A Phase II Biomarker Trial of Avadomide (CC-122) in Combination With Nivolumab in Advanced Melanoma
Phase: PHASE2
Conditions: Melanoma
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

 
 
 
A Phase II Biomarker Trial of Avadomide (CC-122) in Combination with 
Nivolumab in Advanced Melanoma 
 
NCT03834623 
 
Version 3.7 
November 22, 2019 

 
 
 
 
 
A Phase II Biomarker Trial of Avadomide (CC-122) in 
Combination with Nivolumab in Advanced 
Melanoma 
 
Protocol Identifying Number: 
 
 Principal Investigator: 
  
Statistician: 
 
IND/IDE Sponsor: Moffitt Cancer Center 
Funded by: Celgene Corporation   
 
 

 
 
TABLE OF CONTENTS 
  
List of Abbreviations ---------------------------------------------------------------------------------------------------------- 
5 
Statement of Compliance --------------------------------------------------------------------------------------------------- 
6 
Protocol Summary ------------------------------------------------------------------------------------------------------------- 
7 
Schematic of Study Design -------------------------------------------------------------------------------------------------- 
8 
1 Key Roles ------------------------------------------------------------------------------------------------------------------------ 
9 
2 Introduction: Background Information and Scientific Rationale ------------------------------------------- 
9 
     2.1 Background Information ------------------------------------------------------------------------------------------- 
9 
     2.2 Rationale ----------------------------------------------------------------------------------------------------------------- 
10 
     2.3 CC-122: Pre-Clinical and Clinical Studies --------------------------------------------------------------------- 
11 
     2.4 Rationale for CC-122 Plus Nivolumab in Melanoma ----------------------------------------------------- 
18 
3 Objectives and Purpose --------------------------------------------------------------------------------------------------- 
22 
4 Study Design and Endpoints --------------------------------------------------------------------------------------------- 
22 
     4.1 Description of the Study Design --------------------------------------------------------------------------------- 
22 
     4.2 Study Endpoints ------------------------------------------------------------------------------------------------------- 
22 
5 Study Enrollment and Withdrawal ------------------------------------------------------------------------------------ 
23 
     5.1 Participant Inclusion Criteria ------------------------------------------------------------------------------------- 
23 
     5.2 Participant Exclusion Criteria ------------------------------------------------------------------------------------- 
23 
     5.3 Strategies for Recruitment and Retention ------------------------------------------------------------------- 
24 
     5.4 Participant Withdrawal or Termination ---------------------------------------------------------------------- 
25 
            5.4.1 Reasons for Withdrawal or Termination ------------------------------------------------------------- 
25 
     5.5 Permanent Termination or Suspension of Study ---------------------------------------------------------- 
25 
6 Study Agent -------------------------------------------------------------------------------------------------------------------- 
26 
     6.1 Study Agent(s) and Control Description ---------------------------------------------------------------------- 
26 
            6.1.1 Dosing and Administration -------------------------------------------------------------------------------- 
26 
            6.1.2 Duration of Therapy ----------------------------------------------------------------------------------------- 
26 
            6.1.3 Dose Modifications ------------------------------------------------------------------------------------------ 
27 
     6.2 Study Agent Accountability Procedures ---------------------------------------------------------------------- 
34 
7 Study Procedures and Schedule ---------------------------------------------------------------------------------------- 
34 
     7.1 Study Procedures/Evaluations ----------------------------------------------------------------------------------- 
34 
     7.2 Schedule of Events Table ------------------------------------------------------------------------------------------- 
33 
     7.3 Concomitant Medications, Treatments, and Procedures ---------------------------------------------- 
38 
     7.4 Justification for Sensitive Procedures ------------------------------------------------------------------------- 
38 
     7.5 Precautionary Medications, Treatments, and Procedures -------------------------------------------- 
38 
     7.6 Prohibited Medications, Treatments, and Procedures -------------------------------------------------- 
39 
     7.7 Prophylactic Medications, Treatments, and Procedures ----------------------------------------------- 
39 
8 Assessment of Safety ------------------------------------------------------------------------------------------------------- 
39 
     8.1 Specification of Safety Parameters ----------------------------------------------------------------------------- 
39 
            8.1.1 Definition of Adverse Events (AE) ---------------------------------------------------------------------- 
39 
            8.1.2 Definition of Serious Adverse Events (SAE) --------------------------------------------------------- 
39 
            8.1.3 Definition of Unanticipated Problems ---------------------------------------------------------------- 
40 
     8.2 Classification of an Adverse Event ------------------------------------------------------------------------------ 
34 
            8.2.1 Severity of Event ---------------------------------------------------------------------------------------------- 
40 
            8.2.2 Relationship to Study Agent ------------------------------------------------------------------------------ 
40 
            8.2.3 Expectedness --------------------------------------------------------------------------------------------------- 
41 
     8.3 Time Period and Frequency for Event Assessment and Follow-Up --------------------------------- 
41 
     8.4 Reporting Procedures ----------------------------------------------------------------------------------------------- 
42 

 
 
TABLE OF CONTENTS 
 
 
 
 
 
            8.4.1 Adverse Event Reporting ---------------------------------------------------------------------------------- 
42 
            8.4.2 Serious Adverse Event Reporting ----------------------------------------------------------------------- 
42 
            8.4.3 Unanticipated Problem Reporting --------------------------------------------------------------------- 
42 
            8.4.4 Events of Special Interest ---------------------------------------------------------------------------------- 
43 
            8.4.5 Reporting of Pregnancy ------------------------------------------------------------------------------------ 
43 
  9 Clinical Monitoring -------------------------------------------------------------------------------------------------------- 
44 
10 Statistical Consideration ------------------------------------------------------------------------------------------------- 44 
     10.1 Statistical and Analytical Plans --------------------------------------------------------------------------------- 
44 
     10.2 Analysis of the Secondary Endpoints (S) -------------------------------------------------------------------- 
44 
     10.3 Efficacy Analysis ----------------------------------------------------------------------------------------------------- 
45 
     10.4 Planned Interim Analyses ---------------------------------------------------------------------------------------- 
46 
            10.4.1 Exploratory Analyses -------------------------------------------------------------------------------------- 
46 
     10.5 Sample Size ------------------------------------------------------------------------------------------------------------ 
48 
 
