Clinical trial NCT04118166
Conditions: Soft Tissue Sarcoma
Sponsor: Kristen Ganjoo
Start date: 2019-10-01; Completion date: 2022-04-26
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this Phase 2 study is to

1. find out if the study drugs (ipilimumab plus nivolumab) in combination with cryotherapy will help participants with metastatic or locally advanced soft tissue sarcoma;.
2. find out how safe are ipilimumab plus nivolumab given in combination with cryotherapy, and what side effects may be related to treatment.
3. find out how do the study drugs in combination with cryotherapy work in soft tissue sarcoma.

Detailed description:
Primary Objectives:

1\) Assess whether the rate of clinical benefit is sufficiently high to merit promise for further study

Secondary Objectives:

1. Characterize the 6-month progression-free survival rate
2. Assess whether the treatment yields a reasonably safe and tolerable profile

Arms: arm 1: 1 mg/kg with nivolumab 3 mg/kg every 3 weeks x 4 doses. (One cycle of treatment is 3 weeks). Cryotherapy (cryoablation) will be performed between investigational agent treatment Cycles 1 and 2
Interventions: intervention 1: Ipilimumab intervention 2: Cryoablation intervention 3: Nivolumab
Intervention descriptions: intervention 1: Ipilimumab 1 mg/kg, injection intervention 2: Cryoablation of the tumors occur between investigational agent treatment Cycles 1 and 2, and will be performed according to standard procedures intervention 3: Nivolumab 3 mg/kg, injection

Protocol documents:
Prot_SAP_000.pdf: 
 
 
IRB-50853 
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Phase 2 Study of Ipilimumab Plus Nivolumab in Combination with 
Cryotherapy in Metastatic or Locally Advanced Soft Tissue Sarcoma 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive  
Stanford, CA 94305 
Protocol Director  
Kristen Ganjoo, MD 
875 Blake Wilbur Dr 
Stanford, CA 94305 
650-924-0900 
Email:  Kganjoo@stanford.edu  
Co-Investigators 
Nam Bui, MD 
780 Welch Rd 
Palo Alto, CA 94304 
Phone:  650-498-3483;  
Fax:  650-725-7760 
nbui@stanford.edu 
David Wang, MD 
Stanford Interventional Radiology 
300 Pasteur Drive, H-3630 
Stanford, CA 94305 
Phone:  650-723-0728;  
Fax:  650-725-0533 
davidwang@stanford.edu 
Gloria Hwang, MD 
Stanford Interventional Radiology 
300 Pasteur Drive, H-3630 
Stanford, CA 94305 
Phone:  650-723-0728;  
Fax:  650-725-0533 
glhwang@stanford.edu 
 
Biostatistician 
Manisha Desai 
1070 Arastradero Road, Rm 305 
Palo Alto, CA 94304 
Phone:  650-725-1946 
Fax:  650-725-6906 
manisha.desai@stanford.edu  
Study Coordinator 
Maria Ahern 
800 Welch Rd 
Palo Alto, CA 94304 
Phone:  650-725-6413;  
Fax:  650-725-7760 
mahern@stanford.edu 
IRB-50853 
SARCOMA0038 
NCT04118166 
IND-144460 
Study Funding Source:  Bristol-Myers Squibb 
Study BMS ISR CA184-566 
26 June 2020 (BMS version 4.0) 
SRC Approval Date:  2 August 2019 


 
 
