... 71 
7.2 
Biological Sample Submissions ............................................................... 73 
8. Drug Formulation and Procurement ................................................................. 74 
8.1 
Nivolumab (NSC 748726) ........................................................................ 75 
8.2 
Cisplatin ................................................................................................... 77 
8.3 
Carboplatin .............................................................................................. 79 
8.4 
Etoposide ................................................................................................ 81 


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9. Statistical Considerations .................................................................................. 84 
9.1 
Study Design and Objectives ................................................................... 84 
9.2 
Study Endpoints ...................................................................................... 84 
9.3 
Statistical Analysis Plan ........................................................................... 84 
9.4 
Sample Size Considerations .................................................................... 85 
9.5 
Projected Accrual .................................................................................... 85 
9.6 
Randomization Scheme........................................................................... 86 
9.7 
Monitoring Plan ...................................................................................... 86 
9.8 
Gender and Ethnicity .............................................................................. 86 
10. Specimen Submissions ...................................................................................... 87 
10.1 Submissions to the ECOG-ACRIN Central Biorepository and Pathology 
Facility (CBFP) .......................................................................................... 87 
10.2 Use of Specimens in Research ................................................................ 89 
10.3 ECOG-ACRIN Sample Tracking System .................................................... 90 
10.4 Sample Inventory Submission Guidelines ............................................... 90 
11. Laboratory Research Studies ............................................................................ 91 
11.1 Circulating Tumor DNA Qualification and Sequencing ........................... 91 
11.2 Lab Data Transfer Guidelines .................................................................. 91 
12. Electronic Data Capture .................................................................................... 92 
13. Patient Consent and Peer Judgment ................................................................ 92 
14. References ........................................................................................................ 92 
Appendix I  Pathology Submission Guidelines ........................................................ 96 
Appendix II  Patient Thank You Letter ................................................................... 100 
Appendix III  Nivolumab (BMS-936558) TOXICITY MANAGEMENT ALGORITHMS 101 
Appendix IV  CRADA/CTA ...................................................................................... 109 
Appendix V  ECOG Performance Status................................................................. 111 
Appendix VI  Instructions for Reporting Pregnancies on a Clinical Trial ............... 112 
Appendix VII  EA5161 Collection and Shipping Kit Order Instructions .................. 115 
 
 
 
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STUDY CHAIR 
Ticiana Leal, MD 
University of Wisconsin Hospital and Clinics 
1111 Highland Ave, WIMR 3037 
Madison, WI 53705 
Phone: 608-263-9063 
Fax: 608-531-2737 
Email: tbleal@medicine.wisc.edu 
 
STUDY CO-CHAIR 
Afshin Dowlati, MD 
University Hospitals Seidman Cancer Center 
11100 Euclid Avenue 
Cleveland, OH 44106  
Phone: 216-844-5181 
Fax: 216-844-5234 
Email: afshin.dowlati@case.edu  
 
STUDY CHAIR LIAISON (SCL) 
Kasey Schneider, RN 
Thoracic Oncology Program Manager  
University of Wisconsin Hospital and Clinics 
600 Highland Ave 
Madison, WI 53792 
Phone: 608-262-3078 
Fax: 608-531-2737 
Email: lunggroup@uwcarbone.wisc.edu 
 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal: 
Regulatory Submission Portal 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory 
tab.)  
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions on 
using the Oncology Patient Enrollment 
Network (OPEN) which can be accessed 
at https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  
Please see the data 
submission section of 
the protocol for further 
instructions.  
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 
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Schema 
1.
Refer to Section 5.1 for specific doses.
2.
Until progressive disease, unacceptable toxicity, patient desire to discontinue study treatment, or up to 2 years (or 50 
doses) maximum.
3.
Until disease progression or non-protocol treatment regimen is initiated.
4.
All patients will proceed to maintenance or observation after 4 cycles of chemotherapy. 
R
A
N
D
O
M
I
Z
E
Cisplatin/Carboplatin
Etoposide and Nivolumab1
Arm A
Arm B
Cycle = 3 weeks during cycles 1-4 (21 days)
Cycle = 6 weeks during maintenance cycle 5+
Accrual goal = 150 patients
Cisplatin/Carboplatin
Etoposide1
Nivolumab Maintenance1,2
Observation3
Stratification
1.
Gender (Male vs. 
Female)
2.
LDH < upper limits of 
normal or > ULN
Cycles 1-44
Cycles 5+
Follow-up
 
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1. 
Introduction 
1.1 
Small Cell Lung Cancer (SCLC)  
Approximately 65% of all cases of SCLC in the US are diagnosed at the 
extensive stage of the disease. There is at present no curative treatment for this 
stage of the disease. The management approach of systemic chemotherapy 
using a platinum-etoposide doublet is the most common regimen in the North 
American patient population. This regimen achieves a response rate of 50-70%, 
a median survival of 9-11 months and median 5-year survival rate of less than 
5%1-4. There has been no significant therapeutic improvement in clinical outcome 
for patients with extensive stage SCLC in the last 2 decades, making it one of the 
most fatal cancers. While SCLC remains very sensitive to frontline platinum-
based doublet chemotherapy with response rate of up to 70%, the majority of the 
patients will relapse and die of their disease. Previous strategies to improve the 
outcome of the disease with the use of high intensity chemotherapy led to an 
improvement in the response rate, which did not translate into survival benefit 
due to the heightened toxicities of intensive chemotherapy5-7.The incorporation of 
novel immunotherapy agents with excellent safety profile and limited additive 
toxicity in combination with standard chemotherapy agents as a strategy for 
improved efficacy has a great potential for improved clinical outcome in this 
disease.  
1.2 
PD-1 inhibition 
The programmed death-1 (PD-1) receptor serves as an immunologic checkpoint, 
limiting bystander tissue damage and preventing the development of 
autoimmunity during inflammatory responses. PD-1 is a negative regulatory 
molecule expressed by activated T and B lymphocytes.8 Binding of PD-1 to its 
ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the 
down-regulation of 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.  
PD-1, a 55-kDa type 1 transmembrane protein, is a member of the CD28 family 
of T-cell co-stimulatory receptors that include Ig super family member CD28, 
CTLA-4, inducible co-stimulator (ICOS), and B and T lymphocyte attenuator 
(BTLA) (Investigator Brochure, version 16, 2017).  PD-1 is transiently but highly 
expressed on activated T cells functioning to limit immune effectors at the site of 
activation.  Chronic stimulation may prevent the re-methylation of the PD-1 gene 
leading to continuous expression and characterizes a state of “exhausted” T cells 
that lose function and proliferative capacity while enhancing a suppressive tumor 
microenvironment.  PD-1 may act together with other T-cell modulating 
molecules, including CTLA-4, TIM-3, lymphocyte-activation gene 3 (LAG-3) as 
well as indoleamine-pyrrole 2,3-dioxygenase 1 (IDO-1), cytokines, and 
transforming growth factor beta (TGF-beta). 
Two ligands specific for PD-1 have been identified:  PD-ligand 1 (PD-L1, also 
known as B7-H1 or CD274, expressed on tumor, antigen-presenting cells 
[APCs], and dendritic cells [DCs]) and PD-L2 (also known as B7-DC or CD273, 
expressed on endothelial cells). The interaction of PD-1 with PD-L1 and PD-L2 
results in negative regulatory stimuli that down-modulate the activated T-cell 
immune response through SHP-1 phosphatase. 


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PD-1 knockout mice develop strain-specific lupus-like glomerulonephritis 
(C57BL/6) and cardiomyopathy (BALB/c).  In transplantable tumor models that 
expressed PD-1 and LAG-3 on tumor-infiltrating CD4+ and CD8+ T cells dual anti-
LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that 
were largely resistant to single antibody treatment.9 Despite minimal 
immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual 
knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in 
multiple organs, leading to eventual lethality. 
PD-L1 expression is found on a number of tumors, and is associated with poor 
prognosis based on overall survival (OS) in many tumors, including melanoma,10 
renal,11 esophageal,12 gastric,13 ovarian,14 pancreatic,15 lung,16 and other cancers 
(Investigator Brochure, version 16, 2017). 
In summary, the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and therefore represents an attractive target for therapeutic intervention.  
1.2.1 
Nivolumab 
Nivolumab (BMS-936558, MDX-1106, and ONO-4538) is a fully 
human monoclonal immunoglobulin G4 (IgG4) antibody (HuMAb) that 
is specific for human programmed death-1 (PD-1, cluster of 
differentiation 279 [CD279]) cell surface membrane receptor 
(Investigator Brochure, version 16, 2017). PD-1 is a negative 
regulatory molecule that is expressed transiently following T-cell 
activation and on chronically stimulated T cells characterized by an 
“exhausted” phenotype.8 Nivolumab is expressed in Chinese hamster 
ovary (CHO) cells and is produced using standard mammalian cell 
cultivation and chromatographic purification technologies. Nivolumab 
is approved for use in multiple countries including the United States 
(US, Dec-2014), the European Union (EU, Jun-2015), and Japan (Jul-
2014). 
1.2.1.1 
Nonclinical Studies of Nivolumab 
Nivolumab has been shown to bind specifically to the 
human PD-1 receptor and not to related members of the 
CD28 family.17 Nivolumab inhibits the interaction of PD-1 
with its ligands, PD-L1 and PD-L2, resulting in enhanced 
T-cell proliferation and interferon-gamma (IFN-γ) release in 
vitro.18 Nivolumab binds with high affinity to activated 
human T-cells expressing cell surface PD-1 and to 
cynomolgus monkey PD-1.17 In a mixed lymphocyte 
reaction (MLR), nivolumab promoted a reproducible 
concentration-dependent enhancement of IFN- release.17  
In intravenous (IV) repeat-dose toxicology studies in 
cynomolgus monkeys, nivolumab was well tolerated at 
doses up to 50 mg/kg, administered weekly for 5 weeks, 
and at doses up to 50 mg/kg, administered twice weekly 
for 27 doses. While nivolumab alone was well tolerated in 
cynomolgus monkeys, combination studies have 
highlighted the potential for enhanced toxicity when 
combined with other immunostimulatory agents, such as 
ipilumumab (Investigator Brochure, version 16, 2017). 
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In addition, an enhanced pre- and postnatal development 
(ePPND) study in pregnant cynomolgus monkeys with 
nivolumab was conducted. Administration of nivolumab at 
up to 50 mg/kg 2QW was well tolerated by pregnant 
monkeys; however, nivolumab was determined to be a 
selective developmental toxicant when administered from 
the period of organogenesis to parturition at  10 mg/kg 
(area under the concentration-time curve [AUC] from time 
zero to 168 hours [AUC (0-168 h)] 117,000 g•h/mL). 
Specifically, increased developmental mortality (including 
late gestational fetal losses and extreme prematurity with 
associated neonatal mortality) was noted in the absence of 
overt maternal toxicity. There were no nivolumab-related 
changes in surviving infants tested throughout the 6-month 
postnatal period. Although the cause of these pregnancy 
failures was undetermined, nivolumab-related effects on 
pregnancy maintenance are consistent with the 
established role of PD-L1 in maintaining fetomaternal 
tolerance in mice.19  
1.2.1.2 
Clinical Development of Nivolumab 
The pharmacokinetics (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.  
Clinical activity of nivolumab has been observed in patients 
with melanoma, NSCLC, SCLC, head and neck cancer, 
RCC, urothelial cancer, and cHL. In addition, the 
combination of nivolumab and ipilimumab (anti-cytotoxic T 
lymphocyte associated antigen-4 [anti-CTLA-4]) in a phase 
1/2 trial showed markedly enhanced clinical activity with an 
acceptable safety profile in melanoma 20-22 and NSCLC 
patients.23 
Nivolumab monotherapy is now 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. In addition, 
nivolumab has been approved for use in combination with 
ipilimumab for unresectable melanoma in multiple 
countries, including the US and EU.  
Nivolumab is being investigated both as monotherapy and 
in combination with chemotherapy, targeted therapies, and 
other immunotherapies.  
1.2.1.3 
Pharmacokinetics (PK) 
The PK of nivolumab was studied in subjects over a dose 
range of 0.1 to 10 mg/kg administered as a single dose or 
as multiple doses of nivolumab every 2 or 3 weeks. The 
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geometric mean (% CV%) clearance (CL) was 9.5 mL/h 
(49.7%), geometric mean volume of distribution at steady 
state (Vss) was 8.0 L (30.4%), and geometric mean 
elimination half-life (t1/2) was 26.7 days (101%). Steady-
state concentrations of nivolumab were reached by 12 
weeks when administered at 3 mg/kg Q2W, and systemic 
accumulation was approximately 3-fold. The exposure to 
nivolumab increased dose proportionally over the dose 
range of 0.1 to 10 mg/kg administered every 2 weeks. 
Additionally, nivolumab has a low potential for drug-drug 
interactions. The clearance of nivolumab increased with 
increasing body weight. The PPK analysis suggested that 
the following factors had no clinically important effect on 
the CL of nivolumab: age (29 to 87 years), gender, race, 
baseline LDH, PD-L1. A PPK analysis suggested no 
difference in CL of nivolumab based on age, gender, race, 
solid tumor type, baseline tumor size, and hepatic 
impairment.  
 Although ECOG status, baseline glomerular filtration rate 
(GFR), albumin, body weight, and mild hepatic impairment 
had an effect on nivolumab CL, the effect was not clinically 
meaningful. PPK analysis suggest that nivolumab CL in 
subjects with cHL was approximately 32% lower relative to 
subjects with NSCLC; however, the lower CL in cHL 
subjects was not considered to be clinically relevant as 
nivolumab exposure was not a significant predictor for 
safety risks for these patients. When nivolumab is 
administered in combination with ipilimumab, the CL of 
nivolumab was increased by 24%, whereas there was no 
effect on the clearance of ipilimumab. Additionally, PPK 
and exposure response analyses have been performed to 
support use of 240 mg Q2W dosing in addition to the 3 
mg/kg Q2W regimen. A flat dose of nivolumab 240 mg 
Q2W was selected since it is identical to a dose of 3 mg/kg 
for subjects weighing 80 kg, the observed median body 
weight in nivolumab-treated cancer patients. Using a PPK 
model, the overall distributions of nivolumab exposures 
(Cavgss, Cminss, Cmaxss, and Cmin1) are comparable 
after treatment with either 3 mg/kg or 240 mg nivolumab. 
(Investigator Brochure, version 16, 2017). 
1.2.1.4 
Clinical Efficacy  
In early clinical trials, nivolumab monotherapy 
demonstrated clinical activity in multiple tumor types, 
including melanoma, renal cell carcinoma, and NSCLC.24 
In a multicenter phase I trial enrolling NSCLC, melanoma, 
renal cell carcinoma, castration-resistant prostate cancer, 
and colorectal cancer, radiographic response rate in 
advanced, previously treated NSCLC was 18% (14 of 76 
patients).25 In some cases, these responses were 
prolonged. For 8 of the 14 responding cases, responses 
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lasted ≥ 24 weeks; in 2 cases, responses lasted more than 
one year. In 7% of cases, stable disease lasted ≥ 24 
weeks.  
Response rates varied according to treatment dose, 
histology, and biomarkers. In the 1.0 mg/kg cohort, 
response rate was 6%. In the 3.0 mg/kg arm, response 
rate was 27%. In the 10.0 mg/kg arm, response rate was 
20%. For squamous cases, response rate was 17% (9/54) 
[22% at the 3.0 mg/kg level], compared to 18% (13/74) 
[26% at the 3.0 mg/kg level] in non- squamous cases. For 
tumors negative for PD-L1 by immunohistochemistry, there 
were no radiographic responses (0/17). For PD-L1-positive 
tumors, response rate was 36% (9/25; P=0.006).26 
While treatment in this study was overall well tolerated, 
there were instances of immune- related adverse events. 
The most common treatment-related adverse events 
included fatigue, rash, diarrhea, pruritus, decreased 
appetite, and nausea. Apparent immune-related adverse 
events included pneumonitis, vitiligo, colitis, hepatitis, 
hypophysitis, and thyroiditis. In total, grade 3 or 4 
treatment-related adverse events occurred in 14% of 
patients. Pneumonitis occurred in 3% of patients (1% 
grade 3-4). There were 3 deaths attributed to pneumonitis 
(2 NSCLC, 1 colorectal cancer). In many cases, early 
pneumonitis was reversible with stopping treatment, 
initiating glucocorticoids, or both.  
Nivolumab has also been given in combination with 
platinum doublet chemotherapy for advanced NSCLC. In a 
phase I trial dose de-escalation trial, 43 patients were 
treated with nivolumab plus either gemcitabine-cisplatin, 
pemetrexed-cisplatin, or carboplatin-paclitaxel.27 No dose-
limiting toxicities (DLTs) were observed with any 
combination when nivolumab was administered 10 mg/kg 
every 3 weeks. Grade 3 pneumonitis developed in 3 
patients (7%). Other apparent immune-related grade 3-4 
toxicities included rash, nephritis, and colitis. 
More recently, two phase 3 clinical trials (Checkmate 05728 
and Checkmate 01729) comparing nivolumab to single-
agent docetaxel chemotherapy in previously treated 
advanced NSCLC have been conducted. Both trials have 
demonstrated improved overall survival with nivolumab 
compared to docetaxel.  
The Checkmate 057 trial enrolled patients with non-
squamous NSCLC; the trial met its primary endpoint of 
improving OS. In the unselected population, for patients 
receiving nivolumab (N=287), median overall survival (OS) 
was 12.2 months compared with 9.4 months for docetaxel 
(N=268) (HR 0.73, 96% CI 0.59-0.89, p=0.002). Fewer 
grade 3 to 5 adverse events were reported for nivolumab 
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(10%) when compared with docetaxel (54%). Clinical 
benefit was particularly evident for patients whose tumors 
had PD-L1 staining of 1% or more, with OS of 17.2 to 19.4 
months compared with 8- 9 months for docetaxel (HR 
0.59). Conversely, there did not appear to be a benefit for 
nivolumab over docetaxel in the PDL1-negative population 
(HR 0.9).29 Treatment-related select adverse events 
observed included infusion-related reactions (3%; no grade 
3-4), rash (9%; < 1% grade 3-4), pneumonitis (3%; 1% 
grade 3-4), ALT/AST increased (3%; < 1% grade 3-4), 
diarrhea (8%; 1% grade 3-4), and hypothyroidism (7%; no 
grade 3-4). 
Checkmate 017 enrolled patients with squamous NSCLC 
and also met its primary endpoint of improving OS.28 
Patients were randomized to nivolumab (3 mg/kg IV over 
60 minutes every 2 weeks) (n=135) versus standard of 
care docetaxel (75 mg/m2 IV every 3 weeks) (n=137). In a 
prespecified interim analysis, compared to docetaxel, 
nivolumab resulted in a 41% reduction in the risk of death 
(HR 0.59; 95% CI 0.44-0.79; P<0.001). Median OS was 
9.2 months in the nivolumab arm (95% CI, 7.3-13.3 
months) and 6 months in the docetaxel arm (95% CI, 5.1-
7.3 months). Notably, the trial included patients regardless 
of tumor PD-L1 status. In the nivolumab arm, the most 
common adverse reactions (reported in ≥ 20% of patients) 
were fatigue (50%), dyspnea (38%), musculoskeletal pain 
(36%), decreased appetite (35%), cough (32%), nausea 
(29%), and constipation (24%). Serious adverse events 
occurred in 59% of patients receiving nivolumab. The most 
frequent serious adverse events reported in ≥ 2% of 
patients were dyspnea, pneumonia, chronic obstructive 
pulmonary disease exacerbation, pneumonitis, 
hypercalcemia, pleural effusion, hemoptysis, and pain. 
Pneumonitis occurred in 7 patients (6%). There were five 
grade 3 cases, and two grade 2 cases. All patients 
discontinued nivolumab and experienced complete 
resolution following high-dose corticosteroids. Median time 
to onset of pneumonitis was 3.3 months (range 1.4- 13.5 
months). Overall, nivolumab was discontinued due to 
adverse events in 27% of patients, and 29% of patients 
receiving nivolumab had a drug delay for an adverse 
event. With at least 10 months of minimum follow up for all 
patients, the confirmed objective response rate (ORR), the 
study’s primary endpoint, was 15% (95% CI, 9-22%), of 
which all were partial responses. Median time to onset of 
response was 3.3 months (range 1.7-8.8 months) after 
treatment initiation. Among responders, 67% had ongoing 
responses with durability of response ranging from 1.9+ to 
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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 
(Investigator Brochure, version 16, 2017). 
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. The most advanced combination 
under development is nivolumab in combination with 
ipilimumab, which is approved in subjects with 
unresectable or metastatic melanoma, and being studied 
in multiple tumor types. Results to date suggest that the 
safety profile of nivolumab in combination with ipilimumab 
is consistent with the mechanisms of action of nivolumab 
and ipilimumab. The nature of the AEs is similar to that 
observed with either agent used as monotherapy; 
however, both frequency and severity of most AEs are 
increased with the combination.  
1.2.1.5 
Biomarker studies 
The clinical use of monoclonal antibodies to T-cell 
inhibitory receptors has provided transformative 
information on the nature of the immune system and 
cancer. An emerging picture suggests that endogenous 
immune responses can mediate effective tumor regression 
and/or improved survival even in patients with large 
volume tumors resistant to other forms of therapy. It is not 
yet clear what factors determine responses and which 
components of the immune system are needed for this to 
occur. It seems likely that both memory helper and effector 
T cells would be needed to sustain long-term responses. 
Understanding the relationships of the tumor, cellular 
infiltrate, and immunologic milieu surrounding each tumor 
is key. 
The effect of tumor PD-L1 expression on treatment 
response to anti-PD-1 targeted immunotherapy is a key 
focus of ongoing investigation. The observation that tumor 
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radiation or chemotherapy, further suggests that baseline 
assessment of this biomarker may not adequately define 
the target population most likely to benefit. Nevertheless, 
these results cannot be extrapolated to this clinical trial due 
to important clinical and biologic differences between 
populations and treatment paradigms.  
In Checkmate 032, PD-L1 expression was assessable in 
148 (69%) of 216 patient specimens, of which 39 (27%) 
were provided as fresh biopsies and 109 (74%) were 
archived specimens. 25 (17%) had 1% or greater PD-L1 
expression, and seven (5%) had 5% or greater PD-L1 
expression. In a pre-planned exploratory analysis of the 
nivolumab 3 mg/kg, nivolumab 1 mg/kg plus ipilimumab 3 
mg/kg, and nivolumab 3 mg/kg plus ipilimumab 1 mg/kg 
cohorts, tumor responses occurred in patients irrespective 
of PD-L1 expression.30 
For these reasons, this trial does not restrict enrollment to 
PD-L1-positive SCLC. To investigate the association 
between this biomarker and clinical outcomes, we will 
correlate baseline tumor PD-L1 expression with clinical 
outcomes in this trial. 
Tumor mutational burden (TMB) is emerging as an 
independent biomarker predictive of responses with 
immunotherapy. In Checkmate 032, patients with high 
TMB, determined by whole exome sequencing, had higher 
response rates, progression-free survival and overall 
survival compared to patients with low/medium TMB. 
However, optimization of TMB cutoffs and assay to use are 
still investigational in SCLC56 
1.3 
Immunotherapy in SCLC 
Increasing evidence suggests that immune responses against SCLC cells make 
immunotherapy a viable approach. Preclinical data have shown that certain 
chemotherapeutic regimens may augment the immunotherapeutic response in 
lung cancer. In the M109 mouse model of lung cancer, treatment of animals with 
an anti-CTLA-4 monoclonal antibody in combination with chemotherapy such as 
gemcitabine, etoposide, and ixabepilone, revealed synergistic anti-tumor effects. 
Furthermore, after combination treatment with CTLA-4 blockade and 
chemotherapy, animals rejected a subsequent rechallenge, suggesting the 
development of a protective immune response in this model.31,32 This may 
suggest that chemotherapy may improve the effect of CTLA-4 blockade. 
Early studies have shown promising efficacy of immune checkpoint therapy in the 
second-line setting in SCLC after prior platinum-based chemotherapy. In 
CheckMate 032, 216 patients were enrolled and treated with nivolumab on a 
variety of different schedules. Responses and stable disease were seen in all 
treatment cohorts. A 10% response rate was seen in patients receiving 
nivolumab at 3 mg/kg, 23% response rate was noted in patients receiving 
nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg, followed by nivolumab at 3 
mg/kg maintenance and 19% response rate in patients receiving nivolumab 3 
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mg/kg plus ipilimumab 1 mg/kg.30 In a post-hoc analysis in patients treated with a 
platinum agent as a first-line treatment, objective responses were achieved in 
patients with both platinum- sensitive and platinum-resistant disease. Median 
overall survival was 4·4 months in the nivolumab 3 mg/kg cohort, 7·7 months in 
the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and 6·0 months in the 
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort. 1-year overall survival was 
33% for the nivolumab 3 mg/kg cohort, 43% for the nivolumab 1 mg/kg plus 
ipilimumab 3 mg/kg cohort, and 35% for the nivolumab 3 mg/g plus ipilimumab 1 
mg/kg cohort. Grade 3 or 4 treatment-related adverse events occurred in 13 
(13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 
mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg 
plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 
treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) 
and diarrhea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg 
plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse 
event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the 
nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the 
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to 
treatment-related adverse events. Two patients who received nivolumab 1 mg/kg 
plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia 
gravis and worsening of renal failure), and one patient who received nivolumab 3 
mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. Two 
patients had grade 2 limbic encephalitis: one in the nivolumab 3 mg/kg cohort 
(reported as not treatment-related by investigator) and one in the nivolumab 1 
mg/kg plus ipilimumab 3 mg/kg cohort (reported as treatment-related by 
investigator); both events resolved with immunosuppressive treatment. One 
patient in the nivolumab 3 mg/kg cohort had grade 4 limbic encephalitis (reported 
as treatment- related by investigator) that did not resolve with intravenous 
immunoglobulin and corticosteroid treatment. Treatment-related pneumonitis 
occurred in eight patients and resolved in six of eight patients with treatment. The 
outcome was unknown for one patient, and one patient died. In summary, these 
findings showed that nivolumab and nivolumab in combination with ipilimumab 
provide clinically meaningful activity with durable responses and with 
manageable safety profile, but both frequency and severity of most AEs are 
increased with the combination. These promising results led the National 
Comprehensive Cancer Network® to add both nivolumab monotherapy and 
nivolumab plus ipilimumab as potential treatment options in second-line SCLC 
while awaiting the results of ongoing confirmatory trials with these and other 
immune checkpoint inhibitors.33,34 
Additionally, ipilimumab has been studied in combination with chemotherapy in 
the first-line setting.35,36 In the phase 2 setting, ipilimumab in combination with 
paclitaxel and carboplatin was investigated in patients with ED-SCLC. One 
hundred thirty patients with treatment-naive ED-SCLC were randomized to 1 of 3 
treatment arms: 1) concurrent ipilimumab (ipilimumab plus chemotherapy for 4 
cycles followed by 2 cycles of chemotherapy plus placebo), 2) phased ipilimumab 
(chemotherapy plus placebo for 2 cycles followed by chemotherapy plus 
ipilimumab for 4 cycles), or 3) chemotherapy plus placebo. In the patients who 
received phased ipilimumab, an improvement was observed in progression-free 
survival based on immune- related response criteria (HR 0.64; P=0.03), with a 
trend for improved overall survival (12.5 months vs 9.1 months).
 