 
11 Source Documents and Access to Source Data/Documents ----------------------------------------------- 
48 
12 Quality Assurance and Quality Control ---------------------------------------------------------------------------- 
48 
13 Ethics/Protection of Human Subjects ------------------------------------------------------------------------------ 
49 
     13.1 Ethical Standard ----------------------------------------------------------------------------------------------------- 
49 
     13.2 Institutional Review Board -------------------------------------------------------------------------------------- 
49 
     13.3 Informed Consent Process --------------------------------------------------------------------------------------- 
49 
            13.3.1 Consent/Assent and Other Informational Documents Provided to Participants ---- 
49 
            13.3.2 Consent Procedures and Documentation --------------------------------------------------------- 
49 
     13.4 Participant and Data Confidentiality ------------------------------------------------------------------------- 
50 
            13.4.1 Research Use of Stored Human Samples, Specimens or Data ----------------------------- 
50 
     13.5 Future Use of Stored Specimens ------------------------------------------------------------------------------ 
50 
14 Data Handling and Record Keeping --------------------------------------------------------------------------------- 
51 
     14.1 Data Collection and Management Responsibilities ----------------------------------------------------- 
51 
     14.2 Study Records Retention ----------------------------------------------------------------------------------------- 
52 
     14.3 Protocol Deviations ------------------------------------------------------------------------------------------------ 
52 
     14.4 Publication and Data Sharing Policy -------------------------------------------------------------------------- 
53 
15 Study Administration ----------------------------------------------------------------------------------------------------- 
53 
     15.1 Study Leadership ---------------------------------------------------------------------------------------------------- 
53 
16 Conflict of Interest Policy ----------------------------------------------------------------------------------------------- 
54 
17 Literature References ---------------------------------------------------------------------------------------------------- 
55 
Appendix A 
58 
Appendix B 
59 
Appendix C 
60 
Appendix D 
61 

LIST OF ABBREVIATIONS 
5 
 
 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Science 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CMS 
Centers for Medicare and Medicaid Services 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICH E6 
International Conference on Harmonisation Guidance for Industry, Good Clinical Practice: 
Consolidated Guidance 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Investigational Review Board 
ISO 
International Organization for Standardization 
LSMEANS 
Least Squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute & Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 

6 
STATEMENT OF COMPLIANCE 
 
 
 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), and the <NIH IC> Terms of Award. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the sponsor and documented approval from the Institutional Review Board, except 
where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed of their 
obligation to meet the above commitments. 
 
 
Principal Investigator: 
  
 
 
Print/Type Name 
 
 
Signed: 
   
 Date: 
 

PROTOCOL SUMMARY 
7 
Avadomide plus Nivolumab 
November 22, 2019 
 
 
 
 
A Phase II Biomarker Trial of CC-122 in Combination with Nivolumab in Advanced Melanoma 
 
Précis: 
Preliminary pre-clinical data suggest that the novel immunomodulatory agent CC-122 can restore metabolic 
function of T-cells and will increase immunosurveillance in melanoma. The synergy of the combination of 
CC-122 and the anti-PD1 agent nivolumab will enhance reversal of T-cell exhaustion and improve anti-tumor 
immunity in patients with advanced melanoma.  Our goal is to link pharmacodynamic markers to immune 
mechanism of action and efficacy.  In addition, we seek to define sub-populations that may be enriched for 
response to CC-122 plus nivolumab in melanoma.    
 
Objectives: 
Primary: To determine the response rate to combination CC-122 plus nivolumab in both anti-PD1 naïve and 
anti-PD1 refractory advanced melanoma. 
Secondary: (1) To assess the toxicity of this combination. (2) To determine the progression-free survival 
and overall survival with this combination. (3) Examine blood and tissue-based biomarkers that will further 
our understanding of the complex interplay between the metabolic needs/changes in the tumor and the 
immune microenvironment. 
 
 
Population: 
Adults with advanced melanoma who are appropriate for treatment with anti-PD1 therapy or who are 
appropriate to resume anti-PD1 therapy after prior progression on anti-PD1 therapy with the goal of 
reversing resistance. 
 
      
Number of Sites 
 
This study will be conducted at the Moffitt Cancer Center 
      
Study Agent(s) and Administration: 
Oral CC-122 at 2mg daily for 5 consecutive days every 7 days, with intravenous nivolumab (240mg) in days 
1 and 15 within a 28-day cycle.   
 
 
Study Duration:  
Subjects will receive up to 52 weeks of therapy.  Decision to continue beyond this will be made based on 
response at that time. Based on planned futility analyses and enrollment across cohorts, the total number of 
subjects is anticipated to be 44-66.  
 
 
Participant Duration: 
Participants to be followed for up to 24 months following completion of study therapy. 
 
 

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Version 3.7
Nov 22, 2019
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cycle.  While regulatory approval for dosing at 480mg IV every 28 days was also recently obtained, we will 
maintain the approved biweekly dosing schedule in this trial based on the safety data from Study CC-122-
HC-002 in hepatocellular carcinoma.  Dose administration of +/- 2 days is permissible and will not constitute 
a deviation. There will be no dose adjustments for nivolumab.  Please refer to the OPDIVO Package Insert 
(November-2018) for full prescribing information.  
 