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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ................................................................................................. 4 
SCHEMA ......................................................................................................................... 6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS (EXAMPLE) ...................... 7 
1. OBJECTIVES ........................................................................................................... 8 
1.1 PRIMARY OBJECTIVES ..................................................................................................... 8 
1.2 SECONDARY OBJECTIVES ................................................................................................ 8 
1.3 EXPLORATORY OBJECTIVES ............................................................................................. 8 
2. BACKGROUND ........................................................................................................ 8 
2.1 STUDY DISEASE .............................................................................................................. 9 
2.2 STUDY AGENT/DEVICE/PROCEDURE ................................................................................. 9 
2.3 RATIONALE ..................................................................................................................... 9 
2.4 STUDY DESIGN ............................................................................................................... 9 
2.5 CORRELATIVE STUDIES  ..................................................................................................10 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ...................... 11 
3.1 INCLUSION CRITERIA ......................................................................................................11 
3.2 EXCLUSION CRITERIA .....................................................................................................11 
3.3 INFORMED CONSENT PROCESS .......................................................................................12 
3.4 REGISTRATION PROCESS................................................................................................13 
3.5 STUDY TIMELINE ............................................................................................................13 
4. TREATMENT PLAN ............................................................................................... 13 
4.1 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ......................14 
4.2 CRITERIA FOR REMOVAL FROM STUDY ............................................................................14 
4.3 ALTERNATIVES ...............................................................................................................14 
5. INVESTIGATIONAL AGENT .................................................................................. 14 
5.1 INVESTIGATIONAL AGENT (IPILIMUMAB) ............................................................................14 
5.2 INVESTIGATIONAL AGENT (NIVOLUMAB) ............................................................................15 
5.3 CRYOABLATION ..............................................................................................................16 
6. DOSE MODIFICATIONS ........................................................................................ 17 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ...................................... 17 
7.1 POTENTIAL ADVERSE EVENTS .........................................................................................17 
7.2 ADVERSE EVENT REPORTING .........................................................................................20 
8. CORRELATIVE/SPECIAL STUDIES ..................................................................... 22 
8.1 ARCHIVAL TUMOR SAMPLES ...........................................................................................22 
8.2 TUMOR SAMPLES COLLECTED THROUGHOUT STUDY ........................................................22 
8.3 BLOOD COLLECTION .......................................................................................................22 
9. STUDY CALENDAR ............................................................................................... 24 
10. MEASUREMENT .................................................................................................. 25 
10.1  PRIMARY AND SECONDARY OUTCOME MEASURES ............................................................25 
11. REGULATORY CONSIDERATIONS .................................................................... 27 
11.1 REGULATORY OVERSIGHT ...............................................................................................27 


 
 
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11.2 DATA AND SAFETY MONITORING PLAN .............................................................................28 
11.3 PROTOCOL REVIEW AND AMENDMENTS ...........................................................................28 
11.4 DATA MANAGEMENT PLAN ..............................................................................................28 
11.5 STUDY DOCUMENTATION ................................................................................................28 
12. STATISTICAL CONSIDERATIONS ..................................................................... 28 
13. REFERENCES ...................................................................................................... 30 
APPENDICES ............................................................................................................... 31 
APPENDIX A:  PARTICIPANT ELIGIBILITY CHECKLIST ...............................................................31 
APPENDIX B:  RECIST 1.1  ....................................................................................................34 
APPENDIX C:  IMMUNE-RELATED RESPONSE EVALUATION CRITERIA IN SOLID TUMORS  
(IMMUNE-RELATED RECIST, IRRECIST)  .........................................................43 
APPENDIX D:  TOXICITY MANAGEMENT ..................................................................................50 
APPENDIX E:  ADVERSE EVENTS REPORTING  ........................................................................57 
APPENDIX F:  PATIENT-REPORTED OUTCOME (PRO) QUESTIONNAIRES ....................................63 
APPENDIX  REFERENCES ..................................................................................................92 
 
 


 
 