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The common AEs seen during the study that are typically associated with 
paclitaxel/carboplatin, including alopecia, fatigue, nausea and peripheral 
neuropathy, were generally unaffected by the addition of ipilimumab. Consistent 
with previous experience from other studies, the most common irAEs involved 
skin (rash and pruritus) and gastrointestinal tract (diarrhea), and occurred more 
frequently in the ipilimumab-containing arms. Treatment-related AEs, irAEs and 
laboratory abnormalities were mostly grade 1/2. Overall rates of treatment-
related grade 3/4 AEs appeared higher for ipilimumab-containing regimens 
compared with the control, as were the occurrence of alanine aminotransferase 
and aspartate aminotransferase elevations. Most grade 3/4 irAEs were managed 
by the protocol-specified treatment guidelines including close patient follow-up 
and the early administration of systemic corticosteroids. Overall, in this phase 2 
trial, the combination of ipilimumab plus paclitaxel/carboplatin exhibited an 
acceptable safety profile in ED-SCLC patients. 
 In the largest randomized phase III study in patients with ED-SCLC, patients 
were randomly assigned at a ratio of 1:1 to receive etoposide and platinum 
(cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for 
a total of four doses each in a phased induction schedule (chemotherapy in 
cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle 
six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary 
end point was overall survival (OS) among patients receiving at least one dose of 
blinded study therapy. Ipilimumab in combination with carboplatin and etoposide 
did not result in improvement in OS versus etoposide and platinum. Of note, no 
new or unexpected adverse events were observed37, and a majority of grade 2 to 
4 immune-related events resolved.35 It is unclear why ipilimumab did not confer 
additional benefit over etoposide and platinum. One possible explanation is that 
without corresponding T-cell activation in the tumor microenvironment, 
ipilimumab monotherapy, which stimulates peripheral T-cell activation, may not 
be effective in mounting a sufficiently strong antitumor response in ED-SCLC. 
1.4 
Rationale for the combination 
Increasing evidence suggests that the antitumor activity of chemotherapy is 
mediated not only though cytotoxic effects, but also through immunological 
effects, including reducing T-regulatory cell activity and enhancing cross-
presentation of tumor antigens.38-40 It has also been hypothesized that 
decreasing tumor burden through chemotherapy decreases the 
immunosuppressive properties of tumor and creates an environment better 
suited for T-cell activation.41  
In addition, in the vast majority of patients, the development of SCLC is 
associated with tobacco exposure.42,43 This combined with frequent TP53 
mutation (>75-90% pf SCLCs),44,45 results in an aggressive, highly complex 
disease at the molecular level with a large number of mutations present in each 
tumor.46 A number of studies have suggested that tumor mutational burden is 
associated with benefit from immunotherapy.47,48 Presumably, increased 
mutational burden results in increased tumor antigenicity, thereby priming the 
tumor for immune attack. As shown in Figure 1 below, SCLC carries one of the 
highest mutational burdens of any malignancy. In this figure, each dot represents 
a sample, the red horizontal lines represent median numbers of mutations, and 
the vertical axis (log scale) shows the number of mutations per megabase. 
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Given the rapid progression and high tumor burden associated with SCLC, 
combining chemotherapy with nivolumab is the favored approach. This will allow 
time required for an immune response to translate into clinical antitumor activity.  
The proposed study has the potential to advance the management strategy in 
SCLC if it results in improved clinical outcome. A positive outcome in this phase 
II evaluation will provide a strong rationale to conduct a large definitive phase III 
trial of this novel combination in SCLC.  
Hypothesis: We hypothesize that the combination of nivolumab with platinum-
etoposide chemotherapy will result in improved progression-free survival in 
patients with extensive-stage SCLC without concomitant increased toxicity.  
1.5 
Correlatives Background 
The need for biomarkers for identification of a suitable patient population for this 
type of therapy is now pressing.49 
1.5.1 
Optional Blood Collection for Blood Biomarkers  
Circulating tumor DNA quantification and sequencing: We will collect 
peripheral blood at baseline, and cycle 2 day 1. Circulating tumor 
DNA will be assessed using Guardant 360 platform that will inform on 
allelic frequency of mutations, mutational burden and specific targeted 
exome sequencing and amplification of relevant cancer related genes. 
Immunoregulatory proteins such as soluble PD-L1, IL-10, IL-6, IL-8, 
MIP-1 alpha, MCP-1, TNF-alpha, ICAM-1, IL-1ra, MMP-3, AAT, CRP, 
vWF, RANTES, TIMP-1, TNFR2, IP-10, MCP-2, MIG, IL-2 using 
multiplex immunoassay will be performed. 
Additional biomarkers will be considered depending on evolving 
science in SCLC. 
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2. 
Objectives 
2.1 
Primary Endpoints 
2.1.1 
To evaluate the progression-free survival (PFS) of patients with ED-
SCLC treated with cisplatin/carboplatin and etoposide (CE) or CE with 
nivolumab (CEN) as front-line treatment.  
2.2 
Secondary Endpoints 
2.2.1 
To estimate overall survival of patients with ED-SCLC treated with 
cisplatin/carboplatin and etoposide (CE) or CE with nivolumab (CEN) 
as front-line treatment.  
2.2.2 
To assess best overall response rate after treatment with CE with or 
without nivolumab as first line treatment  
2.2.3 
To evaluate the toxicity profile of Nivolumab with CE 
2.3 
Exploratory objectives 
2.3.1 
To evaluate immune biomarkers and biomarkers correlatives 
2.3.2 
To evaluate serial circulating tumor DNA and explore whether clinical 
outcome is associated with fluctuations in DNA levels following the 
administration of therapy. 
 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 3 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 3 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit.  All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1 
Eligibility Criteria 
3.1.1 
Age  18 years 
3.1.2 
Patients must have histologically or cytologically confirmed extensive 
stage small cell lung cancer and must be a candidate for systemic 
therapy 
NOTE: 
The extensive disease SCLC classification for this protocol 
includes all patients with disease sites not defined as 
limited stage. Limited stage disease category includes 
patients with disease restricted to one hemithorax with 
regional lymph node metastases, including hilar, ipsilateral 
and contralateral mediastinal, and/or ipsilateral 
supraclavicular nodes. Extensive disease patients are 
defined as those patients with extrathoracic metastatic 
disease, malignant pleural effusion, bilateral or 
contralateral supraclavicular adenopathy. Patients with 
locally recurrent SCLC who are not eligible for curative 
intent chemoradiation are eligible. 
3.1.3 
Patients must have measurable disease based on RECIST 1.1 (see 
Section 6.1.2) 
3.1.4 
ECOG performance status 0 or 1 (see Appendix V) 
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3.1.5 
Patients must have acceptable organ and marrow function as defined 
below (these must be obtained ≤ 7 days prior to protocol registration) 
Absolute neutrophil count ≥ 1,500/mm3 
ANC:__________ Date of Test:__________ 
Platelets ≥ 100,000/mm3 
Platelet:__________ Date of Test:__________ 
Leukocytes ≥ 3000/mm3 
Leukocytes:__________ Date of Test:__________ 
Hemoglobin ≥ 9 g/dL 
Hemoglobin: __________Date of Test:__________ 
Total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN) (except 
subjects with Gilbert Syndrome, who must have total bilirubin < 3 
mg/dL) 
Bilirubin:__________ Date of Test:__________ 
AST (SGOT) and ALT (SGPT) ≤ 3 X institutional upper limit of normal 
(ULN) (≤ 5 X ULN if LFT elevations due to known liver metastases) 
ALT:_______ Institutional ULN:_________ 
Date of Test:_______ 
AST:_______Institutional ULN:_________ 
Date of Test:_______ 
Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance > 50 
mL/min (using the Cockcroft-Gault formula) 
Serum creatinine ______________Date of Test:________ 
or 
Creatinine clearance:__________ Date of Test:_________ 
3.1.6 
Patients are eligible if CNS metastases are adequately treated and 
neurological symptoms have returned to baseline or are controlled for 
at least 2 weeks prior to enrollment. In addition, subjects must be 
either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg 
daily prednisone (or equivalent). Patients with untreated CNS 
metastases are eligible if they are not symptomatic and the lesions 
are less than 1 cm in size. 
3.1.7 
Patients cannot have had prior chemotherapy or biologic therapy for 
extensive stage small cell lung cancer for front line treatment. Patients 
receiving prior whole brain radiation cannot register within 7 days after 
completion of radiation and must have resolved adverse events 
attributed to radiation to ≤ grade 1. A 1-week washout is permitted for 
palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease. 
3.1.8 
Patients who have received prior chemoradiation treatment with 
chemotherapy regimen including cisplatin or carboplatin/etoposide for 
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limited-stage SCLC are eligible if treated with curative intent at least 6 
months since last treatment from diagnosis of extensive-stage SCLC. 
3.1.9 
Patients may not be receiving any other investigational agents while 
on study. 
3.1.10 
Patients must not have history of allergic reactions attributed to 
compounds of similar chemical or biologic composition to nivolumab 
or other agents used in the study. 
3.1.11 
Women must not be pregnant or breast-feeding. Because there is an 
unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with the agents used in this 
study, breastfeeding must be discontinued or the subject is not eligible 
for the study.   
All females of childbearing potential must have a blood test or urine 
study, with a minimum sensitivity 50mlU/L or equivalent units of HCG, 
within 14 days prior to registration to rule out pregnancy. A female of 
childbearing potential is any woman, regardless of sexual orientation 
or whether they have undergone tubal ligation, who meets the 
following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e. has had menses at any time in the 
preceding 24 consecutive months). 
Female of childbearing potential? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.12 
Women of childbearing potential (WOCBP) and males who are 
sexually active with WOCBP must use accepted and effective 
method(s) of contraception or abstain from sexual intercourse for at 
least one week prior to the start of treatment, and continue for 5 
months after the last dose of protocol treatment for women of 
childbearing potential and 7 months after the last dose of protocol 
treatment for males who are sexually active with WOCBP. 
3.1.13 
No prior or current invasive malignancy (except non-melanomatous 
skin cancer, localized bladder and prostate cancer) unless disease 
free for a minimum of 2 years (for example, carcinoma in situ of the 
breast, oral cavity, or cervix are all permissible);  
3.1.14 
No prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-
L2, anti-CTLA-4 antibody, or any other antibody or drug specifically 
targeting T-cell costimulation or immune checkpoint pathways; 
3.1.15 
Patient must not have leptomeningeal disease 
3.1.16 
No patients with an active, known or suspected autoimmune disease 
and neuromuscular paraneoplastic syndromes including but not 
limited to myasthenia gravis, Lambert-Eaton myasthenic syndrome, 
limbic encephalitis, myositis, Guillain-Barré. Subjects 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. 
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3.1.17 
No patients with a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalent) or other 
immunosuppressive medications within 7 days of randomization. 
Inhaled or topical steroids, and adrenal replacement steroid doses > 
10 mg daily prednisone equivalent, are permitted in the absence of 
active autoimmune disease. 
3.1.18 
No patients with interstitial lung disease that is symptomatic or may 
interfere with the detection or management of suspected drug-related 
pulmonary toxicity 
3.1.19 
Patients must NOT have uncontrolled intercurrent illness including, 
but not limited to, ongoing or active infection, symptomatic congestive 
heart failure, unstable angina pectoris, uncontrolled cardiac 
arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
3.1.20 
HIV-positive patients on combination antiretroviral therapy are 
ineligible because of the potential for pharmacokinetic interactions 
with Nivolumab. In addition, these patients are at increased risk of 
lethal infections when treated with marrow-suppressive therapy.  
Appropriate studies will be undertaken in patients receiving 
combination antiretroviral therapy when indicated. 
3.1.21 
Any positive test for hepatitis B virus or hepatitis C virus indicating 
acute or chronic infection, patients are excluded. 
3.1.22 
Patients are ineligible if they received a live, attenuated vaccine within 
4 weeks before randomization 
3.1.23 
No history of severe hypersensitivity reaction to any monoclonal 
antibody or allergy to study drug components; 
 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
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4. 
Registration and Randomization Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
Documentation requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. For questions, please 
contact the RCR Help Desk by email at <RCRHelpDesk@nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
to make a determination of whether a site has fulfilled all regulatory criteria including but 
not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
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• 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory For 
sites using the CIRB, IRB approval information is received from the CIRB and applied to 
the RSS in an automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRB Manager to indicate their intent 
to open the study locally. The CIRB’s approval of the SSW is then communicated to the 
CTSU Regulatory Office. In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the EA5161 protocol page located on 
the CTSU members’ website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol EA5161 
• 
Click LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided. 
Requirements For EA5161 Site Registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation 
and IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects 
Assurance Identification/IRB Declaration of Exception Form, or combination is 
accepted) 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission 
When applicable original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
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Required Protocol Specific Regulatory Documents 
1. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB. 
2. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE:  
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU 
website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements outlined by the 
Lead Network. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
Patient Enrollment 
Patients must not start protocol treatment prior to registration. 
Treatment should start within seven working days after registration. 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the LPO or participating 
organization roster. Registrars must hold a minimum of an AP registration type. 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
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patient in the Rave Database. OPEN can be accessed at https://open.ctsu.org or from 
the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. To 
assign an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), 
or investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form 
FDA 1572 in RCR the IRB number used on the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes, including 
verifying availability of tumor tissue as per eligibility criteria. 
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Protocol Number  
4.2 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 
4.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3. 
4.5 
Stratification Factors 
4.5.1 
Gender (Male vs. Female) 
4.5.2 
LDH (≤ upper limits of normal vs. > ULN) 
4.6 
Additional Requirements  
4.6.1 
Patients must provide a signed and dated, written informed consent 
form. 