 
 
 
In the absence of progression or intolerable toxicity, therapy will continue up to a maximum of 52 weeks (13 
cycles).  For those patients who demonstrate continued improvement in radiographic response at scheduled 
restaging (anticipated around week 48) performed prior to reaching this landmark will be given the option of 
continuation of therapy.  This provision is based on the recently reported analysis of advanced melanoma 
patients who achieved a complete response to pembrolizumab on KEYNOTE-001 where the median time to 
achieve CR was 12 months (range, 3-36).44 For these subjects, therapy will continue for 1 cycle beyond CR 
(should they achieve this) or until 2 consecutive staging studies demonstrate a plateau in response.  For 
those patients achieving CR as best response prior to 52 weeks, therapy can be discontinued provided they 
have completed at least 26 weeks of treatment. 
 
If either CC-122 or nivolumab require discontinuation due to toxicity attributed exclusively to that agent 
(e.g., neutropenia secondary to CC-122), the second drug can continue for the duration as outlined above. 
 
 
 
Dose delay criteria apply for all drug-related adverse events regardless of whether or not the event is 
attributed to nivolumab, CC-122, or both unless it is explicitly clear that the toxicity is exclusive to one 
drug alone. All study drugs must be delayed until treatment can resume, unless in the judgement of the 
clinical investigator (with discussion with the PI), there is compelling evidence to continue one of the agents 
without the other. 
 
Causality should be assessed and provided individually for each study drug (CC-122 and nivolumab) for 
every AE/SAE based on currently available information.  Causality is to be reassessed and provided as 
additional information becomes available. 
 
6.1.3.1 
CC-122 Dose Delay and/or Modifications: 
 
The criteria for dose reduction and/or interruption for non-hematological toxicities attributed to CC-122 
are listed in the following table.  Chronic Grade 2 toxicity attributed to CC-122 may warrant dose reduction 
of CC-122. If necessary, the PI may reach out to the appropriate medical personnel at Celgene to discuss 
this further. 
  
Toxicity 
Action 
Any Grade 4 including LFT elevation 
(exceptions include lymphopenia, 
asymptomatic amylase and lipase) 
• 
Discontinue CC-122 
Grade 3 or 4 clinical liver failure 
• 
Discontinue CC-122 
6.1.2 DURATION OF THERAPY 
6.1.3 DOSE MODIFICATIONS 

CC-122 + Nivolumab
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If recurrence of Grade 3 event after 
dose-reduction 
• 
Reduce dose to the next lower dose level; if available –
If none available, CC-122 should be discontinued. 
If recurrence of Grade 4 event after 
dose reduction 
• 
Discontinue CC-122 
Any non-hematological toxicity 
requiring interruption for > 4 
weeks  
• 
Discontinue CC-122 
Troponin-T/I > ULN with 
associated significant elevation in 
BNP or with cardiac symptoms or 
significant changes in ECG or 
LVEF1 
• 
Hold CC-122 
• 
Consider cardiology evaluation 
• 
Follow troponin-T/I, BNP, and ECG at least every 7 days 
• 
If troponin-T/I returns to normal levels in < 7 days 
and there are no other significant cardiac findings, 
resume CC-122 at the next lower dose level 
• 
If troponin T/I level elevation persists > 7 days, or 
recurs upon re-challenge, discontinue CC-122 
Rash ≥ Grade 3 
 
  
• 
If Grade 3 hold CC-122 until recovery to grade ≤ 1; if AE 
resolution to Grade ≤ 1 occurs ≤ 8 days, reintroduce CC-
122 at the same dose level 
• 
If AE resolution to Grade ≤ 2 or > 7 days, reintroduce 
CC122 on lower level, if available 
• 
Discontinue CC-122 for 2nd occurrence of ≥ Grade 3 
rash 
• 
For desquamating (blistering) Grade 3 or any Grade 4 
rash, discontinue CC-122 
• 
For maculopapular, aceiform, or pustular rashes lasting 
≤ 7 days medical management is warranted including topical 
corticosteroids, anti-pruritic agents (if indicated).  If this 
does not improve, oral steroids may be used.  It is likely 
that this intervention will be utilized given the overlap of 
this toxicity with nivolumab (see appendix D) 
Peripheral Neuropathy 
(neuropathies which begin or 
worsen while on study) 
≥ Grade 3 
• 
Hold CC-122 
• 
When the toxicity resolves to ≤ Grade 2 or to baseline, 
restart CC-122 at the next lower dose level 
Allergic Reaction or 
Hypersensitivity 
≥ Grade 3 
• 
Discontinue CC-122 

CC-122 + Nivolumab
Version 3.7
Nov 22, 2019
29 
 
 
Venous Thrombosis / Embolism 
(VTE) 
≥ Grade 2; anticoagulation 
indicated 
• 
Hold CC-122 and start anticoagulation; restart CC-122 
(maintain dose level) once therapeutic anticoagulation 
achieved AND it is clinically appropriate to resume.2 
Pneumonitis / Interstitial Lung 
Disease3 
 
• 
Grade 1: continue CC-122 
• 
Grade 2: interrupt CC-122; can resume at one dose 
level lower once < grade 1 AND steroid taper 
completed.  If recurrent Grade 2 toxicity on re-
challenge, permanently discontinue CC-122 
• 
> Grade 3: permanently discontinue CC-122  
Other Grade 34 
• 
Hold one or both study drugs (based on 
attribution) 
• 
When the toxicity resolves to < Grade 2, restart CC-
122 at the next lower dose level 
       