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PROTOCOL SYNOPSIS 
TITLE 
Phase 2 Study of Ipilimumab Plus Nivolumab in Combination 
with Cryotherapy in Metastatic or Locally Advanced Soft 
Tissue Sarcoma 
STUDY PHASE 
Phase 2 
INDICATION 
Soft tissue sarcoma 
INVESTIGATIONAL 
PRODUCT OR 
PROCEDURE 
Ipilimumab plus nivolumab in combination with cryotherapy 
PRIMARY 
OBJECTIVE(S) 
 Assess whether the rate of clinical benefit is sufficiently 
high to merit promise for further study  
SECONDARY 
OBJECTIVE(S) 
 Characterize the 6-month progression-free survival rate 
 Assess whether the treatment yields a reasonably safe 
and tolerable profile 
EXPLORATORY 
OBJECTIVE(S) 
 Correlate the mutation burden by NGS with response 
 Correlate PDL1 expression with response 
 Correlate tumor infiltrating lymphocytes/macrophages 
with response 
TREATMENT 
SUMMARY 
 Ipilimumab 1 mg/kg and nivolumab 3 mg/kg every 
3 weeks for 4 doses followed by nivolumab 480 mg every 
4 weeks until progression or intolerance (maximum 
24 months). 
 Cryoablation of at least one tumor mass between Cycle 1 
and 2 of above immunotherapy 
SAMPLE SIZE  
30 
STATISTICAL 
CONSIDERATIONS 
It is anticipated that 3 to 4 subjects will be enrolled per 
month.  It is expected that 12 months will be required to 
accrue the number of subjects necessary to complete the 
trial. 
Treatment response will be assessed for each subject at 
16 weeks.  The null hypothesis is that the response rate (ie, 
sum of CR and PR) is ≤ 30%, & alternative hypothesis is that 
the response rate (RR) is ≥ 60%.  The selection of 60% as a 
threshold for determining the treatment is worthy of further 
study is due to recent trials of sarcoma FDA approved drugs 
showing ~60% PFS rate at 3 months (ie, pazopanib, 
trabectedin, and eribulin). 


 
 
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STATISTICAL 
CONSIDERATIONS 
(continued) 
A Simon-2-stage design will be used to address primary 
objective.  The null hypothesis that the true response rate is 
30% will be tested against a one-sided alternative.  Our 
decision rule works as follows.  In the first stage, we will 
accrue and assess 10 subjects.  If 3 or fewer subjects 
(< 30% of 10 subjects) achieve a clinical response, the trial 
will be stopped for futility.  If more than 3 subjects achieve a 
clinical response, we will enroll and treat an additional 
18 subjects.  If 12 or fewer of the 28 treated subjects 
(< 42.8%) demonstrate a clinical response (either CR or 
PR), we will conclude the treatment is not worthy of further 
study.  If, however, more than 12 of the 28 treated subjects 
(≥ 42.8%) responds, we will claim the treatment promising.  
Assuming a true response rate of 60%, we have 90% power 
to correctly conclude the treatment promising.  In contrast, if 
the true response rate is only 30%, we have a low probability 
(0.04) of incorrectly continuing to study the treatment.   
Rates of toxicity will be characterized by level of toxicity as 
well as by other subject-level characteristics. 
To address secondary objectives, we will use Kaplan-Meier 
methods to graphically depict PFS.  This tool will also be 
used to demonstrate survival across various sub-groups of 
interest.  Generalized linear regression methods (with a logit 
link) will be utilized to characterize relationships between 
features such as mutation burden, PDL1 expression, and 
tumor infiltrating lymphocytes and response. 


 
 
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SCHEMA 
Baseline: 
(Collect archival tumor tissue and blood) 
(Routine labs and Scans) 
 
Cycle 1:  Ipilimumab plus nivolumab  
(Routine labs and Blood for research) 
 
(CRYOABLATION WITH BIOPSY IMMEDIATELY BEFORE ABLATION:   
Procedure may be repeated) 
 
Cycle 2:  Ipilimumab plus nivolumab  
(Routine labs and blood for research) 
 
Cycle 3:  Ipilimumab plus nivolumab  
(Routine labs and blood for research) 
 
Cycle 4:  Ipilimumab plus nivolumab  
(Routine labs and blood for research) 
 
Response Scans 
 
(Continue to maintenance Nivolumab if stable disease or response) 
(Routine labs and blood for research) 