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NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office – Boston. 
4.6.2 
Pathological materials are to be submitted for future undefined 
laboratory research studies per patient consent as outlined in Section 
10. 
4.6.3 
Peripheral blood specimens are to be submitted for defined laboratory 
research studies per patient consent as outlined in Section 10.  
4.6.4 
Data collection for this study will be done exclusively through the 
Medidata Rave clinical data management system. Access to the trial 
in Rave is granted through the iMedidata application to all persons 
with the appropriate roles assigned in Regulatory Support System 
(RSS). To access Rave via iMedidata, the site user must have an 
active CTEP-IAM account (check at  
<  https://ctepcore.nci.nih.gov/iam  >) and the appropriate Rave role 
(Rave CRA, Read-Only, CRA, Lab Admin, SLA, or Site Investigator) 
on either the LPO or participating organization roster at the enrolling 
site. To the hold Rave CRA role or CRA Lab Admin role, the user 
must hold a minimum of an AP registration type.  To hold the Rave 
Site Investigator role, the individual must be registered as an NPIVR 
or IVR.  Associates can hold read-only roles in Rave. 
Upon initial site registration approval for the study in RSS, all persons 
with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the 
“accept” link in the upper right-corner of the iMedidata page. Please 
note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. 
Trainings will be in the form of electronic learnings (eLearnings), and 
can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
Users that have not previously activated their iMedidata/Rave account 
at the time of initial site registration approval for the study in RSS will 
also receive a separate invitation from iMedidata to activate their 
account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting 
the CTSU Help Desk at 1-888-823-5923 or by e-mail at 
ctsucontact@westat.com. 
4.7 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
Rave according to the schedule in the EA5161 Forms Completion Guidelines. 
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5. 
Treatment Plan 
5.1 
Agent Administration  
Treatment will be administered on an outpatient basis unless local institutional 
standard practice requires inpatient administration. No therapies (investigational 
or commercial agents) other than those described below may be administered 
with the intent to treat the patient’s malignancy. Reported adverse events and 
potential risks for nivolumab, cisplatin or carboplatin, and etoposide are 
described in Sections 5.3 and 8. Appropriate dose modifications are described in 
Section 5.4. BSA should be recalculated if ≥ 10% weight loss. 
Cycle Length (Cycles 1-4) = 3 weeks (21 days) 
Maintenance Cycle Length (Cycles 5+) = 6 weeks (42 days) 
NOTE: 
All treatment visits must occur +/- 3 days from the scheduled date 
unless otherwise noted. If scheduled dosing and study assessments 
are precluded because of a holiday, weekend, or other event, then 
dosing may be postponed to the soonest following date, with 
subsequent dosing continuing on a 21-day schedule during Cycles 1-
4 or every 2 weeks during maintenance nivolumab. If treatment was 
postponed for fewer than 3 days, the patient can resume the original 
schedule. 
Arm A Description (Nivolumab arm) Cycles 1-4*** 
Agent 
Pre-medications**; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Nivolumab 
**** 
 
360 mg IV over 
30 minutes 
IV 
Day 1  
21 days 
(3 weeks) 
Carboplatin* 
Dexamethasone 
5-HT3 antagonist 
Aprepitant or 
Fosaprepitant 
AUC 5 or 6 IV 
over 30 to 60 
minutes 
IV 
Day 1  after 
nivolumab infusion 
is completed 
Cisplatin* 
Dexamethasone 
5-HT3 antagonist 
Aprepitant or 
Fosaprepitant 
75mg/m2 IV over 
60 to 120 
minutes 
IV 
Day 1 after 
nivolumab infusion 
is completed 
Etoposide 
Dexamethasone 
5-HT3 antagonist  
100 mg/m2 IV 
over 60 to 120 
minutes 
IV 
Days 1, 2, 3 
after platinum 
infusion is 
completed 
Nivolumab is given first, followed by carboplatin/cisplatin, then etoposide.  
* 
The decision to administer cisplatin or carboplatin is at the discretion of the treating 
physician. If the choice is made to administer carboplatin, starting dose of AUC 5 or 6 
is at the discretion of the treating physician. 
** Cisplatin or carboplatin and etoposide (CE) will be administered with standard of care 
pre-medications and pre/post hydration every 3 weeks. 
*** A maximum of 4 cycles of platinum and etoposide will be given. 
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**** After 4 cycles of combination therapy in the investigational arm (Arm A), nivolumab only will 
be continued as maintenance therapy, administered at 240 mg IV over 30 minutes 
every 2 weeks until progressive disease, unacceptable toxicity, patient desire to 
discontinue study therapy or up to 2 years (or 50 doses) maximum. 
Arm B Description (Standard arm) – Cycles 1-4*** 
Agent 
Pre-medications**; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Carboplatin* 
Dexamethasone 5-
HT3 antagonist 
Aprepitant or 
Fosaprepitant  
AUC 5 or 6 IV 
over 30 to 60 
minutes 
IV 
Day 1  
21 days 
(3 weeks) 
Cisplatin* 
Dexamethasone 5-
HT3 antagonist 
Aprepitant or 
Fosaprepitant 
75mg/m2 IV 
over 60 to 120 
minutes 
IV 
Day 1  
Etoposide 
Dexamethasone 
5-HT3 antagonist 
100 mg/m2 IV 
over 60 to 120 
minutes 
IV 
Days 1, 2, 3 
after platinum 
infusion is 
completed 
Carboplatin/Cisplatin is given first, followed by etoposide.  
* The decision to administer cisplatin or carboplatin is at the discretion of the treating 
physician. If the choice is made to administer carboplatin, starting dose of AUC 5 or 6 
is at the discretion of the treating physician. 
** Cisplatin or carboplatin and etoposide (CE) will be administered with standard of care 
pre-medications and pre/post hydration every 3 weeks. 
*** A maximum of 4 cycles of platinum and etoposide will be given then the patient will 
proceed to observation until disease progression or non-protocol treatment regimen is 
initiated. 
5.1.1 
Radiation Therapy  
Patients with good clinical response (i.e. stable or response) after 4 
cycles of first line chemotherapy can receive prophylactic cranial 
radiation (PCI) or whole brain radiation (if patient initially had 
asymptomatic untreated brain metastatic disease that has not 
progressed) as per local standard of care. In the investigational arm, 
nivolumab will not be administered during 1 week before and after 
brain radiation treatment. 
Thoracic radiation with the intent to eliminate residual disease (i.e. 
consolidation thoracic radiation) is not allowed following completion of 
4 cycles of first-line chemotherapy. Palliative radiation is allowed in 
non-measurable sites of disease. A 1-week washout is permitted for 
palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease. 
5.2 
Adverse Event Reporting Requirements 
All toxicity grades described in this protocol and all reportable adverse events 
on this protocol will be graded using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0. 
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All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are a 
required part of every clinical trial, are done so investigators and 
regulatory agencies can detect and analyze adverse events and risk 
situations to ensure the safety of the patients enrolled, as well as 
those who will enroll in future studies using similar agents. 
5.2.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of an agent in humans, whether or not 
considered agent related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
• 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
• 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List):  An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND.  Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports.   
• 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term.  
• 
Expectedness: Expected events are those that have been 
previously identified as resulting from administration of the agent. 
An adverse event is considered unexpected, for expedited 
reporting purposes, when either the type of event or the severity of 
the event is NOT listed in the protocol or drug package insert. 
• 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   
• 
Life Threatening Adverse Event:  Any AE that places the 
subject at immediate risk of death from the AE as it occurred.   


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• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgement, 
they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
• 
SPEER (Specific Protocol Exceptions to Expedited 
Reporting):  A subset of AEs within the CAEPR that contains a 
list of events that are protocol specific exceptions to expedited 
reporting. If an AE meets the reporting requirements of the 
protocol, and it is listed on the SPEER, it should ONLY be 
reported via CTEP-AERS if the grade being reported exceeds the 
grade listed in the parentheses next to the event 
5.2.3 
Mechanisms for Adverse Event Reporting 
Routine reporting: Adverse events are reported in a routine manner 
at scheduled times during a trial using the Medidata Rave clinical data 
management system. Please refer to section 4 of the protocol for 
more information on how to access the Medidata Rave system and 
the EA5161 forms packet for instructions on where and when adverse 
events are to be reported routinely. 
Expedited reporting: In addition to routine reporting, certain adverse 
events must be reported in an expedited manner for timelier 
monitoring of patient safety and care. The remainder of this section 
provides information and instructions regarding expedited adverse 
event reporting. 
5.2.4 
Expedited Adverse Event Reporting Procedure 
Adverse events requiring expedited reporting will use CTEP’s Adverse 
Event Reporting System (CTEP-AERS). CTEP’s guidelines for CTEP-
AERS can be found at http://ctep.cancer.gov. 
For this study, all adverse events requiring expedited reporting 
must initially be reported PROMPTLY upon learning of the event 
on the Adverse Event Form in the appropriate Treatment Cycle 
folder in Medidata Rave, even if the reporting cycle has not 
ended yet. Once the adverse event is entered into Rave, the 
Rules Engine on the Expedited Reporting Evaluation Form will 
confirm whether or not the adverse event requires expedited 
reporting. The CTEP-AERS report must then be initiated directly 
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from the Expedited Reporting Evaluation Form in Medidata Rave.  
Do not initiate the CTEP-AERS report via the CTEP-AERS 
website.  Once the event is reported in CTEP-AERS, ECOG-ACRIN, 
the NCI, and all appropriate regulatory agencies will be notified of the 
event in an expeditious manner. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (857-504-2900) – For Arm A and B 
• 
the NCI (301-897-7497) – For Arm A  
• 
the FDA (1-800-FDA-1088) – For Arm B 
For this study, an electronic CTEP-AERS report MUST be initiated via 
Medidata Rave and submitted immediately upon re-establishment of 
internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the NCI (301-897-7404) – For Arm A 
and FDA (1-800-332-0178) – For Arm B in the same timeframe.  
CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.5 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
• 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. ≥ 30 days after the last 
administration of investigational agent)  
• 
the relationship to the study treatment (attribution) 
• 
the expectedness of the adverse event 
Using these factors, the instructions and tables in the following 
sections have been customized for protocol EA5161 and outline the 
specific expedited adverse event reporting requirements for study 
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5.2.6 
Steps to determine if an adverse event is to be reported in an 
expedited manner – Arm A 
5.2.6.1 
Guidelines for adverse events OCCURRING WHILE ON 
PROTOCOL TREATMENT AND WITHIN 30 DAYS of the 
last administration of the investigational agent(s). 
NOTE: 
For this study, all adverse events requiring 
expedited reporting must initially be 
reported PROMPTLY upon learning of the 
event on the Adverse Event Form in the 
appropriate Treatment Cycle folder in 
Medidata Rave, even if the reporting cycle 
has not ended yet. Once the adverse event is 
entered into Rave, the Rules Engine on the 
Expedited Reporting Evaluation Form will 
confirm whether or not the adverse event 
requires expedited reporting. The CTEP-AERS 
report must then be initiated directly from the 
Expedited Reporting Evaluation Form in 
Medidata Rave. Do not initiate the CTEP-AERS 
report via the CTEP-AERS website. We 
encourage all sites to confirm the Rules Engine 
assessment with the charts below. 
 
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Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the 
six criteria in the top portion of the 
table below in Section 5.2.7. 
Yes 
No 
Identify the type and 
grade of the event 
using the CTCAE 
Determine if the patient 
was hospitalized for  
≥ 24 hours for the event. 
Refer to Section 5.2.8 to 
determine if the event 
meets the protocol specific 
reporting requirements for 
this study. If so, report the 
Refer to Section 5.2.8 to 
determine if the event 
meets the protocol 
specific reporting 
requirements for this 
study. If so, report the 
Rev. Add1 
No 
Rev. 
Add1
Refer 
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5.2.6.2 
Guidelines for adverse events OCCURRING GREATER 
THAN 30 DAYS after the last administration of the 
investigational agent(s). 
NOTE: 
For this study, all adverse events requiring 
expedited reporting must initially be 
reported PROMPTLY upon learning of the 
event on the Adverse Event Form or Late 
Adverse Event Form in the appropriate 
Treatment Cycle or Post Registration folder 
in Medidata Rave, even if the reporting 
cycle/period has not ended yet. Once the 
adverse event is entered into Rave, the Rules 
Engine on the Expedited Reporting Evaluation 
Form will confirm whether or not the adverse 
event requires expedited reporting.  The CTEP-
AERS report must then be initiated directly from 
the Expedited Reporting Evaluation Form in 
Medidata Rave. Do not initiate the CTEP-AERS 
report via the CTEP-AERS website. We 
encourage all sites to confirm the Rules Engine 
assessment with the requirements outlined 
below. 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.2.7, AND has an 
attribution of possible, probably or definite, the following 
events require reporting as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 4 and Grade 5 AEs  
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational agent with an 
attribution of possible, probable or definite must 
be reported in CTEP-AERS accessed via 
Medidata Rave even if the patient is off study. 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
• 
Grade 3 adverse events   
5.2.7 
Expedited Reporting Requirements for Arm A on protocol EA5161 
Investigational Agents: Nivolumab   
Commercial Agents: Cisplatin, Carboplatin, Etoposide 
When an investigational agent(s) is used in combination with a 
commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events follow the 
guidelines for investigational agents.   
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Late Phase 2 and Phase 3 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention.1 
NOTE: 
Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration 
of investigational agent/intervention. 


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


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5.2.8 
Additional instructions, requirements and exceptions for protocol 
EA5161 
Additional Instructions 
• 
For instructions on how to specifically report events that result 
in persistent or significant disability/incapacity, congenital 
anomaly, or birth defect events in CTEP-AERS accessed via 
Medidata Rave, please contact the AEMD Help Desk at 
aemd@tech-res.com  or 301-897-7497. This will need to be 
discussed on a case-by-case basis. 
• 
Reporting a death on study: A death occurring while on study 
or within 30 days of the last dose of treatment requires both 
routine and expedited reporting, regardless of causality. 
Attribution to treatment or other cause must be provided. 
NOTE: 
A death due to progressive disease should be 
reported as a Grade 5 “Disease progression” under 
the System Organ Class (SOC) “General disorder 
and administration site conditions”. Evidence that 
the death was a manifestation of underlying disease 
(e.g. radiological changes suggesting tumor growth 
or progression: clinical deterioration associated with 
a disease process) should be submitted 
 
EA5161 specific expedited reporting requirements: 
• 
Infusion Reactions: Any grade 3 and higher infusion reaction 
must be reported in CTEP-AERS accessed via Medidata Rave 
according to the timeframes outlined in the AE table in Section 
5.2.7. 
• 
Pregnancies:  Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless 
of age or disease state) occurring while the female patient is on 
nivolumab, or within 28 days of the female patient’s last dose 
of nivolumab, are considered immediately reportable events. 
The pregnancy, suspected pregnancy, or positive/ inconclusive 
pregnancy test must be reported in CTEP-AERS accessed via 
Medidata Rave within 24 hours of the Investigator’s knowledge.  
Please refer to Appendix VI for detailed instructions on how to 
report the occurrence of a pregnancy as well as the outcome of 
all pregnancies. 
 
EA5161 specific expedited reporting exceptions: 
For study arm A, the adverse events listed below do not require 
expedited reporting: 
• 
If an AE meets the reporting requirements of the protocol, and 
it is listed on the SPEER, it should ONLY be reported 
Rev. Add4 


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expeditiously if the grade being reported exceeds the grade 
listed in the parentheses next to the event 
5.2.9 
Steps to determine if an event is to be reported in an expedited 
manner – Arm B 
NOTE: 
For this study, all adverse events requiring expedited 
reporting must initially be reported PROMPTLY upon 
learning of the event on the Adverse Event Form in the 
appropriate Treatment Cycle folder in Medidata Rave, 
even if the reporting cycle/period has not ended yet. 
Once the adverse event is entered into Rave, the Rules 
Engine on the Expedited Reporting Evaluation Form will 
confirm whether or not the adverse event requires 
expedited reporting.  The CTEP-AERS report must then be 
initiated directly from the Expedited Reporting Evaluation 
Form in Medidata Rave. Do not initiate the CTEP-AERS 
report via the CTEP-AERS website. We encourage all sites 
to confirm the Rules Engine assessment with the charts 
below. 
Rev. Add2 
Rev. Add4 


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Identify the type and grade of the event 
using the CTCAE. 
Determine if the event is related to the 
protocol treatment (attribution). 
With this information, review the chart in 
Section 5.2.10 to determine if event 
requires expedited reporting 
Refer to footnote b in 
Section 5.2.10 to 
determine if the event 
meets the protocol 
specific reporting 
requirements for this 
study. If so, report the 
event in CTEP-AERS 
accessed via Medidata
Is the event 
reportable?
No 
Yes 
Report the event in CTEP-AERS accessed via Medidata 
Rave. 
Determine the expectedness of the 
event. An unexpected event is defined as 
one where the type of severity of the 
event is not listed in the investigator’s 
brochure, package insert or protocol. 