 
1. For BNP, greater than 20% increase from baseline value is considered significant. Any new ST segment 
or T wave changes, new bundle branch block, or new atrial or ventricular arrhythmia while on 
treatment with CC-122 is considered clinically significant.  An absolute decrease in LVEF of > 10% from 
baseline (even if asymptomatic), or a decrease of estimated LVEF to < 45% would mandate holding 
further CC-122 for up to 4 weeks.  If improved LVEF (repeated 2-4 weeks after holding drug) to 
baseline value, resume CC-122 at next lower dose level, if available.  If the decrease in LVEF is > 20% 
(absolute decrease) from baseline or there is any evidence of symptomatic congestive heart failure, 
CC-122 will be permanently discontinued. 
2. There are no prospective data available on the need to interrupt immunomodulatory agents like 
thalidomide, lenalidomide, CC-122 at the time of diagnosis of the VTE event.  However as these drugs 
are prothrombotic, it is reasonable to hold CC-122 till therapeutic anticoagulation is achieved.  For 
anticoagulants that do not require monitoring (such as low molecular weight heparin), CC-122 will be 
restarted 7 days after the initial hold.  For drugs requiring monitoring (unfractionated heparin, 
warfarin), CC-122 will be resumed once the aPTT or INR are in the recommended therapeutic range for 
that individual agent, but no sooner than 7 days from the hold.  Prior to resuming CC-122, clinically 
significant symptoms or signs related to VTE (e.g., chest pain, dyspnea, etc.) should have resolved.  
Persistence of leg/arm swelling (in case of DVT) would not be a contra-indication to resume therapy.       
3. As pneumonitis is an expected toxicity with nivolumab, it may be difficult to ascertain the causality to 
one specific drug in this combination.  The management algorithm to be followed based on the grade 
of toxicity is outlined in Appendix D. 
4. Exceptions to this include lymphopenia, asymptomatic elevation in amylase or lipase, and isolated 
electrolyte imbalances/abnormalities that are not associated with clinical sequelae.  Isolated 
electrolyte aberrations (e.g., sodium, potassium, magnesium, etc.) may require appropriate exogenous 
supplementation, but repeat levels must meet criteria outlined in the table to resume therapy. 
 
 
 
 
 

C C -1 2 2 + Niv ol u m a b  
V ersi o n 3. 7  
N o v 2 2 , 2 0 1 9 
3 0  
 
 
 
 
 
 
 
 
 
G ui d eli n es f or h e m at ol o gic al t o xicit y attri b ut e d t o C C -1 2 2 : 
 
 
T oxicit y  
Acti o n  
Gr a d e 2 t hr o m b ocyt o p e ni a 
•  
N o  acti o n  
Gr a d e  3 t hr o m b ocyt o p e ni a 
•  
H ol d u ntil r es ol uti o n t o Gr a d e  1 
•  
F oll o w C B C at l e ast ev ery 7 d ays  
•  
If r es ol uti o n t o Gr a d e 1 occ urs  ≤ 8 d ays, r ei ntr o d uc e  
C C -1 2 2  at  t h e s a m e d os e  l ev el 
•  
If A E r es ol uti o n occ urs > 8 d ays, or ev e nt occ urs  
wit hi n t h e s a m e cycl e, r ei ntr o d uc e  C C -1 2 2  at  t h e 
l o w er d os e l ev el, if av ail a bl e 
Gr a d e  4 t hr o m b ocyt o p e ni a 
•  
H ol d C C -1 2 2 u ntil r ec ov ery t o Gr a d e  1 
•  
F oll o w C B C at l e ast ev ery 7 d ays  
•  
R ei ntr o d uc e C C -1 2 2  at t h e  l o w er d os e l ev el, if 
av ail a bl e  
Gr a d e  3 n e utr o p e ni a  
•  
H ol d u ntil r es ol uti o n t o Gr a d e  ≤ 1 
•  
F oll o w C B C at l e ast ev ery 7 d ays  
•  
If A E r es ol uti o n t o Gr a d e  ≤ 1 occ urs  ≤ 8 d a ys,  
r ei ntr o d uc e C C -1 2 2  at  t h e s a m e d os e  l ev el 
•  
If A E r es ol uti o n occ urs > 8 d ays, or ev e nt occ urs  
wit hi n t h e s a m e c ycl e, r ei ntr o d uc e C C -1 2 2  at  o n e  
d os e l ev el l o w er, if av ail a bl e  
Gr a d e  4 n e utr o p e ni a  
•  
Gr a d e 4:  H ol d C C -1 2 2 u ntil r ec ov ery t o Gr a d e  1.  
•  
F oll o w C B C at l e ast ev ery 7 d ays  
•  
R ei ntr o d uc e C C -1 2 2  at t h e  l o w er d os e l ev el, if 
av ail a bl e  
•  
Us e  of gr o wt h f act ors ( G -C SF,  G M -CS F)  is p er mitt e d  
at t h e discr eti o n of t h e I nv esti g at or * 
F e bril e  n e utr o p e ni a  
•  
H ol d f urt h er d osi n g u ntil  r ec ov ery t o Gr a d e  ≤ 1 t h e n 
r es u m e d osi n g at o n e  d os e  l ev el l o w er, if av ail a bl e  
•  
Us e  of gr o wt h f act ors ( G -C SF,  G M -CS F)  is p er mitt e d  
at t h e discr eti o n of t h e I nv esti g at or * 

CC-122 + Nivolumab
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31 
 
 
Any hematological toxicity requiring 
interruption for > 3 weeks 
• 
Discontinue CC-122 
*The use of myeloid growth factors (filgastrim, sargramostin, peg-filgastrim, or biosimilars), if considered 
should be in accordance with the 2015 American Society of Clinical Oncology guidelines for the use of WBC 
growth factors.45  This includes use in subjects with neutropenia and fever who are at high risk for infection-
related complications.  These high-risk features are sepsis, age > 65 years, pneumonia, invasive fungal 
infection, other clinically documented infections, profound neutropenia (< 0.1 X 109/L) and hospitalization at 
the time of neutropenia. The growth factor should be continued until the absolute neutrophil count (ANC) 
has improved to < grade 1 (equal to or greater than 1.5 X 109/L). If resumption of CC-122 in planned at a 
lower dose (if available), growth factors should have been discontinued at least 48 hours prior with 
reconfirmation of acceptable ANC on the day of planned resumption of treatment. 
 