 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADL 
Activities of daily living 
AE 
Adverse event 
BID 
Twice daily 
BSA 
Body surface area 
CBC 
Complete blood count 
CI 
Confidence interval 
CMAX 
Maximum concentration of drug 
CNS 
Central nervous system 
CRF 
Case report form 
CR 
Complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field  
HTN 
Hypertension 
IRB 
Institutional Review Board 
irRECIST 
Immune–related response evaluation criteria in solid 
tumors (RECIST) 
IV 
Intravenous 
LLN 
Lower limit of normal  
MIBI 
Multiplexed ion beam imaging 
NGS 
Next generation sequencing 
OS 
Overall survival  
PLT 
Platelets 
PD 
Progressive disease 
PFS 
Progression free survival  
PR 
Partial response 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
WBC 
White blood cell 
WHO 
World Health Organization 


 
 
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1. OBJECTIVES 
1.1. 
Primary Objectives  
a. Assess whether the rate of clinical benefit is sufficiently high to merit 
promise for further study  
1.2. 
Secondary Objectives 
a. Characterize the 6-month progression-free survival (PFS) rate  
b. Assess whether the treatment yields a reasonably safe and tolerable 
profile 
1.3. 
Exploratory Objectives 
a. Correlate the mutation burden by NGS with response 
b. Correlate PDL1 expression with response 
c. Correlate tumor infiltrating lymphocytes/macrophages with response 
2. BACKGROUND 
Immunotherapy with PD1 antibody, nivolumab, and CTLA-4 antibody, ipilimumab, has 
been administered safely in subjects with metastatic sarcoma.  The combination of 
these two antibodies improved response rate and overall survival when compared to 
nivolumab alone (1).  Radiation therapy of metastatic melanoma lesions while on 
immunotherapy has improved response rates both in the irradiated and non-radiated 
fields (2-5).   
We have treated about 40 subjects with metastatic sarcoma with combination 
ipilimumab and nivolumab in the past 24 months.  Many of these subjects had external 
beam radiation therapy while receiving immunotherapy.  However, a minority of subjects 
were not able to receive radiation due to prior exposure or location of the metastatic 
lesions.  These subjects were treated with cryoablation.  We observed tumor responses 
in both non-ablated and ablated tumors.  Theoretically, tumor antigens are released 
from cryotherapy which can augment the response to immunotherapy.  Abdo et al 
proposed that by priming the immune system with CTLA-4 and PD1 inhibitors, cytotoxic 
CD8+ cell develop after tumor antigens are released by cryotherapy (6), thus facilitating 
tumor kill by the host’s immune system.   
In this study, we will prospectively study the response rate, toxicity and outcome in 
subjects with metastatic sarcoma when treated with cryotherapy while receiving 
immunotherapy with ipilimumab and nivolumab. 


 
 
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2.1 
Study Disease 
a. Metastatic or locally advanced soft tissue sarcomas with at least one tumor 
area amendable to ablation.   
b. Subjects able to receive immunotherapy (No autoimmune disorders and not 
on chronic immunosuppression). 
c. Subjects must have archival tumor samples available for Next Generation 
Sequencing. 
2.2 
Study Agents and Procedures 
a. Ipilimumab 
b. Nivolumab 
c. Cryoablation 
For clinicaltrials.gov compliance 
The US Food and Drug Administration (FDA) has not approved ipilimumab nor 
nivolumab for the treatment of soft tissue sarcoma.  An IND will be submitted by the 
principal investigator of this study; however, it is possible that the FDA may deem this 
study to be IND-exempt.    
2.3 
Rationale 
Subjects with relapsed or refractory metastatic sarcoma have a dismal prognosis.  
Response rates to conventional therapy are generally very low, in the range of 10-20%, 
and new therapeutic approaches are needed for this disease.7-11 
Most subjects with soft tissue sarcomas (STS) are treated with gemcitabine and 
docetaxel, and some with pazopanib if they tolerate the drug.  However, subjects do not 
have many options following these treatments.  Pazopanib will give less than a 10% 
response rate and has many side effects, and it only improves PFS by 3 months.6  
Gemcitabine and docetaxel give less than a 20% response rate, and subjects are 
unable to take these two drugs long-term due to side effects.1  These are not optimal 
therapies for STS.  This is why we are bringing in immunotherapy and cryoablation 
therapy, as we hope that they will improve outcome.  Based on the encouraging results 
from the early clinical experience in various types of solid tumors, a clinical study which 
combines anti-PD-1 and anti-CTLA4 IT with ablation to treat subjects with relapsed or 
refractory metastatic sarcoma shows great promise to enhance antitumor immune 
response and improve clinical outcomes.    
2.4 
Study Design 
 The primary purpose for the protocol is treatment 
 The interventional model is non-randomized single group  
 One intervention arm 
o Ipilimumab 1 mg/kg with nivolumab 3 mg/kg every 
3 weeks x 4 doses.  (One cycle of treatment is 3 weeks) 