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5.2.10 
Expedited Reporting Requirements for Arm B on protocol EA5161 
Commercial Agents: Cisplatin, Carboplatin, Etoposide   
Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents 
only – Arm B 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated or Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event. 
a 
A death occurring while on study or within 30 days of the last dose of treatment requires both routine and 
expedited reporting, regardless of causality.  Attribution to treatment or other cause must be provided. 
NOTE: A death due to progressive disease should be reported as a Grade 5 “Disease progression” 
under the System Organ Class (SOC) “General disorder and administration site conditions”.  
Evidence that the death was a manifestation of underlying disease (e.g. radiological changes 
suggesting tumor growth or progression: clinical deterioration associated with a disease 
process) should be submitted. 
NOTE: Any death that occurs > 30 days after the last dose of treatment and is attributed possibly, 
probably, or definitely to the treatment must be reported within 7 calendar days of learning of 
the event. 
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported in CTEP-AERS accessed via 
Medidata Rave within 7 calendar days of learning of the event. For instructions on how to 
specifically report these events, please contact the AEMD Help Desk at aemd@tech-
res.com or 301-897-7497. This will need to be discussed on a case-by-case basis. 
5.2.11 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI, as the IND sponsor, is responsible for submitting all 
expedited AE reports for Arm A to the Food and Drug Administration. 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to the FDA. Any additional written AE information 
requested by DCTD/NCI or ECOG-ACRIN MUST be submitted to 
BOTH the DCTD/NCI and ECOG-ACRIN. 
Adverse events determined to require expedited reporting must also 
be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.2.12 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
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• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
2. For this study: Report the diagnosis expeditiously by initially 
reporting it PROMPTLY upon learning of the secondary 
malignancy in the Adverse Event Form or Late Adverse Event 
Form in the appropriate Treatment Cycle of Post Registration 
folder in Medidata Rave. Once the adverse event is entered 
into Rave, the Rules Engine on the Expedited Reporting 
Evaluation Form will confirm whether or not the adverse event 
requires expedited reporting. The CTEP-AERS report must 
then be initiated directly from the Expedited Reporting 
Evaluation Form in Medidata Rave. Do not initiate the CTEP-
AERS report via the CTEP-AERS website. 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The ECOG-ACRIN Second Primary Form and the CTEP-
AERS report should not be used to report recurrence or 
development of metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the ECOG-ACRIN Second Primary Form 
must be submitted for the most recent trial. ECOG-ACRIN 
must be provided with a copy of the form and the 
associated pathology report and cytogenetics report (if 
available) even if ECOG-ACRIN was not the patient's most 
recent trial. 


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NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the ECOG-ACRIN 
Second Primary Form. 


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5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Nivolumab 
(NSC 748726) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 2069 patients. 
Below is the CAEPR for Nivolumab. 
NOTE: 
If an AE meets the reporting requirements of the protocol, and it is 
listed on the SPEER, it should ONLY be reported expeditiously if the 
grade being reported exceeds the grade listed in the parentheses next 
to the event.  Since some arms on this protocol use multiple 
investigational agents, if an AE is listed on multiple SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
Version 2.4, December 2, 20201 
Adverse Events with Possible 
Relationship to Nivolumab 
(CTCAE 5.0 Term) 
[n= 2069] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
  
 
 
Myocarditis 
  
 
 
Pericardial tamponade2 
  
 
 
Pericarditis 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency3 
 
  
 
Hyperthyroidism3 
 
  
 
Hypophysitis3 
 
  
 
Hypothyroidism3 
 
  
EYE DISORDERS 
  
 
 
Blurred vision 
  
 
 
Dry eye 
  
 
 
Eye disorders - Other 
(diplopia)3 
  
 
 
Eye disorders - Other (Graves 
ophthalmopathy)3 
  
 
 
Eye disorders - Other (optic 
neuritis retrobulbar)3 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada) 
  
 
Uveitis 
 
  
Rev. Add2 


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Adverse Events with Possible 
Relationship to Nivolumab 
(CTCAE 5.0 Term) 
[n= 2069] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Colitis3 
 
  
 
 
Colonic perforation3 
  
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
 
Enterocolitis 
  
 
 
Gastritis 
  
 
 
Mucositis oral 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis4 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatobiliary disorders - 
Other (immune-mediated 
hepatitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
 
Autoimmune disorder3 
  
 
 
Cytokine release syndrome5 
  
 
 
Immune system disorders - 
Other (GVHD in the setting of 
allotransplant)3,6 
  
 
 
Immune system disorders - 
Other (sarcoidosis)3 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction7 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased3 
 
 Alanine aminotransferase 
increased3 (Gr 3) 
 
Aspartate 
aminotransferase 
increased3 
 
 Aspartate aminotransferase 
increased3 (Gr 3) 
 
Blood bilirubin increased3  
 Blood bilirubin increased3 (Gr 
2) 
 
CD4 lymphocytes 
decreased 
 
 CD4 lymphocyte decreased 
(Gr 4) 
 
Creatinine increased 
 
  
 
Lipase increased 
 
  
 
Lymphocyte count 
decreased 
 
 Lymphocyte count decreased 
(Gr 4) 
 
Neutrophil count 
decreased 
 
  
 
Platelet count decreased 
 
  
 
Serum amylase increased  
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  


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Adverse Events with Possible 
Relationship to Nivolumab 
(CTCAE 5.0 Term) 
[n= 2069] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
 
Hyperglycemia 
 Hyperglycemia (Gr 2) 
 
 
Metabolism and nutrition 
disorders - Other (diabetes 
mellitus with ketoacidosis)3 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
 
Musculoskeletal and 
connective tissue disorder - 
Other (polymyositis) 
  
 
 
Myositis 
  
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy3 
  
 
 
Facial nerve disorder3 
  
 
 
Guillain-Barre syndrome3 
  
 
 
Myasthenia gravis3 
  
 
 
Nervous system disorders - 
Other (demyelination 
myasthenic syndrome) 
  
 
 
Nervous system disorders - 
Other (encephalitis)3 
  
 
 
Nervous system disorders - 
Other (meningoencephalitis) 
  
 
 
Nervous system disorders - 
Other (meningoradiculitis)3 
  
 
 
Nervous system disorders - 
Other (myasthenic syndrome)   
 
 
Peripheral motor neuropathy   
 
 
Peripheral sensory 
neuropathy 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome3 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury3 
  
 
 
Renal and urinary disorders - 
Other (immune-mediated 
nephritis) 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pleural effusion3 
 
  
 
Pneumonitis3 
 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(bronchiolitis obliterans with 
organizing pneumonia)3 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme3 
  
 
Pruritus3 
 
 Pruritus3 (Gr 2) 
 
Rash maculo-papular3 
 
 Rash maculo-papular3 (Gr 2) 


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Adverse Events with Possible 
Relationship to Nivolumab 
(CTCAE 5.0 Term) 
[n= 2069] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
 
Skin and subcutaneous tissue 
disorders - Other (bullous 
pemphigoid) 
  
 
Skin and subcutaneous 
tissue disorders - Other 
(Sweet's Syndrome)3 
 
  
 
Skin hypopigmentation3 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
3 Nivolumab being a member of class of agents involved in the inhibition of “immune checkpoints”, may 
result in severe and possibly fatal immune-mediated adverse events probably due to T-cell activation 
and proliferation.  This may result in autoimmune disorders that can include (but are not limited to) 
autoimmune hemolytic anemia, acquired anti-factor VIII immune response, autoimmune aseptic 
meningitis, autoimmune hepatitis, autoimmune nephritis, autoimmune neuropathy, autoimmune 
thyroiditis, bullous pemphigoid, exacerbation of Churg-Strauss Syndrome, drug rash with eosinophilia 
systemic symptoms [DRESS] syndrome, facial nerve disorder (facial nerve paralysis), limbic 
encephalitis, hepatic failure, pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, 
endocrine disorders (e.g., autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune 
hypophysitis/hypopituitarism, thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, myasthenia 
gravis, polymyositis, and Guillain-Barre syndrome. 
4 Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
5 Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with accompanying 
fever and pancytopenia. 
6 Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have occurred in 
patients receiving allo stem cell transplant (SCT) after receiving Nivolumab.  These complications may 
occur despite intervening therapy between receiving Nivolumab and allo-SCT. 
7 Infusion reactions, including high-grade hypersensitivity reactions which have been observed following 
administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, hypertension or 
hypotension, or difficulty breathing during and immediately after administration of nivolumab. 
Adverse events reported on Nivolumab trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that Nivolumab caused the adverse 
event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; 
Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; 
Gastrointestinal disorders - Other (mouth sores); Vomiting 


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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; 
Malaise; Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other (autoimmune 
thrombotic microangiopathy); Immune system disorders - Other (limbic encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper 
respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Investigations - 
Other (protein total decreased); Lymphocyte count increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal 
and connective tissue disorder - Other (polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (Histiocytic 
necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other 
(tubulointerstitial nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; Cough; 
Dyspnea; Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Pain 
of skin; Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other 
(rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
NOTE: 
Nivolumab in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination 
may result in events never previously associated with either agent. 


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5.4 
Dose Modifications  
Dose modifications for platinum and etoposide are permitted for toxicity 
according to the prescribing information. Dose modification guidelines are 
provided below. 
In order to ensure accurate determination of the duration of adverse events, 
patients must be evaluated at least once weekly (intervals should not be longer 
than every 7 days) while awaiting resolution of any adverse event whose duration 
may necessitate dose modification. 
5.4.1 
Cisplatin/Carboplatin and Etoposide Supportive Care  
NOTE: 
Dose reductions for all events are permanent and should 
be for all subsequent cycles. Patients may receive a 
maximum of two chemotherapy dose reductions. If a third 
chemotherapy dose reduction is required, the patient 
should discontinue chemotherapy protocol treatment. If 
different percentages of dose reductions for a specific drug 
are required because of two different types of toxicities, the 
greater percentage dose reduction should be undertaken. 
5.4.1.1 
Hematologic Toxicity 
Neutropenia and/or Thrombocytopenia 
Granulocyte or platelet counts for Day 1: Based on counts 
within 3 days of the start of each cycle, give the following:  
Granulocytes/mm
3 
 
Platelets
/ mm3 
Cisplatin/carboplati
n and etoposide 
ANC ≥ 1,500 
and  
PLT  
≥ 
100,000  
100% 
ANC < 1,500 
and/o
r 
PLT  
< 
100,000  
Hold dose* 
* Hold cisplatin/carboplatin and etoposide; repeat counts at least 
once weekly and reinstitute therapy at 100% when 
granulocytes ≥ 1,500/mm3 and platelets ≥ 100,000/mm3 if 
recovery within 7 days.  
If cisplatin administered, reinstitute at 75% of the original dose 
if more than 7 days. If carboplatin administered, reinstitute 
carboplatin AUC with decrease by one dose level (i.e. starting 
dose of AUC 6 dose reduction 1= AUC 5), if more than 7 days.  
If counts do not reach these levels within 3 weeks of the next 
scheduled treatment, discontinue chemotherapy protocol 
therapy. 
Neutropenia or Febrile Neutropenia  
For nadir neutropenia in the absence of fever or with fever 
that is successfully treated by oral antibiotics, there will be 
no dose adjustment. Filgrastim, sargramostim, or 
pegfilgrastim are allowed (for the next cycle of 
chemotherapy). Growth factors may be used in 
Rev. Add1 
Rev. Add3 
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accordance with American Society of Clinical Oncology 
(ASCO) and NCCN guidelines. 
For treatment delays (hold both chemotherapy and 
nivolumab) due to chemotherapy toxicities of more than 7 
days, both chemotherapy drugs, cisplatin and etoposide, 
should be dose reduced by 25%. If carboplatin 
administered, reinstitute carboplatin AUC with decrease by 
one dose level (i.e. starting dose of AUC 6 dose reduction 
1= AUC 5), if more than 7 days.  
For neutropenic fever (ANC <1000/mm3 with a single 
temperature of >38.3 degrees C (101 degrees F) or a 
sustained temperature of ≥ 38 degrees C (100.4 degrees 
F) for more than one hour) requiring intravenous 
antibiotics, the doses of all chemotherapy drugs should be 
reduced by 25% for the next cycle. If carboplatin 
administered, reinstitute carboplatin AUC with decrease by 
one dose level (i.e. starting dose of AUC 6 dose reduction 
1= AUC 5), if more than 7 days. If counts do not recover 
within 3 weeks, discontinue chemotherapy protocol 
therapy. 
Thrombocytopenia  
For grade 4 nadir platelet count decrease (platelets  
< 25,000 mm3), the dose of all chemotherapy drugs should 
be reduced by 25% from the previous dose for the next 
cycle. If carboplatin administered, reinstitute carboplatin 
AUC with decrease by one dose level (i.e. starting dose of 
AUC 6 dose reduction 1= AUC 5), if more than 7 days. If 
counts do not recover within 3 weeks, discontinue 
chemotherapy protocol therapy.  
Anemia  
No dose reductions will be made for anemia. Patients 
should be supported per the treating physician’s discretion. 
The use of blood transfusions for anemia will be allowed as 
indicated. The use of growth factors for anemia is not 
permitted during cycle 1 for patients and may be use for 
cycle 2 (please refer to supportive care guidelines in 
Section 5.5).   
5.4.1.2 
Gastrointestinal Toxicity, Nausea and Vomiting 
All patients should receive antiemetics* to prevent nausea 
and vomiting. Specific antiemetic therapy is left to the 
discretion of the treating physician (steroids and 5-HT3 
antagonists should be used). If vomiting is severe, 
consider hospital admission and/or use of aprepitant if 
possible. Do not modify chemotherapy doses, until anti-
emetics have been maximally optimized.  
*Aprepitant, when given once daily for 14 days as a 100 
mg capsule with an oral contraceptive containing 35 mcg 
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of ethinyl estradiol and 1 mg of norethindrone, decreased 
the AUC of ethinyl estradiol by 43% and decreased the 
AUC of norethindrone by 8%. Women of childbearing 
potential using pregnancy contraception that includes 
ethinyl estradiol should not receive Aprepitant for the 
treatment of nausea/delayed emesis. Patients may change 
to a different method of contraception if they wish to use 
Aprepitant. 
5.4.1.3 
Hepatic toxicity 
This table only lists Etoposide dose modifications.  
Bilirubin  
Etoposide*  
≤ 1.5 x ULN  
100%  
>1.5 – 3.0 x ULN  
50%  
> 3.0 x ULN - ≤ 5.0 x ULN  
30%  
> 5 x ULN  
Hold**  
* Please note that the % dose administered is based on the 
original starting dose of etoposide (100mg/m2).  
** For bilirubin greater than 5 X ULN it is recommended not to 
use etoposide for that cycle but this is at the discretion of the 
treating physician. If holding, repeat labs on a weekly basis for 
up to 3 weeks until total bilirubin is ≤ 5 x ULN. The cisplatin 
and nivolumab doses should also be held if etoposide is held 
so that all drugs are kept on the same schedule. If bilirubin 
improves within 3 weeks to ≤ 5 x ULN, then resume treatment 
and use reduced dose per table above. If bilirubin does not 
improve to ≤ 5 x ULN within 3 weeks, discontinue all protocol 
therapy. 
A clinically relevant overlap in toxicity may arise between 
the immune-related hepatic toxicity attributed to nivolumab 
and hepatic toxicity attributed to etoposide. The 
management of hepatic toxicity should be guided by 
clinical judgment and an assessment of the most likely 
causative etiology, with special consideration given to the 
potential for immune-mediated hepatic toxicity. Nivolumab 
administration should be delayed for toxicities as indicated 
in the management algorithms (Appendix III) that in the 
opinion of the treating physician are related to nivolumab. 
Please refer to Section 5.4.2.2. 
5.4.1.4 
Nephrotoxicity (based on measured or calculated 
creatinine clearance) 
Creatinine Clearance (ml/min)  
Cisplatin*  
≥ 60  
100%  
59 – 50  
67%  
< 50  
0**  
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**Only patients randomized to Arm A will receive Nivolumab. If 
serum creatinine clearance is < 50 ml/min on day 1 of the next 
cycle, delay the start of that cycle for up to 2 weeks (check 
creatinine at least weekly). If CrCl decrease persists beyond 2 
weeks, skip cisplatin for that cycle and proceed with etoposide 
and nivolumab. NOTE: The etoposide and nivolumab doses 
will be held if cisplatin is held until a decision is made to skip 
cisplatin for the current cycle so that all drugs are kept on the 
same schedule. If the serum creatinine returns to ≥ 50 ml/min 
within 3 weeks of original hold, cisplatin may be reinstituted at 
67% of the full dose during the next cycle (permanent dose 
reduction). A more aggressive hydration regimen (as tolerated 
by patient clinical state) should be instituted as well with all 
subsequent doses of cisplatin. If CrCl does not recover to ≥ 50 
ml/min after 3 weeks, remove patient from all protocol therapy. 
5.4.1.5 
Hypomagnesemia 
Hypomagnesemia is not an indication for stopping therapy. 
Oral or parenteral magnesium supplementation is indicated 
for serum magnesium levels < 1.5 mEq/L. 
5.4.1.6 
Nervous System Disorder (Neurologic Toxicity) 
Grade 
Cisplatin* 
0-1 
100% 
2 
75%** 
3 
0*** 
* Please note that the % dose administered is based on the 
original starting dose of cisplatin (75mg/m2).  
** Patients with a grade 2 nervous system disorder 
(neurotoxicity) should hold all protocol treatment until recovery 
to grade 1 or less, then administer 75% dose. If grade 2 
nervous system disorder (neurotoxicity) recurs with 75%, drug 
will be given at 50% upon resolution of nervous system 
disorder (neurotoxicity) to grade 1 or less. If grade 2 nervous 
system disorder (neurotoxicity) persists for 3 weeks, remove 
the patient from all protocol therapy.  
*** Discontinue all protocol therapy for nervous system disorder 
(neurotoxicity) ≥ grade 3. 
5.4.1.7 
Allergic Reactions  
Discontinue infusion that has led to allergic reaction 
promptly if ≥ grade 3 anaphylaxis develops.  
Suggested Management of Allergic Reaction:  
In case of mild allergic symptoms (e.g., Grade 1 – systemic 
intervention not indicated; Grade 2 – oral intervention 
indicated), symptomatic treatment may be given (e.g., oral 
antihistamine or topical corticosteroids).  
Patient experiencing significant allergic reaction should be 
managed according to local institutional standards. A 
combination of corticosteroids, antihistamines, nebulized 
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respiratory therapy with beta (2) agonists and isotonic fluid 
support should be employed as appropriate based on 
patient’s clinical condition.  
For Grade 3 or Grade 4 symptoms: (Grade 3: 
bronchospasm; hospitalization indicated for clinical 
sequelae; intravenous intervention indicated; Grade 4: life-
threatening consequences; urgent intervention indicated):  
Immediately discontinue infusion that has led to Grade 3 or 
Grade 4 allergic reaction. Begin an IV infusion of normal 
saline and treat the subject as follows: Recommend 
bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 
solution for subcutaneous administration, 0.3 mg of a 
1:1,000 solution for intramuscular administration, or 0.1 to 
0.25 mg of a 1:10,000 solution slowly for IV administration, 
and/or diphenhydramine 50 mg (oral or IV) with 
methylprednisolone 100 mg IV (or equivalent), as needed. 
Subject should be monitored until the Investigator is 
comfortable that the symptoms will not recur. Investigators 
should follow their institutional guidelines for the treatment 
of anaphylaxis. Remain at bedside and monitor subject 
until recovery from symptoms. 
For Grade 3 or Grade 4 allergic reaction attributed to IV 
etoposide, it is acceptable to switch to oral etoposide, if 
clinically appropriate. 
5.4.1.8 
Ototoxicity 
Remove patient from therapy for grade ≥ 3 ear and 
labyrinth disorder (ototoxicity). 
5.4.1.9 
Grade 3 or 4 Non-Hematologic Toxicity 
If patient develops grade 3 or 4 non-hematologic toxicity 
attributed to protocol therapy but not detailed above 
[excluding the following: anorexia, fatigue and fever 
without grade 3 or 4 neutrophil count decrease 
(neutropenia)] hold all therapy. Therapy can be restarted if 
the toxicity has resolved to < grade 1 by the time of the 
next treatment. Doses of all chemotherapy should then be 
reduced by 25% (of the dose received during the previous 
cycle). If carboplatin administered, reinstitute carboplatin 
AUC with decrease by one dose level (i.e. starting dose of 
AUC 6 dose reduction 1= AUC 5). If chemotherapy is held 
for more than 3 weeks, remove the patient from all protocol 
therapy. 
A clinically relevant overlap in toxicity may arise between 
the immune-related dermatologic and cardiac toxicities 
attributed to nivolumab and dermatologic and cardiac 
toxicities attributed to etoposide. The management of 
overlapping toxicities should be guided by clinical 
judgment and an assessment of the most likely causative 
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for immune-mediated toxicities. Nivolumab administration 
should be delayed for toxicities as indicated in the 
management algorithms (Appendix III) that in the opinion 
of the treating physician are related to nivolumab. Please 
refer to Section 5.4.2.2. 
5.4.2 
Nivolumab  
There are no nivolumab dose modifications. Depending on toxicities, 
nivolumab will either be given at full dose, withheld, or discontinued.  
NOTE: 
Nivolumab treatment may only be held for a maximum of 
12 weeks for nivolumab-specific toxicity, otherwise the 
patient should be removed from all protocol therapy.  
Grading of AEs is based on the NCI CTCAE. 
If a patient discontinued nivolumab due to nivolumab-specific 
toxicities, chemotherapy may continue, if appropriate. Patient should 
be followed for assessment of the toxicities until the AEs resolve or 
are deemed irreversible. 
5.4.2.1 
Management Algorithms for Nivolumab 
Immuno-oncology (I-O) agents are associated with 
adverse events that can differ in severity and duration than 
adverse events caused by other therapeutic classes. 
Nivolumab is considered an immuno-oncology agent in this 
protocol. Management algorithms have been developed to 
assist investigators in assessing and managing the 
following groups of adverse events: Gastrointestinal, 
Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, and 
Neurological. See Appendix III for the treatment 
algorithms.  
Early recognition and intervention are recommended 
according to the management algorithms found in 
Appendix III. In addition, the Investigator Brochure (IB, 
version 16, 2017) includes ophthalmologic evaluations for 
any visual symptoms in order to evaluate for nivolumab 
related uveitis. Investigators should follow the algorithms in 
Appendix III for immune- related events. 
NOTE: 
The algorithms are essential guides for AE 
management, but the guidance provided in 
these algorithms should not replace the 
investigator’s medical judgment but should 
complement it.  
For patients expected who require more than 4 weeks of 
corticosteroids or other immunosuppressants to manage 
an adverse event, consider the following 
recommendations: Antimicrobial/antifungal prophylaxis per 
institutional guidelines to prevent opportunistic infections 
such as Pneumocystis jiroveci and fungal infections.  
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Early consultation with an infectious disease specialist 
should be considered. Depending on the presentation, 
consultation with a pulmonologist for bronchoscopy or a 
gastroenterologist for endoscopy may also be appropriate.
 In patients who develop recurrent adverse events in the 
setting of ongoing or prior immunosuppressant use, an 
opportunistic infection should be considered in the 
differential diagnosis.  
Additional details on the safety of nivolumab, including 
results from clinical studies, are available in the IB (IB, 
version 16, 2017). 
Please refer to the Nivolumab Investigator Brochure or 
Appendix III to the protocol for toxicity management 
algorithms which include specific treatment guidelines. 
These algorithms should be followed unless there are 
specific clinical circumstances for which the treating 
physician decides an alternative treatment approach is 
clinically appropriate. Consultation with the study PI is 
recommended.  
In places that there are differences from the algorithms 
regarding protocol directed drug modifications, please 
follow the protocol specific guidelines in this section. 
Generally we strongly encourage early evaluation while 
withholding drug, and appropriate treatment as indicated in 
the management tables and event specific guidelines. 
ALL OTHER 
EVENTS 
Management/Next Dose for Nivolumab  
≤ Grade 1 
No change in dose  
Grade 2 
Hold until ≤ Grade 1 OR baseline 
(exceptions as noted below)  
Grade 3 
Off protocol therapy (exceptions as noted 
below) 
Grade 4 
Off protocol therapy 
Recommended management: As clinically indicated  
• 
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 
should go off protocol 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 study drug dosing should go off 
protocol treatment.  
• 
Any grade 3 or 4 drug-related laboratory abnormality 
(i.e. amylase, lipase) or electrolyte abnormality, that 
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hormone replacement, insulin or that does not require 
treatment does not require discontinuation. 
Skin Rash and Oral 
Lesions 
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose * 
Grade 2 
Hold* until Grade ≤ 1 or resolved.  Resume at same dose level. 
Grade 3 
Hold* until ≤ Grade 1.  Resume at same level at investigator discretion  
Grade 4 
Off protocol therapy 
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-Johnson syndrome, 
TEN, and autoimmune bullous disease including oral lesions of bullous pemphigus/pemphigoid. Pruritus 
may occur with or without skin rash and should be treated symptomatically if there is no associated liver 
or GI toxicity.  Note skin rash typically occurs early and may be followed by additional events particularly 
during steroids tapering.   
Recommended management:  AE management guidelines 
 