Additional toxicity-related precautions with CC-122: 
 
CC-122 absorbs ultraviolet (UV) light between the frequencies of 290 and 700 nm and has been shown to 
distribute to the skin and eyes in nonclinical animal studies. As a precautionary measure, it is recommended 
that subjects avoid prolonged exposure to UV light, wear protective clothing and sunglasses, and use UV-
blocking topical preparations while taking CC-122.  This is outlined in the informed consent document. 
   
6.1.3.2  
Nivolumab Dose Delays and/or Modifications: 
 
Nivolumab administration should be delayed for the following: 
 
• 
Grade 2 non-skin, drug-related adverse event, with the exception of fatigue 
• 
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities 
• 
Grade 3 skin, drug-related adverse event 
• 
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
− Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay 
− Grade 3 AST, ALT, Total Bilirubin will require dose discontinuation 
• 
Any adverse event, laboratory abnormality, or inter-current illness, which in the judgment of the 
investigator warrants delaying the dose of study medication. 
 
Participants who require delay of study drug administration should be re-evaluated weekly or more 
frequently if clinically indicated and resume dosing when re-treatment criteria are met. 
 
Criteria to Resume Treatment with Nivolumab: 
 
Participants may resume treatment with study drug when the drug-related AE(s) resolve to Grade < 
1 or baseline value, with the following exceptions: 
• 
Participants may resume treatment in the presence of Grade 2 fatigue 
• 
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment in the 
presence of Grade 2 skin toxicity 
• 
For participants with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is complete. 
• 
Participants with combined Grade 2 AST/ALT AND total bilirubin values meeting discontinuation 
parameters should have treatment permanently discontinued. 
• 
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before treatment is 
resumed. Participants with persistent Grade 1 pneumonitis after completion of a steroid taper over at 
least 1 month may be eligible for retreatment if they are asymptomatic and with normal pulse oximetry 

CC-122 + Nivolumab
Version 3.7
Nov 22, 2019
32 
 
 
readings in the absence of oxygen supplementation.  
 
Participants with drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment provided any symptoms attributed to this event have improved to 
baseline. If the criteria to resume treatment are met, the participant should restart treatment at the 
next scheduled time point per protocol. However, if the treatment is withheld past the window period of 
the next scheduled time point per protocol to ensure adequate recovery from the adverse event or 
tapering of immunosuppression, the next scheduled time point will be delayed until dosing resumes. 
If treatment is withheld > 6 weeks from the last dose, the participant must be permanently 
discontinued from study therapy. 
 
Treatment with Nivolumab should be permanently discontinued for the following: 
 
• 
Any Grade 2 drug-related uveitis, 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 
 
• 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, or recurs with the following 
exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug- related uveitis, 
pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and endocrinopathies: 
− Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, bronchospasm, 
hypersensitivity reaction, or infusion reaction of any duration requires discontinuation 
− Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic hormone 
replacement do not require discontinuation. Adrenal insufficiency requires discontinuation regardless of 
control with hormone replacement. 
− Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation except: 
♦ Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation 
♦ Any drug-related liver function  test  (LFT)  abnormality that  meets  the  following criteria 
require discontinuation: 
o Grade 3 drug-related AST, ALT or Total Bilirubin requires discontinuation 
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN 
 
• 
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited to 
creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not require 
discontinuation: 
− Grade 4 neutropenia < 7 days 
− Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase 
− Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical sequelae 
and are corrected with supplementation/appropriate management within 72 hours of their onset 
− Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, may 
not require discontinuation of nivolumab. 
 
• 
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions: 
− Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events are 
allowed. 
 

C C -1 2 2 + Niv ol u m a b  
V ersi o n 3. 7  
N o v 2 2 , 2 0 1 9 
3 3  
 
 
T h e al g orit h ms f or m a n a g e m e nt of i m m u n e t oxicity attri b ut e d t o niv ol u m a b will f oll o w r ec o m m e n d ati o ns 
o utli n e d i n t h e O P DI V O p ack a g e i ns ert a n d l a b eli n g i nf or m ati o n ( N ov e m b er -2 0 1 8) pl us g e n er ally acc e pt e d 
g ui d eli n es f or cli nic al c ar e of I O t oxicity m a n a g e m e nt.  T h es e g ui d eli n es ar e s u m m ariz e d i n A p p e n dix D . 
 
T u m or  ass ess m e nts  s h o ul d c o nti n u e as  p er  pr ot oc ol  ev e n  if d osi n g  is d el a y e d. P eri o dic  st u dy visits t o 
ass ess  s af et y a n d  l a b or at or y st u di es s h o ul d als o  c o nti n u e e v er y 6 w e e ks  or  m or e  fr e q u e ntly if cli nic ally 
i n dic at e d d uri n g s uc h d osi n g d el ays. 
 