 
 
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o Cryoablation of at least one tumor mass between Cycle 1 to 2 of 
above immunotherapy 
o Maintenance therapy with nivolumab 480 mg every 4 weeks (up to 
24 months).  (Each cycle of maintenance therapy is 4 weeks). 
o Additional ablations are allowed per investigator’s discretion 
 Subject number:  30  
 Primary endpoints  
o Clinical benefit (CR, PR, SD) based on the response evaluation 
criteria in solid tumors (RECIST) criteria v1.1 and Immune-related 
RECIST (irRECIST), assessed at 16 weeks. 
 Secondary endpoints 
o 6-month progression-free survival 
o Safety and tolerability 
o Correlative measures (See below) 
2.5 
Correlative Studies (Dr van de Rijn and Dr Katherine Ferrera) 12-14 
2.5.1. Archival tumor samples: 
Histology, immunohistochemistry for lymphocyte subsets (include multi-marker 
studies such as MIBI or other) and for Gene Expression profiling with additional 
analysis of immune subsets by Cibersort and for Gene Expression profiling within 
the immune cells by CibersortX.  The latter dataset can be validated by 
performing LCM-SMART-3SEQ. 
2.5.2 Tumor samples collected throughout study:   
Histology, immunohistochemistry for lymphocyte subsets (include multi-marker 
studies such as MIBI or other) and for Gene Expression profiling (GEP) with 
additional analysis of immune subsets by Cibersort and for GEP within the 
immune cells by CibersortX.  The latter dataset can be validated by performing 
LCM-SMART-3SEQ. 
2.5.3 Blood collection:   
 Determine ctDNA levels  
 Gene expression profiling on blood lymphocytes, followed by CibersortX to 
assess subsets.   
 Gene expression profiling on blood lymphocytes:  It is estimated that 
there will be approximately 20 million white blood cells in 2.5 mL of 
blood drawn into a PAXgene tube.  Two 2.5-mL tubes will be collected 
at each time point, so approximately 40 million white blood cells will be 
collected in that volume of blood.  Gene expression profiles in blood 
and tumor may be compared over time. 
 Perform flow with purification of T-cells, followed by gene expression profiling  


 
 
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 Perform proteomic analysis for cytokines 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 
Inclusion Criteria 
3.1.1 Unresectable or metastatic soft tissue sarcoma 
3.1.2 ≥ 1 prior systemic therapy for sarcoma, including adjuvant systemic therapy 
3.1.3 Age ≥ 18 years 
3.1.4 Life expectancy > 3 months 
3.1.5 Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
3.1.6 Lab values as below:   
o Absolute neutrophil count (ANC) ≥ 1,000/mm3 
o Platelet count ≥ 75,000/mm3 
o Creatinine ≤ 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinine 
clearance > 45 mL/min using the lean body mass formula only 
o Total bilirubin ≤ 1.5 x ULN in absence of Gilbert disease (total bilirubin 
≤ 3 x ULN with Gilbert);  also, if hyperbilirubinemia is clearly attributed to liver 
metastases total bilirubin ≤ 3 x ULN is permitted 
o AST/ALT ≤ 3 x ULN  
o Thyroid stimulating hormone (TSH) within normal limits (WNL); 
supplementation is acceptable to achieve a TSH WNL; in subjects with 
abnormal TSH if free T4 is normal and subject is clinically euthyroid, subject 
is eligible 
3.1.7 Any toxic effects of prior therapy (except alopecia) must be resolved to NCI 
CTCAE, version 5.0, Grade 1 or less 
3.1.8 Ability to understand and the willingness to sign a written informed consent 
document 
3.1.9 Women of childbearing potential (WOCBP) receiving nivolumab must be willing 
to adhere to contraception for a period of 5 months after the last dose of 
nivolumab.  Men receiving nivolumab and who are sexually active with WOCBP 
will be instructed and must be willing to adhere to contraception for a period of 
7 months after the last dose of nivolumab. 
3.2 
Exclusion Criteria 
3.2.1 Prior therapy with ipilimumab or nivolumab, or any agent targeting programmed 
cell death 1 (PD-1), PD-L1 or cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4) 