Liver Function AST, 
ALT, Bilirubin 
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until WNL or baseline.  Resume at same dose level.  
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy 
Continued treatment with active immune mediated hepatitis may exacerbate ongoing inflammation.  
Holding drug to evaluate LFT changes and early treatment are recommended.   
LFT changes may occur during steroid taper from other events and may occur together with other GI 
events including cholecystitis/pancreatitis.  
Recommended management:  see Hepatic AE management algorithm 
 
Diarrhea/ Colitis  
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until baseline.  No change in dose 
Grade 3 
Off protocol therapy. 
Grade 4 
Off protocol therapy 
See GI AE Algorithm for management of symptomatic colitis.  
Patients with grade 2 symptoms but normal colonoscopy and biopsies may be retreated after resolution.  
Evaluation for all patients for additional causes includes C. diff, acute and self-limited infectious and 
foodborne illness, ischemic bowel, diverticulitis, and IBD.  
Recommended management:  see GI AE management Algorithm 
 
Pneumonitis 
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose   
Grade 2 
Hold dose pending evaluation. Resume no change in dose after pulmonary 
and/or ID consultation as needed. 
Recurrent Grade 2 or 
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Pneumonitis 
Management/Next Dose for Nivolumab 
Grade 4 
Off protocol therapy 
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who do not 
respond to antibiotics and have no causal organism identified including influenza.  Most patients with 
respiratory failure or hypoxia will be treated with steroids.  Bronchoscopy may be required and analysis 
of lavage fluid for lymphocytic predominance may be helpful.  Patients with new lung nodules should be 
evaluated for sarcoid like granuloma.  Please consider recommending seasonal influenza killed vaccine 
for all patients. 
Recommended management:  See Pulmonary Adverse Event Management Algorithm  
 
Neurologic events  
Management/Next Dose for Nivolumab 
≤ Grade 1 
No change in dose. 
Grade 2 
Hold dose pending evaluation and observation. Hold until ≤ Grade 1. Off 
protocol therapy per investigator discretion. Resume at same dose level for 
peripheral isolated n. VII (Bell’s palsy). 
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy  
Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic hypophysitis, or 
myopathy, peripheral demyelinating neuropathy, cranial neuropathy (other than peripheral n. VII), 
Guillain-Barre Syndrome, myasthenia gravis should be off study. 
Recommended management:  See Neurologic Adverse Event Management Algorithm  
 
Renal   
Management/Next Dose for Nivolumab  
≤ Grade 1 
No change in dose  
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Off protocol therapy.  
Grade 4 
Off protocol therapy. 
Recommended management:  See Renal Adverse Event Management Algorithm 
5.4.2.2 
Treatment of Nivolumab-Related Infusion Reactions  
Since nivolumab contains only human immunoglobulin 
protein sequences, it is unlikely to be immunogenic and 
induce infusion or hypersensitivity reactions.  However, if 
such a reaction were to occur, it might manifest with fever, 
chills, rigors, headache, rash, urticaria, angioedema, 
pruritis, arthralgias, hypo- or hypertension, bronchospasm, 
or other symptoms.  
All Grade 3 or 4 infusion reactions should be reported as 
an SAE if criteria are met.  Infusion reactions should be 
graded according to NCI CTCAE guidelines. 
Treatment recommendations are provided below and may 
be modified based on local treatment standards and 
guidelines as medically appropriate: 
Remain at bedside and monitor subject until recovery from 
symptoms  
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For Grade 1 symptoms:  (Mild transient reaction; infusion 
interruption not indicated; intervention not indicated) 
If clinically appropriate, infusion rate may be slowed or 
interrupted and restarted at 50% of the original infusion 
rate when symptoms resolve; if no further complications 
ensue after 30 minutes, the rate may be increased to 
100% of the original infusion rate.  Monitor patient closely. 
The following prophylactic premedications are 
recommended for future infusions:  diphenhydramine 50 
mg (or equivalent, oral) and/or acetaminophen 325 to 1000 
mg at least 30 minutes before additional nivolumab 
administrations, slowing infusion rate as above. 
For Grade 2 symptoms:  (Therapy or infusion interruption 
indicated but responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for ≤ 24 hrs), and no 
further nivolumab administration should be considered at 
that visit. 
Stop the nivolumab infusion, begin an IV infusion of normal 
saline, and treat the subject with diphenhydramine 50 mg 
IV (or equivalent, oral) and/or acetaminophen 325 to 1000 
mg; remain at bedside and monitor patient until resolution 
of symptoms. Corticosteroid or bronchodilator therapy may 
also be administered as appropriate. If it is deemed 
clinically appropriate to restart, then restart the infusion at 
50% of the original infusion rate when symptoms resolve; if 
no further complications ensue after 30 minutes, the rate 
may be increased to 100% of the original infusion rate. 
Monitor patient closely. If symptoms recur, re administer 
diphenhydramine 50 mg (oral or IV), and remain at bedside 
and monitor the patient until resolution of symptoms.  The 
amount of study drug infused must be recorded on the 
electronic case report form (eCRF). 
The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg 
(or equivalent, oral) and (acetaminophen) 325 to 1000 mg 
should be administered at least 30 minutes before 
additional nivolumab administrations.  If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms: (Severe reaction), 
Grade 3 symptoms: prolonged [i.e., not rapidly responsive 
to symptomatic medication and/or brief interruption of 
infusion]; recurrence of symptoms following initial 
improvement; hospitalization indicated for other clinical 
sequelae [e.g., renal impairment, pulmonary infiltrates]).   
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Nivolumab will be permanently discontinued 
Immediately discontinue infusion of nivolumab.  Begin an 
IV infusion of normal saline, and bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1,000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 
1:10,000 solution injected slowly for IV administration, 
and/or diphenhydramine 50 mg (oral or IV) with 
methylprednisolone 100 mg IV (or equivalent), as needed.  
Patient should be monitored until the investigator is 
comfortable that the symptoms will not recur.   
Investigators should follow their institutional guidelines for 
the treatment of anaphylaxis.  Remain at bedside and 
monitor patient until recovery from symptoms.  
In the case of late-occurring hypersensitivity symptoms 
(e.g., appearance of a localized or generalized pruritis 
within 1 week after treatment), symptomatic treatment may 
be given (e.g., oral antihistamine, or topical or oral 
corticosteroids).  Additional treatment prior to next dose as 
per guidelines above.  
Please note that late occurring events including isolated 
fever and fatigue may represent the presentation of 
systemic inflammation.  Please evaluate accordingly. 
5.5 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study. Supportive care (including IVF hydration) is not considered 
non-protocol therapy  
The clinical tolerance of the patients, the overall tumor response, and the medical 
judgment of the investigator will determine if it is in the patient’s best interest to 
continue or discontinue treatment. If treatment is discontinued due to any toxicity, 
the patient must be followed to monitor duration of toxicity, response and time to 
progression (even if non-protocol therapy is initiated). Suggested supportive care 
medications may be substituted at the discretion of the investigator based on 
drug availability.  
Hyperalimentation may be used, but details must be clearly outlined on treatment 
forms.  
Concomitant aminoglycoside antibiotic use should be avoided during cisplatin 
therapy until patient has fully recovered (i.e., at least 4 weeks from last dose of 
cisplatin).  
The use of bisphosphonates or denosumab is allowed for patients with bone 
metastasis or hypercalcemia. 
Systemic treatment with either corticosteroids (> 10 mg daily prednisone 
equivalent) or other immunosuppressive medications are prohibited. Topical, 
ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal 
systemic absorption) and adrenal replacement steroid doses > 10 mg daily 
prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids 
for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune 
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conditions (eg, delayed-type hypersensitivity reaction caused by a contact 
allergen) or prevention of nausea/vomiting is permitted. 
The use of erythropoiesis-stimulating agents (ESAs) is allowed if clinically 
indicated based on the recommendations by the American Society of Clinical 
Oncology (2010). For patients undergoing myelosuppressive chemotherapy who 
have a hemoglobin (Hb) level less than 10 g/dL, the ASCO Guideline Update 
Committee recommends that clinicians discuss potential harms (e.g., 
thromboembolism, shorter survival) and benefits (e.g., decreased transfusions) of 
ESAs and compare these with potential harms (e.g., serious infections, immune-
mediated adverse reactions) and benefits (e.g. rapid Hb improvement) of RBC 
transfusions. If used, ESAs should be administered at the lowest dose possible 
and should increase Hb to the lowest concentration possible to avoid 
transfusions. Available evidence does not identify Hb levels of 10 g/dL either as 
thresholds for initiating treatment or as targets for ESA therapy. Starting doses 
and dose modifications after response or nonresponse should follow US Food 
and Drug Administration– approved labeling. ESAs should be discontinued after 
6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer 
not receiving concurrent chemotherapy, except for those with lower risk 
myelodysplastic syndromes.  
G-CSF and pegylated G-CSF should be used in accordance with American 
Society of Clinical Oncology (ASCO) and NCCN guidelines. G-CSF and 
pegylated G-CSF may be used during all treatment cycles for patients for cycle 2 
and beyond as indicated. These agents (G-CSF and pegylated G- CSF) may be 
used at the discretion of the investigator after neutropenia is documented, or 
prophylactically to reduce the chance of febrile neutropenia at all other times 
during the study. Growth factor use or dose reduction is only mandated, 
however, in the setting of prior febrile neutropenia. 
The ASCO guidelines state, “even if febrile neutropenia has not occurred, the 
use of CSFs may be considered if prolonged neutropenia is causing excessive 
dose reduction or delay in chemotherapy. However, in the absence of clinical 
data supporting the maintenance of chemotherapy dose intensity, physicians 
should consider chemotherapy dose reduction as an alternative to the use of 
CSFs. There are inadequate data to know whether patients with neutropenia but 
no fever will benefit clinically from the initiation of a CSF at the time neutropenia 
is diagnosed; intervention with a CSF in afebrile neutropenic patients is not 
recommended. For the majority of patients with febrile neutropenia, the available 
data does not support the routine initiation of CSFs as adjuncts to antibiotic 
therapy. However, certain febrile neutropenic patients may have prognostic 
factors that are predictive of clinical deterioration, such as pneumonia, 
hypotension, multiorgan dysfunction (sepsis syndrome), or fungal infection. The 
use of CSFs together with antibiotics may be reasonable in such high risk 
patients, even though the benefits of administration under these circumstances 
have not been definitively proved (ASCO, 2013).”  
Diarrhea may occur on either arm. Appropriate supportive measures including 
Imodium and/or Lomotil should be implemented immediately to prevent 
dehydration.  
Hydration guidelines may be modified at the discretion of the treating physician 
provided adequate pre and post cisplatin hydration is achieved and renal function 
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250 cc to 1000 cc of IV fluids following adequate hydration and the establishment 
of adequate urinary output. It is suggested the pre-cisplatin hydration consist of 
NS at 500 cc/hr x 1 liter and post-cisplatin hydration consist of 1/2 NS + 10 meq 
KCl/liter + 1 gram magnesium sulfate/liter + 25 grams mannitol/liter at 500 cc/hr 
for at least one hour, followed by additional hydration at the discretion of the 
investigator.  
Antiemetic therapy is critical for proper administration of cisplatin/carboplatin. The 
specific antiemetic regimen is at the discretion of the treating physician, provided 
adequate control is achieved. However, on the day of cisplatin therapy the 
investigator should use a steroid medication, a 5HT3 antagonist and NK1 
antagonist such as fosaprepitant or aprepitant since cisplatin is highly 
emetogenic. One such regimen consists of 10 mg of dexamethasone and a high 
dose of a 5HT3 antagonist (such as 2 mg oral of 10 mcg/kg IV granisetron or 24 
mg ondansetron or equivalent) and continuing with 4 days or dexamethasone or 
equivalent steroid and 4 days of scheduled anti- emetic such as a 5HT3 
antagonist. If this regimen is ineffective, consideration of the long-acting 5HT3 
antagonist palonosetron should be considered at the discretion of the 
investigator. 
NOTE: 
Aprepitant should be used with caution in patients receiving 
concomitant medicinal products, including chemotherapy agents that 
are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by 
aprepitant could result in elevated plasma concentrations of these 
concomitant medicinal products. The effect of aprepitant on the 
pharmacokinetics of orally administered CYP3A4 substrates is 
expected to be greater than the effect of aprepitant on the 
pharmacokinetics of intravenously administered CYP3A4 substrates.  
Dexamethasone dose should be reduced by 50% when administered with 
aprepitant. 
Patients are ineligible if administration of a live, attenuated vaccine within 4 
weeks before randomization. 
5.6 
Duration of Therapy  
Treatment may continue for up to 4 cycles of chemotherapy (CE) as described in 
Section 5.1. In the investigational arm (Arm A), nivolumab in combination with 
chemotherapy (CE) will be given for up to 4 cycles, followed by maintenance 
nivolumab for up to a total of 2 years (or 50 doses) of treatment with nivolumab 
as described in Section 5.1. Treatment may continue until one of the following 
criteria applies: 
Patients will receive protocol therapy unless: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
EA5161 Forms Packet. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered. 
• 
Disease progression as defined in Section 6. 
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5.7 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
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6. 
Measurement of Effect 
6.1 
Antitumor Effect – Solid Tumors  
For the purposes of this study, patients should be re-evaluated for response 
every 6 weeks. All patients will be evaluated for response every 6 weeks for the 
first 6 months on study, every 8 weeks until 1 year on study, and then every 12 
weeks after 1 year on study. 
Response and progression will be evaluated in this study using the international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [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 RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline to which subsequent measurements will be compared. All 
baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than four weeks before registration. 
2. Measurable disease is defined by the presence of at least one measurable 
lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or 
calipers.  
4. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up.  
6.1.1 
Definitions 
Evaluable for Objective Response 
Only those patients 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 response. 
These patients will have their response classified according to the 
definitions stated below. 
NOTE: 
Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable. 
Evaluable Non-Target Disease Response 
Patients 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 lesion assessment. The 
response assessment is based on the presence, absence, or 
unequivocal progression of the lesions. 
6.1.2 
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, as ≥ 10 mm with CT scan, or ≥ 10 mm 
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with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: 
Previously irradiated lesions can only be considered as 
measurable disease if disease progression has been 
unequivocally documented at that site since radiation. 
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. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
NOTE: 
Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, 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 
of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the 
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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 or absence of 
unequivocal progression of each should be noted throughout follow-
up.  
6.1.3 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more 
than 4 weeks before registration. 
The same method of assessment and the same technique must 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 (e.g., skin nodules and palpable lymph nodes) and ≥ 10 
mm in diameter as assessed using calipers (e.g., skin nodules). In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also 
acceptable 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 must 
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.  
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acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, 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. However, if the site can document 
that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and 
can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET 
portion of the CT introduces additional data which may bias an 
investigator if it is not routinely or serially performed. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken 
from one assessment to the next.  If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances. 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor Markers 
Tumor markers alone cannot be used to assess response. If markers 
are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin 
Oncol 26:1148-1159, 2008]. In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
Cytology, Histology 
These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., 
residual lesions in tumor types, such as germ cell tumors, where 
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The cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when the measurable tumor 
has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be 
a side effect of the treatment) and progressive disease. 
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. 
6.1.4 
Response Criteria 
6.1.4.1 
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 