Tr e at m e nt of Ni v ol u m a b R el at e d I nf usi o n R e acti o ns:  
 
Si nc e  niv ol u m a b  c o nt ai ns o nl y  h u m a n  i m m u n o gl o b uli n pr ot ei n  s e q u e nc es, it is u nlik ely  t o b e  
i m m u n o g e nic a n d  i n d uc e i nf usi o n or  hy p ers e nsitivity  r e acti o ns. H o w ev er,  if s uc h  a r e acti o n w er e  t o 
occ ur,  it mi g ht  m a nif est  wit h  f ev er, c hills, ri g ors, h e a d ac h e,  r as h, pr uritis,  art hr al gi as,  hy p o - or  
hy p ert e nsi o n,  br o nc h os p as m,  or  ot h er  sy m pt o ms. I nf usi o n r e acti o ns s h o ul d b e  gr a d e d  acc or di n g  t o 
N ati o n al  C a nc er  I nstit ut e C o m m o n  T er mi n ol o gy  Crit eri a  f or A dv ers e  E v e nts  ( N CI C T C A E   [v ersi o n  5. 0]) 
g ui d eli n es.  
 
Tr e at m e nt  r ec o m m e n d ati o ns ar e  pr ovi d e d  b el o w  a n d  m ay  b e  m o difi e d  b as e d  o n  l oc al tr e at m e nt 
st a n d ar ds a n d g ui d eli n es as a p pr o pri at e: 
 
F or  Gr a d e   1 s y m pt o ms: ( Mil d r e acti o n; i nf usi o n i nt err u pti o n n ot  i n dic at e d; i nt erv e nti o n n ot  i n dic at e d) 
 
R e m ai n  at  b e dsi d e  a n d  m o nit or  p artici p a nt  u ntil  r ec ov ery fr o m sy m pt o ms. T h e  f oll o wi n g pr o p hyl actic  
pr e m e dic ati o ns  ar e  r ec o m m e n d e d f or f ut ur e i nf usi o ns: di p h e n hy dr a mi n e  5 0  m g  ( or e q uiv al e nt)  a n d/ or  
p ar ac et a m ol  3 2 5  t o 1 0 0 0  m g  ( ac et a mi n o p h e n) at  l e ast 3 0  mi n ut es  b ef or e  a d diti o n al  ni v ol u m a b  
a d mi nistr ati o ns.  
 
F or  Gr a d e  2 s y m pt o ms: ( M o d er at e r e acti o n r e q uir es t h er a py or  i nf usi o n i nt err u pti o n b ut  r es p o n ds 
pr o m ptly  t o s y m pt o m atic tr e at m e nt [ e g, a nti hist a mi n es,  n o n -st er oi d al a nti - i nfl a m m at or y dr u gs,  
n arc otics,  c ortic ost er oi ds, br o nc h o dil at ors,  I V fl ui ds]; pr o p hyl actic  m e dic ati o ns  i n dic at e d f or <2 4 h o urs).  
 
St o p  t h e niv ol u m a b  i nf usi o n, b e gi n  a n  I V i nf usi o n of  n or m al  s ali n e, a n d  tr e at t h e p artici p a nt  wit h  
di p h e n hy dr a mi n e  5 0  m g  I V ( or e q ui v al e nt)  a n d/ or  p ar ac et a m ol  3 2 5  t o 1 0 0 0  mg  ( ac et a mi n o p h e n); r e m ai n 
at  b e dsi d e  a n d  m o nit or  p artici p a nt  u ntil  r es ol uti o n of  s y m pt o ms. C ortic ost er oi d  or  br o nc h o dil at or  t h er a py 
m ay  als o  b e  a d mi nist er e d  as  a p pr o pri at e.  If t h e i nf usi o n is i nt err u pt e d, t h e n r est art t h e i nf usi o n at  
5 0 %  of  t h e ori gi n al  i nf usi o n r at e w h e n  sy m pt o ms r es olv e; if n o  f urt h er c o m plic ati o ns e ns u e  aft er  3 0  
mi n ut es,  t h e r at e m ay  b e  i ncr e as e d t o 1 0 0 %  of  t h e ori gi n al  i nf usi o n r at e. M o nit or  p artici p a nt  cl os ely. If 
s y m pt o ms r ec ur t h e n n o  f urt h er niv ol u m a b  will  b e  a d mi nist er e d  at  t h at visit. A d mi nist er  
di p h e n hy dr a mi n e  5 0  m g  I V, a n d  r e m ai n at  b e dsi d e a n d  m o nit or  t h e p artici p a nt  u ntil  r es ol uti o n of  
s y m pt o ms. T h e  a m o u nt  of  st u dy dr u g  i nf us e d m ust  b e  r ec or d e d o n  t h e el ectr o nic  c as e r e p ort f or m ( e C R F). 
T h e f oll o wi n g  pr o p hyl actic  pr e m e dic ati o ns  ar e  r ec o m m e n d e d f or f ut ur e i nf usi o ns: di p h e n hy dr a mi n e  5 0  
m g  ( or e q uiv al e nt)  a n d/ or  p ar ac et a m ol  3 2 5  t o 1 0 0 0  m g  ( ac et a mi n o p h e n) s h o ul d b e  a d mi nist er e d  at  l e ast 
3 0  mi n ut es  b ef or e  a d diti o n al  niv ol u m a b  a d mi nistr ati o ns.  If n ec ess ary,  c ortic ost er oi ds (r ec o m m e n d e d 
d os e:  u p  t o 2 5  m g  of  I V hy dr oc ortis o n e  or  e q ui v al e nt)  m ay  b e  us e d.  
 
F or  Gr a d e   3 or  Gr a d e   4 s y m pt o ms: ( S e v er e r e acti o n, Gr a d e  3:  pr ol o n g e d  [i e, n ot  r a pi dly r es p o nsiv e 
t o sy m pt o m atic m e dic ati o n  a n d/ or  bri ef  i nt err u pti o n of  i nf usi o n]; r ec urr e nc e of  sy m pt o ms f oll o wi n g 
i niti al i m pr ov e m e nt; h os pit aliz ati o n  i n dic at e d f or ot h er  cli nic al s e q u el a e [ e g, r e n al i m p air m e nt, 
p ul m o n ary  i nfiltr at es]). Gr a d e  4:  (lif e t hr e at e ni n g; pr ess or or  v e ntil at ory  s u p p ort i n dic at e d). 
 