 
 
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3.2.2 History of the following: 
3.2.2.1 Active known or suspected autoimmune disease 
3.2.2.2 Known human immunodeficiency virus (HIV) (Subjects with lymphocytes 
> 350 cluster of differentiation (CD)4+ cells and no detectable viral load 
are eligible) 
3.2.2.3 Active known Hepatitis B.  Testing is unrequired in the absence of 
history. 
Hepatitis B can be defined as: 
 Hepatitis B surface antigen (HBsAg) > 6 months 
 Serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) 
20,000 IU/mL (105 copies/mL), lower values 2,000 to 20,000 IU/mL 
(104 to 105 copies/mL) are often seen in hepatitis B-e antigen 
(HbeAg)-negative chronic hepatitis B 
 Persistent or intermittent elevation in alanine aminotransferase 
(ALT)/alanine aminotransferase (AST) levels.   
 Liver biopsy showing chronic hepatitis with moderate or severe 
necroinflammation 
3.2.2.4 Active known Hepatitis C.  Testing is unrequired in the absence of 
history. 
 Hepatitis C antibody (Ab) positive 
 Presence of hepatitis C virus (HCV) ribonucleic acid (RNA) 
3.2.2.5 Known active pulmonary disease with hypoxia defined as:  
 Oxygen saturation < 85% on room air or 
 Oxygen saturation < 88% despite supplemental oxygen 
3.2.3 Systemic treatment with either corticosteroids (> 10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 7 days of 
registration 
3.2.4 Received any live/attenuated vaccine (eg, varicella, zoster, yellow fever, 
rotavirus, oral polio and measles, mumps, rubella (MMRI) within 30 days before 
initiation of treatment on this protocol. 
3.2.5 If female, pregnant or lactating.  (Women of childbearing potential are required to 
have a negative pregnancy test within 24 hours prior to the initial administration 
of study drug) 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient 
information for participants to make an informed decision regarding their participation.  
Participants must sign the IRB approved informed consent prior to participation in any 


 
 