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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 progression, See Section 
6.1.4.3. 
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. (Note: a change of 20% or 
more that does not increase the sum of the diameters by 5 
mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 6 weeks.  
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest 
“increase” in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
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declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace” to “large”, an increase in nodal 
disease from “localized” to “widespread”, or an increase 
sufficient to require a change in therapy. 
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). 
6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it:  
a) increases in size to ≥ 15 mm in the short axis, or  
b) there is new pathological confirmation that it is disease 
(regardless of size). 
new effusion or ascites that appears during treatment 
should only be reported as a new lesion (and therefore 
progressive disease) if it has cytological confirmation of 
malignancy. 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment until disease 
progression/recurrence or non-protocol therapy (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). The 
patient’s best response assignment will depend on the 
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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target  
Lesions 
New 
Lesions* 
Best Overall 
Response 
Remarks  
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD*** 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
Documented at least once 
≥ 6 wks. from study entry 
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. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease section for further explanation. 
NOTE: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
6.1.4.5 
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). 
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. 
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.  
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of 6 weeks.  
 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. Pre- study screening CT scans and MRIs used to assess all measurable or 
non-measurable sites of disease must be done within 4 weeks prior to 
randomization/registration. 
2. Pre-study screening CBC (with differential and platelet count) and chemistries 
as outlined in Section 3.1 should be done ≤ 1 week before 
randomization/registration. All other pre-study screening labs should be done 
within 2 weeks prior to randomization/registration. Screening assessments 
performed ≤ 72 hours before Cycle 1, Day 1 are not required to be repeated 
for Cycle 1, Day 1. 
3. Please see Section 5.1 for more information on treatment administration 
parameters. 
Therapeutic 
parameters 
Pre-study 
screening 
Cycle 
1 
Day 1 
Cycle 
2 
Day 1 
Cycle 
3 
Day 1 
Cycle 
4 
Day 1  
Maintenance 
Nivolumab 
Cycle 5+ Day 
1, 15, 29 
Observation 
(Arm B)11 
Post 
Treatment/
Observation
12 to 5 years 
from study 
entry 
Full Medical History 
X 
 
 
 
 
 
 
 
Interval History1 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs including 
weight1 
X 
X 
X 
X 
X 
X 
X 
X 
Performance 
status1 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with 
Differential2 
X 
X 
X 
X 
X 
X 
X11 
 
Serum chemistry2 
X 
X 
X 
X 
X 
X 
X11 
 
TSH, reflex free T3, 
reflex free T43 
X 
X 
 
X 
 
X3 
 
 
Amylase4 
 
X 
 
 
 
 
 
 
Lipase4 
 
X 
 
 
 
 
 
 
HIV, HBV, HCV 
serology5 
X 
 
 
 
 
 
 
 
Pregnancy Test6 
X 
 
 
 
 
 
 
 
EKG7 
X 
 
 
 
 
 
 
 
Urinalysis8 
X 
X 
X 
X 
X 
X8 
 
 
CT chest9 
X 
 
 
X 
 
X 
X 
X 
CT abdomen9 
X 
 
 
X 
 
X 
X 
X 
CT pelvis9 
X 
 
 
X 
 
X 
X 
X 
MRI brain10 
X 
 
 
 
 
 
 
 
Rev. Add1 
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1. At subsequent visits, symptom-directed history and physical examinations including vital signs, weight 
and performance status should be performed. Symptom-directed history, physical exam and 
performance status may be performed up to 72 hours prior to each cycle. 
2. CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct, and 
chemistry to include Albumin, alkaline phosphatase, total bilirubin, carbon dioxide, BUN, calcium, 
chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium, required for protocol therapy must be done ≤ 72 hours prior to treatment administration. 
Magnesium is only required for patients receiving cisplatin on day 1 of each cycle that cisplatin is 
administered. For cycle 1 day 1, need not be repeated if the screening labs were done within 72 hours 
of treatment administration. 
3. TSH, reflex free T3 and reflex free T4 will be done at screening as clinically indicated. For the 
Nivolumab Arm only, these tests will also be done on C1D1, C3D1, C5D1, and every 8 weeks during 
the maintenance phase. Thyroid labs collected at screening do not need to be repeated at C1D1 if 
done within 72 hours of treatment administration. 
4. Amylase, lipase will be required for patients receiving nivolumab on C1D1 and when clinically 
indicated. 
5. All patients will be tested for HIV, hepatitis B and hepatitis C at screening, if clinically indicated. 
6. Blood or Urine pregnancy test (women of childbearing potential). All women of childbearing potential 
must have a negative pregnancy test (sensitivity of at least 50 mIU/mL). The pregnancy test must be 
performed within 14 days prior to registration. 
7. All patients will have an EKG at screening, if clinically indicated. Patients randomized to the Nivolumab 
Arm will have troponin as clinically indicated. Further cardiac evaluation is recommended including 
troponin, EKG, echocardiogram, and cardiology consult when clinically indicated. 
8. Urinalysis will be required at screening for all patients and on day 1 of every cycle on the Nivolumab 
Arm. It does not need to be performed on days 15 or 29 for Cycle 5+. 
9. Screening assessments will include CT chest and abdomen. CT pelvis should be performed as 
clinically indicated. On study and follow-up assessments will include a CT chest and abdomen at each 
time point, and CT pelvis as clinically indicated. For both Arm A and Arm B, all patients will be 
evaluated for response while on study using radiographic evaluations with tumor measurements every 
6 weeks (+/- 7 days) for the first 6 months on study, every 8 weeks (+/- 7 days) until 1 year on study, 
and then every 12 weeks (+/- 7 days) after 1 year on study until the patient discontinues protocol 
treatment (Arm A) or the end of observation (Arm B) and enters follow-up (see footnote 12 for follow-
up schedule). Documentation (radiologic) must be provided for patients removed from study for 
progressive disease. For all patients on Arm A and Arm B, CT scans will be done until disease 
progression. 
10. Head CT allowed, if patient cannot tolerate MRI. Brain imaging will be done at screening and then as 
clinically indicated. 
11. For Arm B patients on observation, symptom-directed history and physical examinations including vital 
signs, weight and performance status should be performed every 6 weeks (+/- 7 days) for the first 6 
months on study, then every 8 weeks (+/- 7 days) until 1 year on study; and every 12 weeks (+/- 7 
days) after 1 year on study, alongside the radiologic evaluations. Labs (CBC w/diff, serum chemistries) 
are done as clinically indicated. CT scans will be done until disease progression 
12. Follow-up after patient discontinues protocol treatment (Arm A) or the end of observation (Arm B): 
every 3 months for patients < 2 years from registration, every 6 months if patient is 2-3 years from 
registration, and yearly until 5 years from registration. Patients in the observation phase on Arm B may 
be seen more frequently per schedule of CT scans as per footnote 9. All patients, including those who 
discontinue protocol therapy early, will be followed for response until progression, even if non-protocol 
therapy is initiated, and for survival for 5 years from the date of registration. For all patients during 
follow-up, symptom-directed history and physical examinations including vital signs, weight and 
performance status should be performed until progression. Follow-up for survival after progression 
may occur via phone calls. 
 


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7.2 
Biological Sample Submissions 
Specimens are to be submitted as outlined in Section 10. 
All specimens must be entered and tracked via the online ECOG-ACRIN Sample 
Tracking System (STS). 
Biological Materials 
Prior to Start of 
Treatment 
Cycle Two (2), 
Day One (1) 
Submit to: 
Submit from patients who answer ‘Yes’ to ‘I agree to have my samples collected and I 
agree that my samples and related information may be used for the laboratory studies.’ 
Peripheral Blood (two 
10mL Streck Cell-
Free DNA tubes) 
X 
X 
CBPF 
Submit from patients who answer ‘Yes’ to ‘I agree to provide additional samples for 
research.’ 
Tumor Tissue Biopsy  
X 
 
CBPF 
1. Kits are being provided for the collection and shipment of the peripheral blood 
specimens. See Appendix VII for instructions. Kit orders will on average be delivered 
within three (3) business days from the time the order is placed. 
 


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8. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
NCI Supplied Nivolumab – General Information  
Drug Ordering: Bristol-Myers Squibb is supplying Nivolumab, through the Division of 
Cancer Treatment and Diagnosis, NCI, for this protocol. Maintenance of NCI drug 
accountability records is required. Nivolumab (NSC #748726 and IND#)] may be 
requested by eligible participating Investigators (or their authorized designees) at each 
participating institution. The CTEP-assigned protocol number must be used for ordering 
all CTEP-supplied investigational agents.  The eligible participating investigators at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent 
Shipment Form, and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead participating investigator at that 
institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status,  a 
“current” password, and active person registration status.  For questions about drug 
orders, transfers, returns, or accountability, call or email PMB any time.  Refer to the 
PMB’s website for specific policies and guidelines related to agent management.   
NOTE: Under no circumstances can commercially supplied nivolumab be used or 
substituted for the NCI-supplied nivolumab. 
NOTE: In general, sites may order an initial 5 vials of Nivolumab when a subject is 
being screened for enrollment onto the study. 
Drug Returns: All unused drug supplies must be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed vials remaining when a patient permanently 
discontinues protocol treatment, expired vials recalled by the PMB), investigators must 
return the study drug to the PMB using the NCI Return Agent Form available from the 
link below, or by calling the PMB at 240-276-6575. 
Agent Inventory Records: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI Investigational 
Agent (Drug) Accountability Record (DARF) available on the CTEP forms page.  Store 
and maintain separate NCI Investigational Agent Accountability Records for each agent, 
strength, formulation and ordering investigator on this protocol. 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP  
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• 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
• 
CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• 
PMB IB Coordinator: IBCoordinator@mail.nih.gov 
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
Investigator Brochure Availability 
The current version of the IB for Nivolumab will be accessible to site investigators and 
research staff through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, a 
“current” password, and active person registrations status.  Questions about IB access 
may be directed to the PMB IB coordinator via email. 
8.1 
Nivolumab (NSC 748726) 
8.1.1 
Other Names  
BMS-936558, MDX1106, Opdivo™ 
8.1.2 
Classification  
Anti-PD-1MAb 
8.1.3 
Mode of Action 
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. 
8.1.4 
Description 
Nivolumab Injection is a clear to opalescent, colorless to pale yellow 
liquid; light (few) particulates may be present. The drug product is a 
sterile, nonpyrogenic, single-use, isotonic aqueous solution 
formulated in sodium citrate dihydrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), polysorbate 80 
(Tween® 80), and water for injection.  Dilute solutions of hydrochloric 
acid and/or sodium hydroxide may be used for pH adjustment (pH 
5.5-6.5). 
8.1.5 
Storage and Stability  
Vials of Nivolumab injection must be stored at 2°-8°C (36°-46°F) and 
protected from light, freezing, and shaking. The unopened vials can 
be stored at room temperature (up to 25°C, 77°F) and room light for 
up to 48 hours. 
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If a storage temperature excursion is identified, promptly return 
Nivolumab to 2°C-8°C and quarantine the supplies.  Provide a 
detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Shelf-life surveillance of the intact vials is ongoing. 
If not used immediately, the infusion solution may be stored up to 24 
hours in a refrigerator at 2°-8°C (36°-46°F) and a maximum of 8hours 
of the total 24 hours can be at room temperature (20°-25°C, 68°-77°F) 
and room light.  The maximum 8-hour period under room temperature 
and room light conditions includes the product administration period. 
CAUTION:  The single-use dosage form contains no antibacterial 
preservative or bacteriostatic agent.  Therefore, it is advised that the 
product be discarded 8 hours after initial entry. 
8.1.6 
Dose Specifics  
Refer to Section 5.1 for specific dosing of nivolumab 
8.1.7 
Preparation  
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted 
with 0.9% Sodium Chloride Injection, USP or 5% Dextrose. When the 
dose is based on patient weight (i.e., mg/kg), nivolumab injection can 
be infused undiluted or diluted to protein concentrations as low as 
0.35 mg/mL. 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. For patients 
weighing less than 40 kilograms (kg), the total volume of infusion must 
not exceed 4 mL per kg of patient weight. During drug product 
preparation and handling, vigorous mixing or shaking is to be avoided.  
8.1.8 
Route of Administration  
Intravenous infusion over 30 minutes. Do not administer as an IV 
push or bolus injection.  See Section 5.1 
8.1.9 
Availability  
Nivolumab is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
Nivolumab is provided to the NCI under a Collaborative Agreement 
between the Pharmaceutical Collaborator and the DCTD, NCI (see 
Appendix IV). 
Nivolumab is supplied as 100 mg vials (10 mg/mL) with a 0.7mL 
overfill, in 10 mL type I flint glass vials, with fluoropolymer film-
laminated rubber stoppers and aluminum seals. 
8.1.10 
Side Effects  
See Section 5.3 
8.1.11 
Nursing/Patient Implications  
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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. 
Administer through a 0.2 micron to 1.2 micron pore size, low-protein 
binding (polyethersulfone membrane) in-line filter. Do not co-
administer other drugs through the same intravenous line. The 
infusion line should be flushed as per institution guidelines after 
completion of the infusion to ensure the entire dose was administered. 
8.1.12 
References  
Nivolumab IB, Version 16, 23-JUN-2017 
8.2 
Cisplatin 
8.2.1 
Other Names  
Cisdiaminedichloroplatinum, Cis-diaminedichloroplatinum (II), 
diaminedichloroplatinum, cis-platinum, platinum, Platinol, Platinol-AQ, 
DDP, CDDP, DACP, NSC 119875. 
8.2.2 
Classification  
Cytotoxic chemotherapy, alkylating agent 
8.2.3 
Mode of Action  
Inhibits DNA synthesis by forming inter- and intra-strand crosslinks. 
Other possible mechanism include chelation of DNA and binding to 
cell membranes thereby stimulating immune mechanisms. 
8.2.4 
Storage and Stability  
Intact vials of cisplatin are stored at room temperature. Protect 
unopened container from light. Refer to the cisplatin package insert 
for stability of the infusion solution after prepared. Due to the risk of 
precipitation, cisplatin solutions should not be refrigerated. 
8.2.5 
Dose Specifics  
Refer to Section 5.1 for specific cisplatin dosing. 
8.2.6 
Preparation  
Cisplatin to be mixed per institutional standard. 
8.2.7 
Route of Administration  
Intravenous 
8.2.8 
Incompatibilities  
Amsacrine, cefepime, gallium nitrate, mesna, piperacillin, sodium 
bicarbonate, thiotepa. Cisplatin may react with aluminum which is 
found in some syringe needles or IV sets, forming a black precipitate. 
Compatibilities: 
Admixture: Amphotericin-B, aztreonam, carmustine, cefazolin, 
cephalothin, droperidol, etoposide, floxuridine, hydroxyzine, 
ifosphamide, leucovorin, magnesium sulfate, mannitol, potassium 
chloride. Y-site: Allopurinol, bleomycin chlorpromazine, cimetidine, 
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cyclophosphamide, dexamethasone, diphenhydramine, doxapram, 
doxorubicin, famotidine, filgrastim, fludarabine, fluorouracil, 
furosemide, ganciclovir, heparin, hydromorphone, lorazepam, 
melphalan, methotrexate, methylprednisolone, metoclopramide, 
mitomycin, morphine, ondansetron, paclitaxel, prochlorperazine, 
ranitidine, sargramostim, vinblastine, vincristine, vinorelbine. 
Consult your pharmacist regarding specific concentrations. 
8.2.9 
Availability  
Commercially available as a 1 mg/mL solution in 50, 100, and 200 mg 
vials. 
8.2.10 
Side Effects  
Please refer to the package insert for a comprehensive list of adverse 
events.  
8.2.11 
Nursing/Patient Implications  
8.2.11.1 
Monitor CBC, platelet count, BUN and creatinine prior to 
drug administration. 
8.2.11.2 
Monitor for signs of ototoxicity or neurotoxicity. 
8.2.11.3 
Symptom management of expected nausea and vomiting. 
Ondansetron (or other 5HT3 antagonist) and 
dexamethasone will be given daily prior to chemotherapy 
administration. Additional antiemetics may be provided per 
physician discretion. 
If the treating physician chooses to use Aprepitant, when 
given once daily for 14 days as a 100 mg capsule with an 
oral contraceptive containing 35 mcg of ethinyl estradiol 
and 1 mg of norethindrone, this decreased the AUC of 
ethinyl estradiol by 43% and decreased the AUC of 
norethindrone by 8%. Women of childbearing potential 
using pregnancy contraception that includes ethinyl 
estradiol should not receive Aprepitant for the treatment of 
nausea/delayed emesis. Patients may change to a 
different method of contraception if they wish to use 
Aprepitant. 
8.2.11.4 
Pre- and post-treatment hydration may be administered 
per institutional standards. 
8.2.11.5 
Diuretics may be ordered as needed per physician 
discretion. 
8.2.11.6 
Use of granulocyte colony stimulating factors are 
permitted. 
8.2.11.7 
Observe for signs of allergic reaction. 
8.2.12 
References 
1. Alberts DS. Carboplatin versus cisplatin in ovarian cancer. Semin 
Oncol 1995;22 (5 Suppl 12):88-90. 