I m m e di at el y disc o nti n u e  i nf usi o n of  niv ol u m a b . B e gi n  a n  I V i nf usi o n of  n or m al  s ali n e, a n d  tr e at t h e 

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• 
Confirm informed consent of potential participant has been obtained. 
• 
Review medical history to determine eligibility based on inclusion/exclusion criteria. 
• 
Review medications history to determine eligibility based on inclusion/exclusion criteria. 
• 
Perform medical examinations needed to determine eligibility based on inclusion/exclusion 
criteria. 
• 
Collect/schedule study specific laboratory/biomarker tests and other studies that are outlined in the 
Schedule of Events. 
• 
Schedule biopsy of appropriate metastatic (or appropriately accessible) tumor site for biomarker 
analysis. 
 
 
Baseline Visit (Cycle 1, Day 1) 
 
• 
Verify inclusion/exclusion criteria based on screening studies.  The specific eligibility is typically 
completed ahead of this visit through the Moffitt Internal Monitoring Core. 
• 
Obtain serum or urine pregnancy test for women of child-bearing age; this could have been 
completed and verified negative up to 72 hours prior to this visit. 
• 
Obtain demographic information, medical history, and medication history. 
• 
Record vital signs (including weight), results of examinations.  Recording of height is necessary only 
at screening or baseline visit 
• 
Collect study specific laboratory/biomarker tests and other studies that are outlined in the Schedule 
of Events. This also includes standard of care assessments. 
• 
Administer the study treatment (nivolumab plus CC-122; first dose of CC-122 to be administered in 
the Clinical Research Unit). 
• 
Collect blood for biomarker analysis at 5 hours post CC-122 administration. 
 
Follow-up Visit (Visit 2; C1 Day 15; +/- 2 days)  
 
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs, confirm medical history and perform physical examination 
• 
Collect blood for routine testing and biomarker analysis as specified. 
• 
Administer nivolumab per institutional standard. 
• 
Record participant’s adherence to treatment program. 
• 
Schedule/remind subject of follow-up tumor biopsy (same site as done at screening) to be done 
between days 22 and 29 of cycle 1. 
 
Follow-up Visit (Visit 3; Cycle 2, day 1, +/- 2 days)  
 
• 
Record adverse events as reported by participant or observed by investigator. 
• 
Record vital signs, confirm medical history and perform physical examination 
• 
Administer nivolumab and provide CC-122 for home use  
• 
Record participant’s adherence to treatment program. 
 
Subsequent Visits to follow the ‘Schedule of Events’ calendar: All scheduled visits have the same window of 
+/- 2 days.  If there is a need to schedule outside of this window, this may be done at the discretion of the 
principal investigator as long as there is no perceived jeopardy to the health of the participant. Tumor 
measurements by cross-sectional imaging will be performed every 12 weeks (+/- 7days) unless documented 
progression or subject taken off the clinical trial.  Adverse events as reported by the subject or observed by 
the investigator will be recorded at each visit.  

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• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• 
UPs that are SAEs will be reported to the IRB and to the DCC/study sponsor within <insert 
timeline in accordance with policy> of the investigator becoming aware of the event. 
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within <insert timeline in 
accordance with policy> of the investigator becoming aware of the problem. 
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and OHRP within 
 
 
 
 
Not applicable. 
 
 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of investigators 
or their designees to report any pregnancy or lactation in a subject (spontaneously reported to them), 
including the pregnancy of a male subject's female partner that occurs during the trial or within 120 days of 
completing the trial or 30 days following cessation of treatment. All subjects and female partners of male 
subjects who become pregnant must be followed to the completion/termination of the pregnancy. Any 
subject who becomes pregnant during the study, must be promptly withdrawn from the study and 
discontinue further study treatment. Pregnancy outcomes of spontaneous abortion, missed abortion, 
benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, congenital anomaly, ectopic 
pregnancy, miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the 
pregnancy continues to term, the outcome (health of infant) must also be reported.  
Such events must be reported within 24 hours of their knowledge of the event to Celgene using the Serious 
Adverse Event Form. Because the effect of the Celgene medicinal product on sperm is unknown, 
pregnancies in partners of male subjects exposed to a Celgene medicinal product will be reported by the 
Investigator within 24 hours of their knowledge of the event using the Serious Adverse Event Form. 
Depending on local legislation, this may require prior consent of the partner. Follow-up information 
regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be required. 
8.4.4 
EVENTS OF SPECIAL INTEREST 
8.4.5 REPORTING OF PREGNANCY 

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the time of data analysis will be censored. 
 
 
 
Objective response rate is the primary end point in this combination trial involving an immune checkpoint 
inhibitor in combination with an immunomodulatory agent. Response rates per RECIST 1.1 will be 
evaluated. 
 
RECIST as assessed by the investigator will be used as the primary response rate efficacy end-point and 
make treatment decisions. 
  
Immunotherapeutic agents such as nivolumab and pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses, which may be functionally anergic. The 
response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents, and can manifest a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions. Standard RECIST criteria may not provide a 
complete response assessment of immunotherapeutic agents such as nivolumab, therefore the 
irRECIST have been developed to encompass this.  This will also be assessed as a secondary end-point of 
efficacy. 
 