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study specific procedure.  The participant must receive a copy of the signed and dated 
consent document.  The original signed copy of the consent document must be retained 
in the medical record or research file.   
3.4 Registration Process 
No subject may begin study treatment prior to registration and assignment of a subject 
identification number. 
At registration, Stanford will sequentially assign eligible subjects an identification 
number.  The maximum allowable time between registration and the first administration 
of study treatment is 14 days.  The subject’s identification number will be used on all 
subject-specific Case Report Forms (CRFs) and serious adverse event (SAE) forms.  
Case report forms will be electronic.  Participant information should be entered into 
OnCore within 5 business days.  
3.5 Study Timeline 
Primary Completion:  Primary completion is the date that the final datum is obtained / 
expected to be obtained for the primary outcome.  The timeframe for primary completion 
for an individual subject is 16 weeks after initiation of treatment.  This datum is expected 
to be obtained approximately 40 months from the time the study opens to accrual.  
Study Completion:  The study is expected to reach overall completion (last datum from 
last subject) approximately 60 months (5 years) from the time the study opens to 
accrual.   
4. 
TREATMENT PLAN 
This is an open-label phase 2 study evaluating the safety and efficacy of 
ipilimumab/nivolumab in combination with cryotherapy.   
The main primary objective of this study is to determine if immunotherapy in 
combination with cryoablation adds a clinically-significant benefit as measured by the 
objective response rate (ORR).  The response rate will be evaluated by RECIST v1.1 as 
well as by irRECIST.  Imaging by PET-CT or CT scan will be performed at screening, 
then every 12 weeks ± 7 days until disease progression.  Earlier scans will be 
performed if clinically indicated.  Ablated tumors will not be included as part of the 
treatment response assessment, ie, disease response;  measurable disease;  or 
tumor progression, by either RECIST or irRECIST.  
Subjects will receive ipilimumab 1 mg/kg IV over 30 minutes ± 10 minutes and 
nivolumab 3 mg/kg IV over 30 minutes ± 10 minutes every 3 weeks for 4 doses 
followed by nivolumab 480 mg IV over 30 minutes ± 10 minutes every 4 weeks until 
progression or intolerance (maximum 24 months).  The standard cycle of investigational 
agent treatment is considered to be 3 weeks.  See Study Calendar at Section 9. 
Per protocol cryotherapy (cryoablation) will be performed between investigational agent 
treatment Cycles 1 and 2 (see Section 5.3).  Additional cryoablation procedures may be 
conducted as regular medical care per investigator discretion.   


 
 
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Blood samples will be drawn prior to each immunotherapy administration for routine 
tests as well as correlative studies.  Blood and tissue samples will be retained and used 
for future research. 
After completion of study treatment, a post-treatment biopsy will be obtained if feasible. 
4.1 
General Concomitant Medication and Supportive Care Guidelines 
Subjects will not receive any live/attenuated vaccine (eg, varicella, zoster, yellow fever, 
rotavirus, oral polio and measles, mumps, rubella (MMRI) during treatment and until 
100 days post-last dose. 
Otherwise, there are no restrictions on concomitant medications or supportive care 
medications.  
If clinically indicated, palliative radiation therapy to non-target lesions is permitted.  
4.2 
Criteria for Removal from Study 
Subjects will be removed from study if they have disease progression;  unacceptable 
adverse events in the opinion of the subject or the investigator;  withdrawal of consent;  
non-compliance;  or if subject is female and has become pregnant.   
4.3 
Alternatives 
Alternatives include other systemic therapies, other clinical trials, or supportive care 
(NOTE:  corticosteroid restriction is only an eligibility criteria and not an on-study 
concurrent medication restriction). 
5. 
INVESTIGATIONAL AGENT 
5.1 
Ipilimumab (Yervoy) 
Ipilimumab (BMS-734016, MDX010, MDX-CTLA4) is a fully-human monoclonal 
immunoglobulin (Ig) G1κG1κ specific for human cytotoxic T-lymphocyte antigen 4 
(CTLA-4, CD-152), which is expressed on a subset of activated T cells.  CTLA-4 is a 
negative regulator of T-cell activity.  Ipilimumab is a monoclonal antibody (mAb) that 
binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86.  
Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, 
including the activation and proliferation of tumor-infiltrating T-effector cells.  Inhibition of 
CTLA-4 signaling can also reduce T-regulatory cell (Treg) function, which may 
contribute to a general increase in T-cell responsiveness, including the anti-tumor 
response. 
5.1.1  Effects in Humans 
Bristol-Myers Squibb (BMS) and Medarex, Inc (MDX, acquired by BMS in Sep 2009) 
have co-sponsored an extensive clinical development program for ipilimumab, 
encompassing more than 22,571 subjects (total number of subjects enrolled in 
ipilimumab studies) in several cancer types in completed and ongoing studies, including 
a compassionate use program.   
Ipilimumab 3 mg/kg has been approved for use in advanced melanoma in over 
47 countries, including the United States (US, 25 Mar 2011), the European Union 


 
 