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2. Bonomi P. Platinum/etoposide therapy in non-small cell lung 
cancer. Oncology 1992;49 (Suppl 1):43-50. 
3. Dabholkar M, Reed E. Cisplatin. Cancer Chemother Biol 
Response Modifiers 1993;14:86-97. 
4. Fram RJ. Cisplatin and platinum analogues: recent advances. 
Curr Opin Oncol 1992;4:1073-9. 
5. Garrow GC, Johnson, DH. Treatment of "good risk" metastatic 
testicular cancer. Semin Oncol 1992;19:159-65. 
6. Markman M. Current status of intraperitoneal therapy for ovarian 
cancer. Curr Opinion Obstet Gynecol 1993;5:99-104. 
7. Ozols RF, et al. Advanced ovarian cancer. Dose intensity. Ann 
Oncol 1993; (4 Suppl 4):49-56. 
8. Saxman S. Salvage therapy in recurrent testicular cancer. Semin 
Oncol 1992;19:143-7. 
9. Wheeler RH, Spencer S. Cisplatin plus radiation therapy. J 
Infusional Chemother 1995;5:61-6. 
8.3 
Carboplatin 
8.3.1 
Other Names 
Paraplatin® 
8.3.2 
Classification 
Carboplatin (carboplatin injection) (platinum, diammine[1,1-
cyclobutanedicarboxylato(2-)-O,O’]-, (SP-4-2)) is a platinum 
coordination compound, used as an anti-neoplastic agent. It is a 
second-generation tetravalent organic platinum compound. It is a 
crystalline powder with the molecular formula of C6H12N2O4Pt and a 
molecular weight of 371.25. It is soluble in water at a rate of 
approximately 14 mg/mL, and the pH of a 1% solution is 5 to 7. It is 
virtually insoluble in ethanol, acetone, and dimethylacetamide. 
8.3.3 
Mode of Action 
Like cisplatin, carboplatin binds to DNA, thereby inhibiting DNA 
synthesis, in a cell cycle nonspecific manner. Carboplatin must first 
undergo activation to produce antineoplastic activity. Bidentate 
carboxylate ligands of carboplatin are displaced by water forming 
(aquation) positively charged platinum complexes, which bind to 
nucleophilic sites in DNA, such as the O-6 position on guanine. 
Carboplatin produces predominantly interstrand DNA crosslinks rather 
than DNA-protein crosslinks. Intrastrand crosslinks result from the 
formation of adducts between the activated platinum complexes of the 
drug and the N-7 atom (not exclusively) atom on guanine to produce 
1,2 intrastrand links between adjacent guanine molecules, between 
neighboring guanine and adenosine molecules, or between 
neighboring guanine molecules. Interstrand cross-linking within the 
DNA helix also occurs. Platinum adducts may inhibit DNA replication, 
transcription and ultimately cell division. 
8.3.4 
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Store intact vials at room temperature at 25°C (77°F); excursions 
permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Further 
dilution to a concentration as low as 0.5 mg/mL is stable at room 
temperature (25°C) for 8 hours in NS or D5W. Stability has also been 
demonstrated for dilutions in D5W in PVC bags at room temperature 
for 9 days; however, the manufacturer recommends use within 8 
hours due to lack of preservative. Multidose vials are stable for up to 
14 days after opening when stored at 25°C (77°F) following multiple 
needle entries. 
8.3.5 
Dose Specifics 
See Section 5.1 for specific carboplatin dosing. 
Calvert Formula for Carboplatin (AUC) Dosing 
Total dose (mg) = target AUC (in mg x mL/minute) x [*GFR (in 
mL/minute) + 25] 
For the purposes of this protocol, the GFR is considered to be 
equivalent to the creatinine clearance. 
Glomerular Filtration Rate (GFR)* Estimation: Calculated creatinine 
clearance of ≥ 50 cc/min using the Cockcroft-Gault formula: 
Males: 
(140 – Age in years) x Actual Body Weight in kg 
72 x Serum Creatinine (mg/dL) 
Females: Estimated creatinine clearance for males x 0.85 
With the Calvert formula, the total (final) dose of carboplatin is 
calculated in mg, not mg/m2. 
The minimum serum creatinine value used will be 0.7 mg/dL and a 
CrCl cap will be 125 mL/min. 
Questions about this calculation should be directed to the principal 
investigator. 
8.3.6 
Preparation 
Manufacturer’s labeling states solution can be further diluted to 
concentrations as low as 0.5 mg/mL in NS or D5W; however, most 
clinicians generally dilute dose in either 100 mL or 250 mL of NS or 
D5W. Concentrations used for desensitization vary based on protocol. 
Hazardous agent; use appropriate precautions for handling and 
disposal. Needles or IV administration sets that contain aluminum 
should not be used in the preparation or administration of carboplatin; 
aluminum can react with carboplatin resulting in precipitate formation 
and loss of potency. 
8.3.7 
Route of Administration 
Intravenous 
8.3.8 
Incompatibilities 
Amphoterecin B chloesteryl sulfate complex. Aluminum reacts with 
carboplatin causing precipitate formation and loss of potency; 
therefore, needles or intravenous sets containing aluminum parts that 
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may come in contact with the drug must NOT be used for the 
preparation or administration of carboplatin. 
8.3.9 
Availability 
Carboplatin (Bristol-Myers Oncology Division) is commercially 
available as a 10 mg/mL solution in 50, 150, 450, and 600 mg vials. 
8.3.10 
Side Effects 
Please refer to the package insert for a comprehensive list of adverse 
events. 
8.3.11 
Nursing/Patient Implications 
8.3.11.1 
Monitor CBC and platelet count; nadir occurs at 
approximately day 21 with recovery by day 28-30. 
8.3.11.2 
Premedicate with antiemetics—evaluate effectiveness. 
Ondansetron (or other 5HT3 antagonist) and 
dexamethasone are required. 
8.3.11.3 
Monitor fluid status—maintain adequate hydration. Pre- 
and post-treatment hydration may be administered per 
institutional standards. 
8.3.11.4 
Assess skin/mucous membranes. 
8.3.11.5 
Assess for signs of peripheral neuropathy—coordination, 
sensory loss. 
8.3.12 
References 
1. Calvert AH, et al. Carboplatin dosage: Prospective evaluation of a 
simple formula based on renal function. J Clin Oncol 1989; 
7:1748-1756. 
2. Woloschuk DMM, Pruemer JM, Cluxton RJ. Carboplatin: A new 
cisplatin analog. Drug Intell Clin Pharm 1988; 22:843-849. 
3. Christian MC. Carboplatin. In: Principles and Practice of 
Oncology, PPO Updates 1989; 3(11):1-16. 
8.4 
Etoposide 
8.4.1 
Other Names  
VP-16, VePesid, VP-16-213, EPEG, epipodophyllotoxin, NSC # 
141540. 
8.4.2 
Classification  
Cytotoxic chemotherapy, podophyllotoxin derivative. 
8.4.3 
Mode of Action  
Etoposide inhibits the enzyme topoisomerase II, nucleoside transport 
and incorporation, and causes DNA breakage. 
8.4.4 
Storage and Stability  
The vials should be stored at room temperature. Following dilution in 
0.9% sodium chloride or 5% dextrose to concentrations of 0.2-0.4 
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mg/mL the drug is chemically stable for 96 and 24 hours at room 
temperature respectively. Bristol-Myers in-house data indicate that 
etoposide may be stable in 5% dextrose or normal saline for 24 hours 
(0.6 mg/mL), 4 hours (1 mg/mL), and 2 hours (2 mg/mL). 
8.4.5 
Dose Specifics  
Refer to Section 5.1 for specific etoposide dosing. 
8.4.6 
Preparation 
Etoposide to be prepared per institutional standard.  
8.4.7 
Route of Administration  
Intravenous 
8.4.8 
Incompatibilities  
Please refer to the etoposide prescribing information for more detailed 
information regarding incompatibilities.  
8.4.9 
Availability  
Commercially available 
Etoposide is commercially available as a 20 mg/mL solution in 100 
mg, 500 mg and 1 gm vials. 
8.4.10 
Side Effects  
Please refer to the package insert for a comprehensive list of adverse 
events.  
8.4.11 
Nursing/Patient Implications  
8.4.11.1 
Monitor CBC and platelet count prior to drug 
administration. 
8.4.11.2 
Advise patient of possible alopecia. Instruct how to obtain 
wig, hairpiece, etc. 
8.4.11.3 
Observe for possible phlebitis at injection site or burning 
pain with infusion. 
8.4.11.4 
Monitor for rare anaphylactoid reaction. 
8.4.11.5 
Administer antiemetics as indicated. 
8.4.12 
References 
1. van Maanen JMS, et al. Mechanism of action of antitumor drug 
etoposide: A review. J Natl Cancer Instit 1988; 80:1526-1533. 
2. Stewart CF, Hampton EM. Stability of cisplatin and etoposide in 
intravenous admixtures. Am J Hosp Pharm 1989; 46:1400-1404. 
3. Seargeant LE, et al. In vitro stability and compatibility of 
daunorubicin, cytarabine and etoposide. Cancer Treat Rep 1987; 
71:1189-1192. 
4. Fleming RA, et al. Etoposide: An update. Clin Pharm 1989; 8:274-
293.  


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5. O'Dwyer PJ, et al. Etoposide, current status of an active 
anticancer drug. N Engl J Med 1985; 312:692-7 
 


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9. 
Statistical Considerations 
9.1 
Study Design and Objectives  
This is a randomized phase II clinical trial comparing etoposide combined with a 
choice of platinum-based therapy (carboplatin or cisplatin; CE) with or without 
nivolumab (CEN) in patients with previously untreated extensive stage SCLC.  
The primary objective of the trial is to determine whether combination therapy 
including nivolumab extends progression-free survival (PFS) for this patient 
population. Secondary objectives include estimation of overall survival, best 
objective response, and toxicity with first line therapy. Correlative endpoints 
include evaluation of PD-L1 expression in archival tumor tissues and other serum 
biomarkers in relation to clinical outcome. 
9.2 
Study Endpoints  
PFS is defined as the time from randomization to documented disease 
progression or death from any cause, whichever occurs first. Patients who have 
not experienced an event of interest by the time of analysis will be censored at 
the date they are last known to be alive and progression-free. Overall survival is 
defined as the time from randomization to death from any cause, and patients 
who are thought to be alive at the time of final analysis will be censored at the 
last date of contact. Best objective response will be evaluated via RECIST1.1 
criteria. Toxicity will be determined using the CTCAE criteria. IHC positivity is 
defined as positive membrane staining in more than 1% of viable tumor cells 
among a minimum of 100 evaluable tumor cells. 
9.3 
Statistical Analysis Plan  
The primary and some secondary analyses will include all eligible and treated 
patients. Exception to this include: analysis of toxicity data, which will include all 
patients who received study drug regardless of eligibility, and analyses of 
response, which will include eligible and treated patients with measurable 
disease.  Time-to-event data, such as PFS and OS, will be estimated using the 
Kaplan-Meier method, and Cox proportional hazards models will be used to 
estimate the treatment hazard ratios. The primary comparison of PFS will use a 
logrank test stratified on the randomization stratification factors with a one-sided 
type I error rate of 10%. Other comparisons of groups will be made using the log 
rank test and Cox modeling. Categorical data, such as response rates (CR+PR) 
and toxicity, will be compared using Fisher’s exact tests with a one-sided type I 
error rate of 10%; multivariable logistic regression modeling will be used to adjust 
for the effect of any covariates that are associated with these categorical 
outcomes. Continuous outcomes will be analyzed using Wilcoxon rank sum test, 
and multivariable linear regression models may be used to adjust for multiple 
associations with outcome.  
Modeling procedures will implement backward selection; variables significant at 
the 0.10 level in the univariate setting will be chosen for inclusion in an initial full 
model, and at each step the least significant variable will be removed from the 
model. Only those covariates with p<0.05 will remain in any final models, unless 
there are factors identified by the study team as crucial to model interpretation.  
Point estimates of all endpoints will be accompanied by the corresponding 95% 
confidence intervals; however, 80% confidence intervals will also be provided for 
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the primary endpoint (PFS) hazard ratio. In the event that there are missing data, 
no imputation of the missing data will be conducted. We will assume that data 
are missing at random and will conduct all analyses as originally planned 
because we do not anticipate an excess of missing data.  
Subset analyses are planned for all stratification factors and all known prognostic 
factors, such as performance status, age, sites of metastases, gender, etc. 
Subset analyses of all variables, including correlatives, are considered to be 
exploratory in nature. 
9.4 
Sample Size Considerations  
The primary comparison will include all eligible and treated patients, of whom 135 
will be accrued and randomized equally, for a total accrual of 67 patients per 
arm. After adjusting for an ineligibility rate of 10%, the total required sample size 
for randomization is 150 patients. Using an overall one-sided 0.10 level log rank 
test, this study will have 88% power to detect a 37.5% reduction in the PFS 
hazard rate of 0.139 to 0.087 based on the estimated accrual and follow-up 
period. Assuming an exponential survival, this corresponds to a 60% 
improvement in the median PFS of 5 months on CE to 8 months on CE plus 
nivolumab. The number of PFS events needed to achieve this power is 113 
events under the alternative hypothesis. 
Correlative Study Statistical Considerations: 
Tumor DNA levels obtained from the serial collection of cfDNA samples will be 
examined to explore whether clinical outcome is associated with fluctuations in 
DNA levels following the administration of therapy. Plasma will be collected from 
30 patients on each arm of the study at baseline and cycle 2 day 1. 
A variety of statistical techniques will be employed for the analyses of cfDNA. 
The rate of change at a particular time point may be compared to baseline 
measures of cfDNA and that measure will be analyzed for association with 
subject demographics and/or disease characteristics using the Kruskal Wallis 
test. Landmark analyses of PFS and OS in which the landmark time is defined by 
the cfDNA measurements at a particular time point, may be used as well. 
Presence or absence of mutations in plasma will be analyzed for association with 
other variables using Fisher’s exact test. To account for the repeated measures 
of plasma over time, we may potentially use these data as time varying 
covariates in multivariable Cox models to study their impact on outcomes like 
PFS and OS. Models would be adjusted for known prognostic factors and 
treatment arm; we will also fit a marker by treatment interaction, though it is 
difficult to power for an interaction test in this setting. If we are to dichotomize 
patients according to the median change in plasma levels from baseline to a 
second timepoint such as end of chemotherapy, with at least 60 patients in the 
analysis we would have 85% power to detect a difference in induction response 
rates of 40% among those with low plasma response and 80% among those with 
high plasma response while testing with a one-sided 0.025 level Fisher’s exact 
test. 
9.5 
Projected Accrual  
As reflected by previous ECOG SCLC studies, it is estimated that patient accrual 
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will be reached within approximately 15 months with a follow up period of 
approximately 10 months, for total study duration of 25 months. 
9.6 
Randomization Scheme  
Randomization to treatment will be determined using permuted blocks within 
strata with dynamic balancing on main ECOG-ACRIN institutions plus affiliates. 
The randomization will be stratified by gender (Male vs. Female) and LDH (WNL 
vs. > upper limit of normal). 
9.7 
Monitoring Plan  
9.7.1 
Interim Analysis: Efficacy 
This study will also be monitored for futility and one interim analysis at 
roughly 50% information is planned. At that time, if the point estimate 
of the PFS hazard ratio is consistent with detriment (HR > 1.0), then 
the data monitoring committee may consider terminating the study 
early for overall lack of treatment difference. 
9.7.2 
Interim analyses of toxicity are performed twice yearly for all ECOG-
ACRIN studies. Reports of these analyses are sent to the ECOG-
ACRIN Principal Investigator or Senior Investigator at the participating 
institutions. Expedited reporting of certain adverse events is required, 
as described in Section 5.2. 
9.8 
Gender and Ethnicity  
Based on previous data from E2511 the anticipated accrual in subgroups defined 
by gender and race is: 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or 
Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
2 
0 
0 
2 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
4 
0 
0 
4 
White 
74 
70 
0 
0 
144 
More Than One Race 
0 
0 
0 
0 
0 
Total 
74 
76 
0 
0 
150 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses.  Therefore, overall accrual to the study will not be extended to meet 
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10. 
Specimen Submissions 
Peripheral blood specimens are to be submitted per patient consent for defined 
laboratory research studies described in Section 11. 
Tumor tissue specimens are to be submitted per patient consent for future undefined 
research studies. 
All specimens must be clearly labeled with the ECOG-ACRIN protocol number 
(EA5161), the patient’s initials and ECOG-ACRIN patient sequence number, the 
collection date, and specimen type 
It is required that all specimens submitted on this trial be entered and tracked via the 
ECOG-ACRIN Sample Tracking System (STS) (Section 10.3). An STS shipping manifest 
form is to be included with every submission. 
10.1 
Submissions to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBFP)  
If you have any questions concerning tumor tissue and peripheral blood 
submissions please contact the ECOG-ACRIN CBPF at (844) 744-2420 or 
eacbpf@mdanderson.org 
10.1.1 
Pathological Material Submissions 
Submit from patients who answer "Yes” to “I agree to provide 
additional samples for research.” 
Representative tumor tissue specimens from the pretreatment 
diagnostic biopsy are to be submitted for undefined research studies 
(per patient consent) within one (1) month of randomization. 
Submitting pathologist and clinical research associate may refer to 
Appendix I which outlines the Pathology Submission Guidelines. 
The tumor tissue specimens are to be labeled with the institution’s 
assigned pathology ID# as well as the information above. 
10.1.1.1 
Required Materials 
Forms: Must be submitted with all pathology submissions. 
STS generated shipping manifest form 
Copy of the institutional pathology report 
Immunological study reports, if available 
Tumor Tissue Submission: 
Formalin-fixed paraffin-embedded (FFPE) tumor tissue 
block 
NOTE: 
If blocks are unavailable for submission, cores 
and slides are to be submitted. All cores and 
slides must be adequately labeled, with slides 
numbered sequentially in the order cut. 
Alternative submission requirements: 
• 
One (1) H&E slide  


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• 
Twenty (20) 5 µm unstained, uncharged, 
air-dried plus slides from the thickest part of 
the tumor 
• 
One (1) or more core punches (minimum of 
4mm diameter). If core punch tool is 
unavailable, request core punch kit from the 
ECOG-ACRIN CBPF (844) 744-2420. 
Adequately label every slide and core 
submitted. 
If these criteria cannot be met, please contact the ECOG-
ACRIN CBPF (eacbpf@mdanderson.org) to obtain 
alternative submission requirements. 
10.1.2 
Peripheral Blood Submissions 
Submit from patients who answer ‘Yes’ to ‘I agree to have my 
samples collected and I agree that my samples and related 
information may be used for the laboratory studies.’ 
Kits for the collection and shipment of the peripheral blood specimens 
are ordered online from Cenetron Central Laboratories. Instructions 
are provided in Appendix VII. Questions regarding kits can be directed 
to projectmanagement@cenetron.com or call the Cenetron Clinical 
Trials Group at (512) 439-2000. Kits must be ordered after the patient 
has been randomized to the trial and will generally arrive within three 
(3) business days from when the order was placed. 
10.1.2.1 
Specimen Preparation Guidelines 
Peripheral blood specimens are to be collected at the 
following time points: 
• 
Prior to Start of Treatment 
• 
Cyce Two (2), Day One (1) 
Streck Cell-Free DNA Tubes 
• 
Draw two (2) 10mL Streck Cell-Free DNA BCT tubes of 
whole blood at each time point. Fill each tube 
completely. 
• 
Ensure at least 10mL of blood is drawn. Avoid low 
volume to minimize agitation during shipping. 
• 
Immediately after collection, gently invert tube 180 
degrees and back 10 times to ensure adequate mixing. 
• 
Maintain blood at room temperature (6°C to 37°C) 
until shipping. Do Not place tubes in refrigerator. 
10.1.3 
Shipping Procedures  
Pathology materials are to be shipped at ambient temperature within 
one (1) month following randomization. 
Peripheral blood specimens are to be shipped at ambient temperature 
Monday-Thursday via overnight courier. 