Broadly, irRECIST includes the concept of treatment beyond progression, if radiologic imaging shows 
PD, tumor assessment should be repeated ≥ 4 weeks later in order to confirm PD with the option of 
continuing treatment, while awaiting radiologic confirmation of progression.  If repeat imaging shows a 
reduction in the tumor burden compared to the initial scan demonstrating PD, treatment may be 
continued as per treatment calendar. If repeat imaging confirms progressive disease, subjects will be 
discontinued from trial therapy. In determining whether or not the tumor burden has increased or 
decreased, Investigators should consider all target lesions as well as non-target lesions. 
 
In subjects who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a subject on study treatment, until repeat imaging is obtained a minimum 
of 4 weeks later. This decision should be based on the clinical judgment of the subject’s overall 
clinical condition, including performance status, clinical symptoms, and laboratory data. Subjects may 
receive treatment while waiting for confirmation of PD if they are clinically stable as defined by the 
following criteria: 
• 
Absence of signs and symptoms indicating disease progression 
• 
No decline in ECOG performance status  
• 
Absence of rapid progression of disease 
• 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring urgent 
alternative medical intervention 
 
When feasible, subjects should not be discontinued until progression is confirmed. This allowance to 
continue treatment despite initial radiologic progression takes into account the observation that some 
subjects can have a transient tumor flare in the first few months after the start of immunotherapy, but 
with subsequent disease response. Subjects that are deemed clinically unstable are not required to 
have repeat imaging for confirmation of progressive disease. 
 
Subjects who continue treatment beyond initial radiographic progression while awaiting confirmation 
imaging will need to be re-consented for their ongoing treatment with nivolumab and avadomide on the 
clinical trial.  All other elements of the main consent including description of reasonable foreseeable risks or 
discomfort, and other alternative therapy will still apply. 
10.3 EFFICACY ANALYSIS 

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melanoma. Cancer 116:146-54, 2010 
 
23. 
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with bevacizumab in patients with advanced cancer. Cancer Chemother Pharmacol 77:1097-102, 2016 
 
26. 
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4 antibody ipilimumab and lenalidomide in patients with advanced cancers. Mol Cancer Ther, 2017 
 
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interferon response and has antitumor activity in DLBCL. Blood 126:779-89, 2015 
 
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LeBlanc R, Hideshima T, Catley LP, et al: Immunomodulatory drug costimulates T cells via the 
B7-CD28 pathway. Blood 103:1787-90, 2004 
 
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Robert C, Ribas A, Hamid O, et al: Durable Complete Response After Discontinuation of 
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Appendix B: ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity.  Fully active, able  to  carry  on  all  pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary 
nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self- care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair. 
 
 
 
 
 
 
 

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Appendix C:  iRECIST (immune Response Evaluation Criteria in Solid Tumors) 
 
Tumor response will be assessed by the RECIST 1.1 (primary) and iRECIST (secondary).43,50 The latter is a 
reconciliation of RECIST guidelines v1.1 with the original immune-related Response Criteria (irRC). The 
latter standard incorporated principles important for assessment of immune-checkpoint blocking 
immunotherapy for cancer, but fundamentally differed from RECIST in using 2-dimensional tumor 
assessment. In contrast, iRECIST is based on 1-dimensional tumor measurement, but it differs from 
RECIST guidelines v1.1 in the following key ways: 
 
• 
Under RECIST guidelines v1.1, the appearance of new lesions indicates PD. Under iRECIST, new 
measurable lesions are incorporated in the tumor burden, which is used to determine immune-related 
progressive disease (iPD), immune-related partial response (iPR), and immune-related complete 
response (iCR). New non-measurable lesions preclude iCR. 
 
• 
Under RECIST guidelines v1.1, there is no confirmation for PD. In addition, responses and iPDs must be 
confirmed by consecutive scans at least 4 weeks apart, assuming no clinical deterioration. 
 
The following sub-section describes iRECIST in detail. 
 
Tumor Burden: 
At baseline, the tumor burden is the sum of single diameters (short axis for nodal lesions, longest 
diameter for other lesions) for the target lesions. In subsequent scans, the diameters of new measurable 
lesions are added to the tumor burden. If a subject is retreated, then up to 5 target lesions (perhaps 
different from the original lesions) will be selected and a new baseline tumor burden will be 
established. 
 
Overall Response at a Single Time Point 
 
The table below outlines determination of disease response at a single assessment based on iRECIST. 
 
iRECIST: Overall Response 
 
Tumor Burden 
(Baseline and New) 
Non-Target Lesions 
(Baseline and New) 
Response 
Disappearance of non-nodal lesions. All 
pathologic lymph nodes < 10 mm (short 
axis) 
Disappearance of non-nodal lesions. All 
pathologic lymph nodes < 10 mm (short 
axis) 
irCRa 
≥ 30% decrease from baseline 
Any 
irPRa 
≥ 20% increase from nadir and at least 5 
mm 
Any 
irPDa 
Neither sufficient decrease to qualify for 
PR  nor sufficient increase to qualify for PD 
Any 
irSD 
Disappearance of all non-nodal lesions. All 
pathologic lymph nodes < 10 mm 
Any other than disappearance of all non- 
nodal lesions and reduction of pathologic 
lymph nodes < 10 mm 
irPRa 
 
 
 
a. Selection as best response requires confirmation by 2 consecutive measurements at least 4 weeks apart. 
b. If some lesions are measured, response may be inferred from available measurements. For example, growth in evaluated target lesions 
may be sufficient for irPD regardless of status of non-evaluated lesions. 
 
 
 
 
Not all evaluatedb 
Any 
irNE 

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Appendix D: Immune Adverse Events Management Algorithm 
 
The following section outlines general principles for the management of immune-related adverse events.  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.  The updated 
package insert for OPDIVO (nivolumab) will be concurrently followed to assist with clinical decision making. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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