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Friday shipments are ill advised, similarly shipping before 
holidays is often problematic. The laboratory is closed Saturday, 
Sunday, and holidays.  
Ship using the CBPF’s FedEx account using the FedEx online ship 
manager 
Ship to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3598 
1515 Holcombe Boulevard 
Houston, TX 77030 
Phone: Toll Free (844) 744-2420 (713-745-4440 Local or 
International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
Access to the FedEx shipping account for shipments to the ECOG-
ACRIN CBPF at MD Anderson Cancer Center can only be obtained 
by logging onto fedex.com with an account issued by the ECOG-
ACRIN CBPF. For security reasons, the account number will no 
longer be given out in protocols, over the phone, or via email. If your 
institution needs to have an account created, please contact the 
ECOG-ACRIN CBPF by email at eacbpf@mdanderson.org 
An STS shipping manifest form must be generated and shipped with 
all specimen submissions.  
10.2 
Use of Specimens in Research 
See Section 11 for the description of the laboratory research studies to be 
performed. 
Specimens (tumor tissue and blood leftover after the laboratory research studies) 
from patients who consented to allow their specimens to be used for future 
undefined ECOG-ACRIN approved research studies will be retained in an 
ECOG-ACRIN designated central repository. 
For this trial, specimens will be retained at the ECOG-ACRIN Central 
Biorepository and Pathology Facility.  
Specimens submitted will be processed to maximize their utility for current and 
future research projects. Tissue processing may include, but not limited to, 
extraction of DNA and RNA and construction of tissue microarrays (TMAs). DNA, 
RNA, serum, and plasma (if appropriate) will be isolated from the submitted 
peripheral blood specimens. 
Any residual blocks will be available for purposes of individual patient 
management on specific written request. 
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future research study. Pathology 
materials may be retained for documentation purposes or returned to the 
institution.  All other specimens will be destroyed per guidelines of the respective 
repository. 
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10.3 
ECOG-ACRIN Sample Tracking System 
It is required that all specimens submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the specimens 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software. A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html 
Please take a moment to familiarize yourself with the software prior to using the 
system. 
An STS generated shipping manifest form should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
Study Specific Notes 
Generic Specimen Submission Form (#2981v3) will be required only if STS is 
unavailable at time of specimen submission. Notify the laboratory of the shipment 
by faxing a copy of the completed form to the laboratory. 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
10.4 
Sample Inventory Submission Guidelines  
Inventories of all specimens submitted will be tracked via the ECOG-ACRIN STS 
and receipt and usability verified by the receiving laboratory. Inventories of 
specimens forwarded and utilized for the approved laboratory research studies 
will be submitted by the investigating laboratories to the ECOG-ACRIN 
Operations Office - Boston on a monthly basis in an electronic format defined by 
the ECOG-ACRIN Operations Office - Boston. 


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11. 
Laboratory Research Studies 
Results of these studies are for the purposes of the trial only and will not be returned to 
the institution or reported to the patient. 
11.1 
Circulating Tumor DNA Qualification and Sequencing  
We will collect peripheral blood at baseline and cycle two, day one. Circulating 
tumor DNA will be measured quantitatively and total exonic mutation burden will 
be assessed with whole exome sequencing using the Guardant360 platform that 
will inform on allelic frequency of mutations, mutational burden, and specific 
targeted exome sequencing and amplification of relevant caner related genes. 
Baseline nonsynonymous mutation burden, neo-antigen burden and DNA repair 
pathway mutations will be correlated with response to immunotherapy. 
11.2 
Lab Data Transfer Guidelines 
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office - Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the Investigator. 
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12. 
Electronic Data Capture 
Please refer to the EA5161 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data.  Reports are due January 31, April 30, 
July 31, and October 31.  Instructions for submitting data using the CDUS can be found 
on the CTEP website. 
(http://ctep.cancer.gov/reporting/cdus.html). 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
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11. Thompson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor 
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24. Brahmer JR, Drake CJ, Wollner I, et al. Phase I Study of Single-Agent Anti–
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25. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
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26. Topalian SL, Sznol M, Brahmer JR, et al. Nivolumab (anti-PD-1; BMS-936558; ONO-
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27. Rizvi NA, Antonia SJ, Chow LQM, et al. A phase I study of nivolumab (anti-PD-1; 
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in chemotherapy-naive non-small cell lung cancer (NSCLC) patients (pts). J Clin 
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Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015;373(2):123-35. 
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Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373(17):1627-39. 
30. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus 
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31. Jure-Kunkel M, Masters G, Girit E, et al. Synergy between chemotherapeutic agents 
and CTLA-4 blockade in preclinical tumor models. Cancer Immunol Immunother 
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32. Lee F, Jure-Kunkel MN, Salvati ME. Synergistic activity of ixabepilone plus other 
anticancer agents: preclinical and clinical evidence. Ther Adv Med Oncol  
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33. Ott PA, Fernandez MEE, Hiret S, et al. Pembrolizumab (MK-3475) in patients with 
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KEYNOTE-028.  ASCO Annual Meeting2015. 
34. Ott P, Felip E, Hiret S, et al. Pembrolizumab in Patients with Extensive-Stage Small 
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35. Reck M, Luft A, Szczesna A, et al. Phase III Randomized Trial of Ipilimumab Plus 
Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-
Stage Small-Cell Lung Cancer. J Clin Oncol 2016. 
36. Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and 
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37. Apetoh L, Ladoire S, Coukos G, Ghiringhelli F. Combining immunotherapy and 
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38. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or 
without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a 
randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 
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39. Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional 
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40. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunological Effects of 
Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell 
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41. Zitvogel L, Apetoh L, Ghiringhelli F, André F, Tesniere A, Kroemer G. The anticancer 
immune response: indispensable for therapeutic success? J Clin Invest 
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42. Varghese AM, Zakowski MF, Yu HA, et al. Small-cell lung cancers in patients who 
never smoked cigarettes. J Thorac Oncol 2014;9(6):892-6. 


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43. Ettinger DS, Aisner J. Changing face of small-cell lung cancer: real and artifact. J 
Clin Oncol 2006;24(28):4526-7. 
44. Miller CW, Simon K, Aslo A, et al. p53 mutations in human lung tumors. Cancer Res 
1992;52(7):1695-8. 
45. D'Amico D, Carbone D, Mitsudomi T, et al. High frequency of somatically acquired 
p53 mutations in small-cell lung cancer cell lines and tumors. Oncogene 
1992;7(2):339-46. 
46. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify 
key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44(10):1104-
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47. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair 
Deficiency. N Engl J Med 2015;372(26):2509-20. 
48. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 
2015;348(6230):124-8. 
49. Diggs LP, Hsueh EC. Utility of PD-L1 immunohistochemistry assays for predicting 
PD-1/PD-L1 inhibitor response. Biomark Res 2017;5:12. 
50. Adjei A, Hidalgo M. Intracellular Signal Transduction Pathway Proteins As Targets 
for Cancer Therapy. J Clin Oncol 2005;23:5386-403. 
51. Goldberg AL, Akopian TN, Kisselev AF, Lee DH, Rohrwild M. New insights into the 
mechanisms and importance of the proteasome in intracellular protein degradation. 
Biol Chem 1997;378:131-40. 
52. Ciechanover A, Orian A, Schwartz AL. Ubiquitin-mediated proteolysis: Biological 
regulation via destruction. Bioessays 2000;22:442-51. 
53. Hershko A. Roles of ubiquitin -mediated proteolysis in cell cycle control. Curr Opin 
Struct Bio 1997;9:788-99. 
54. Zwickl P, Baumeister W, Steven A. Dis-assembly lines: The proteosome and related 
ATPase-assisted proteases. Curr Opin Struct Bio 2000;10:242-50. 
55. Oikawa T, Sasaki T, Nakamura M, et al. The proteasome is involved in 
angiogenesis. Biochem Biophys Res Commun 1998;246:243-8. 
56. Antonia, S. J., et al. (2017). "Impact of Tumor Mutation Burden on the Efficacy of 
Nivolumab or Nivolumab + Ipilimumab in Small Cell Lung Cancer: An Exploratory 
Analysis of CheckMate 032." Presented 2017 World Conference on Lung Cancer; 
Yokohama, Japan. Abstract 11063 
 


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Cancer (ED-SCLC) 
Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. ECOG-ACRIN Generic Specimen Submission Form (#2981) 


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Guidelines for Submission of Pathology Materials 
The following pathology materials are to be submitted within one (1) month of randomization:  
1. Pathology Submissions: 
• 
Formalin-fixed paraffin-embedded (FFPE) tumor tissue block from the pretreatment 
diagnostic biopsy 
NOTE: If blocks are unavailable for submission, cores and slides are to be submitted. All 
cores and slides must be adequately labeled, with slides numbered sequentially 
in the order cut. Alternative submission requirements: 
• 
One (1) H&E slide  
• 
Twenty (20) 5 µm unstained, uncharged air-dried plus slides from the thickest 
part of the tumor 
• 
One (1) or more core punches (minimum of 4mm diameter). If core punch 
tool is unavailable, request core punch kit from the ECOG-ACRIN CBPF 
(844) 744-2420 
If these criteria cannot be met, please contact the ECOG-ACRIN CBPF 
(eacbpf@mdanderson.org) to obtain alternative submission requirements. 
2. Forms and Reports: 
NOTE: Adequate patient identifying information must be included with every submission. 
It is strongly recommended that full patient names be provided. The information 
will be used only to identify patient materials, and will help to expedite any 
required communications with the institution (including pathologists). 
The following items are to be included with the pathology materials: 
• 
Institutional Pathology Report 
• 
ECOG-ACRIN Generic Specimen Submission Form (#2981) [if STS is unavailable] 
• 
Sample Tracking System (STS) Shipping Manifest Form  
• 
Immunological study reports, if available 
3. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3598 
1515 Holcombe Boulevard 
Houston, TX 77030 
Phone: Toll Free (844) 744-2420 (713-745-4440 Local or International Sites) 
Fax: (713) 563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact 
the Pathology Coordinator at the ECOG-ACRIN Central Biorepository and Pathology 
Facility by telephone: (844) 744-2420 or email: eacbpf@mdanderson.org 


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MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for EA5161: Randomized Phase 
II Clinical Trial of Cisplatin/Carboplatin and Etoposide (CE) alone or in 
Combination with Nivolumab as Frontline Therapy for Extensive Stage 
Small Cell Lung Cancer (ED-SCLC) 
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by _____________________________ (ECOG-ACRIN Investigator). This 
protocol requires the submission of pathology materials for future undefined laboratory 
research studies.  
Keep a copy of the submission for your records and return any relevant completed 
forms, the surgical pathology report(s), the slides and/or blocks and any other required 
material to the Clinical Research Associate (CRA). The CRA will forward all required 
pathology materials to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF). 
Pathology materials submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future research studies per patient consent. Paraffin blocks will be 
returned upon request for purposes of patient management. 
If you have any questions regarding this request, please contact the ECOG-ACRIN 
Central Biorepository and Pathology Facility at (1-844-744-2420 (713-745-4440 Local or 
International Sites) or email: eacbpf@mdanderson.org 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
Thank you. 
 
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ECOG-ACRIN Generic Specimen Submission Form  
Form No. 2981v3 
Page 1 of 1 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per 
patient, per time- point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all 
specimens into STS once the system is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 Courier Tracking Number   
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or  
Sample ID 
Anatomic  
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma 
Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % 
Lymphocytes % 
 
 
 
 
Study Drug 
Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
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Cancer (ED-SCLC) 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we hope to improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again for being an 
important part of this study. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 


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Cancer (ED-SCLC) 
Appendix III 
 
Nivolumab (BMS-936558) TOXICITY MANAGEMENT ALGORITHMS 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with Study Chair/Medical Oncologist. The guidance applies to all immune-oncology 
agents and regimens.  
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.  
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids.  
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.  
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used.  
ALGORITHMS FOR ENDOCRINOPATHY, GASTROINTESTINAL, HEPATIC, 
NEUROLOGICAL, PULMONARY, RENAL, AND SKIN ADVERSE EVENTS 


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Appendix IV 
 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
investigational Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 
and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all 
Clinical Data and Results and Raw Data will be collected , used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 


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4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator’s 
confidential and proprietary data, in addition to Collaborator(s)’s intellectual property rights, 
are protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) 
days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must also 
be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: 
ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/ proprietary information. 
 


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Appendix V 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 


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Appendix VI 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy 
test regardless of age or disease state) of a female patient while she is on nivolumab, or 
within 28 days of the female patient’s last dose of nivolumab must be reported in an 
expeditious manner. The outcome of the pregnancy and neonatal status must also be 
reported. 
How should the pregnancy be reported? 
For this study, a pregnancy, suspected pregnancy (including a positive or inconclusive 
pregnancy test) must be initially reported on the Adverse Event Form or Late Adverse Event 
Form in the appropriate Treatment Cycle or Post Registration folder in Medidata Rave.  
Once the adverse event is entered into Rave, the Rules Engine on the Expedited Reporting 
Evaluation Form will confirm whether or not the adverse event requires expedited reporting.  
The CTEP-AERS report must then be initiated directly from the Expedited Reporting 
Evaluation Form in Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-
AERS website 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy 
test need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, 
followed by a complete expedited CTEP-AERs report within 5 calendar days of the initial 24-
hour report. 
What other information do I need in order to complete the CTEP-AERs report for a 
pregnancy? 
• 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium 
and perinatal conditions – Other (pregnancy)” under the System Organ Class (SOC) 
“Pregnancy, puerperium and perinatal conditions” 
• 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
• 
The start date of the pregnancy should be reported as the calculated date of conception.   
• 
The potential risk of exposure of the fetus to the investigational agent(s) or 
chemotherapy agent(s) should be documented in the “Description of Event” section of 
the CTEP-AERs report.  
What else do I need to know when a pregnancy occurs to a patient? 
• 
The Investigator must follow the female patient until completion of the pregnancy and 
must report the outcome of the pregnancy and neonatal status in CTEP-AERs accessed 
via Medidata Rave. 
• 
The decision on whether an individual female patient can continue protocol treatment will 
be made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Office – Boston.  Please contact the ECOG-ACRIN Operations Office – 
Boston to ask for a conference call to be set up with the appropriate individuals.   
Rev. Add1 
Rev. Add2 
Rev. Add4 


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• 
It is recommended the female subject be referred to an obstetrician-gynecologist, 
preferably one experienced in reproductive toxicity for further evaluation and counseling.  
How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERs 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself.  
However, if the outcome of the pregnancy occurred on a subsequent cycle, a new CTEP-
AERs report should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions (formerly referred to as disabilities), congenital anomalies, or birth defects.  For 
assistance in recording the grade or category of these events, please contact the CTEP 
AEMD Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed 
on a case by case basis. 
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.” 
For this study, it must initially be reported on the Adverse Event Form or Late Adverse Event 
Form in the appropriate Treatment Cycle or Post Registration folder in Medidata Rave. Once 
the adverse event is entered into Rave, the Rules Engine on the Expedited Reporting 
Evaluation Form will confirm whether or not the adverse event requires expedited reporting. 
The CTEP-AERS report must then be initiated directly from the Expedited Reporting 
Evaluation Form in Medidata Rave. Do not initiate the CTEP-AERS report via the CTEP-
AERS website. The pregnancy loss must be reported as a Grade 4 “Pregnancy loss” under 
the System Organ Class (SOC) “Pregnancy, puerperium and perinatal conditions”. 
A fetal death should NOT be reported as a Grade 5 event as currently CTEP-AERs 
recognizes this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A newborn death occurring during the first 28 
days after birth” that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention.  However, for this protocol, any neonatal death that 
occurs within 28 days of birth, without regard to causality, AND any infant death after 28 
days that is suspected of being related to the in utero exposure to nivolumab must be 
initially reported on the Adverse Event Form or Late Adverse Event Form in the appropriate 
Treatment Cycle or Post Registration folder in Medidata Rave. Once the event is entered 
into Rave, the Rules engine on the Expedited Reporting Evaluation Form will confirm 
whether or not the event requires expedited reporting. The CTEP-AERS report must then be 
initiated directly from the Expedited Reporting Evaluation Form in Medidata Rave. Do not 
initiate the CTEP-AERS report via the CTEP-AERS website. The neonatal death must be 
reported as a Grade 4 “Death neonatal” under the System Organ Class (SOC) “General 
disorder and administration site conditions”. 
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERs 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERs reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any 


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additional medical information to CTEP (301-897-7404). This form is available on CTEP's 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/PregnancyReport
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Appendix VII 
 
EA5161 Collection and Shipping Kit Order Instructions 
Specimen Collection/Shipping Kits are being provided by CENETRON CENTRAL 
LABORATORIES and are to be ordered ONLINE. 
Starter kits are not available. Kit requests are to be made AFTER patient randomization. 
Questions regarding kits can be directed to projectmanagement@cenetron.com or call 
the Cenetron Clinical Trials Group at (512) 439-2000.  
Ordering Process: 
• 
At time of patient randomization, provide the contact for kit ordering in OPEN 
• 
Following randomization of the patient to the trial, go to the website 
www.cenetron.com and click on the ‘Order Kits’ button at the top right. It is 
recommended that kits be ordered same day as patient randomization. 
• 
The order form is not study specific and can be used for any study. Complete the 
online form as follows: 
• 
Sponsor (REQUIRED): ECOG-ACRIN 
• 
Contact Name (REQUIRED): Name of the institution kit contact. Should match 
the name of the individual provided in OPEN as the kit contact 
• 
Protocol Number (REQUIRED): EA5161 
• 
Phone Number (REQUIRED): Phone number of the kit contact. Please ensure 
that this is a number that can be reached from an external caller 
• 
Site Number (REQUIRED): Institution NCI Site ID 
• 
FAX Number: Fax number of the kit contact 
• 
Investigator: Last name of the kit contact is adequate 
• 
Email (REQUIRED): Email of the institution kit contact. Must be entered twice to 
confirm 
• 
Date Supplies Needed (REQUIRED): Add three (3) business days or more to 
order date. (E.g. if ordering on 2/5/2016, indicate 2/10/2016 to accommodate the 
weekend. Reminder that holidays must also be considered in this timeline) 
• 
KIT NAME (REQUIRED): EA5161 Collection Kit 
• 
Quantity: 1 
• 
Comments: Provide EA5161 Patient Case ID# and full shipping address 
• 
‘Patient Case ID =’ ##### 
• 
‘Ship Kit to’ name of the individual to whom the kit is being shipped. (May be 
different than the kit contact provided above) 
• 
Full street address, town, state and zip code 
• 
Answer the security question 
Please complete this form correctly, including the valid ECOG-ACRIN patient case 
number and complete shipping address. If information is missing the kit 
processing will be delayed.