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(EU, 13 Jul 2011), and Australia (Jul 2011).  Ipilimumab 10 mg/kg is approved as 
adjuvant treatment of unresectable or metastatic melanoma in the US.  Ipilimumab is 
approved in the EU for the treatment of adolescents and in the US for the treatment of 
melanoma in pediatric subjects. 
Additionally, ipilimumab has been approved for the following indications: 
 Treatment of subjects with intermediate or poor risk, previously untreated 
advanced renal cell carcinoma, in combination with nivolumab.   
 Treatment of adult and pediatric subjects 12 years of age and older with 
microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) 
metastatic colorectal cancer that has progressed following treatment with a 
fluoropyrimidine, oxaliplatin, and irinotecan, in combination with nivolumab.  This 
indication is approved under accelerated approval based on overall response 
rate and duration of response.  Continued approval for this indication may be 
contingent upon verification and description of clinical benefit in confirmatory 
trials. 
5.1.2 Availability 
Bristol-Myer Squibb will be providing this agent.  
5.1.3 Agent Ordering 
This agent will be requested from Bristol-Myers Squibb in advance.  A supply of the 
drug will be available at Stanford investigational pharmacy at all times.  
5.1.4 Agent Storage and Accountability 
Per the Investigator Brochure, vials of ipilimumab injection must be stored at 2°C to 8°C 
(36°F to 46°F) and protected from light and freezing.  Ipilimumab injection may be 
stored undiluted (5 mg/mL) or following dilution in 0.9% sodium chloride injection or 
5% dextrose injection in PVC, non-PVC/non-DEHP, or glass containers for up to 
24 hours at 2°C to 8°C or room temperature/room light.  
This agent will be kept secure per Stanford investigational pharmacy SOP. 
5.2 
Nivolumab (Opdivo) 
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human 
monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the 
programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface 
membrane receptor.  PD-1 is a negative regulatory molecule expressed by activated T 
and B lymphocytes.1 Binding of PD-1 to its ligands, programmed death–ligands 1 
(PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation.  
Inhibition of the interaction between PD-1 and its ligands promotes immune responses 
and antigen-specific T-cell responses to both foreign antigens as well as self-antigens.  
Nivolumab is expressed in Chinese hamster ovary (CHO) cells and is produced using 
standard mammalian cell cultivation and chromatographic purification technologies.  
The clinical study product is a sterile solution for parenteral administration. 


 
 
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5.2.1 
Effects in Humans 
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), classical Hodgkin Lymphoma (cHL), urothelial carcinoma 
(UC), squamous cell carcinoma of the head and neck (SCCHN), in addition to other 
tumor types. 
Nivolumab monotherapy is approved in multiple regions, including the US and EU, for 
unresectable or metastatic melanoma, previously treated metastatic NSCLC, previously 
treated advanced RCC, previously treated relapsed or refractory cHL, previously treated 
advanced or metastatic UC, and for the treatment of previously treated recurrent or 
metastatic SCCHN; it is also approved for previously treated CRC, previously treated 
HCC, and the adjuvant treatment of melanoma in the US.   
In addition, nivolumab has been approved for use in combination with ipilimumab for 
RCC in the US and unresectable melanoma in multiple countries, including the US and 
EU. 
5.2.2 
Availability 
Bristol-Myers Squibb will be providing this agent.  
5.2.3 
Agent Ordering 
This agent will be requested from Bristol-Myers Squibb in advance.  A supply of the 
drug will be available at Stanford investigational pharmacy at all times.  
5.2.4 Agent Storage and Accountability 
Per the Investigator Brochure, vials of nivolumab injection must be stored at 2°C to 8°C 
(36°F to 46°F) and protected from light and freezing.  The unopened vials can be stored 
at room temperature (up to 25°C, 77°F) and room light for up to 48 hours. 
This agent will be kept secure per Stanford investigational pharmacy SOP.  
5.3 
Cryoablation 
Cryoablation of the tumors occur between investigational agent treatment Cycles 1 
and 2, and will be performed according to standard procedures.  The cryotherapy 
devices will be FDA-approved cryoablation systems that in current use within the 
Stanford University Medical Center.   
Prior to the cryoablation procedure, the interventional radiologist will review 
cross-sectional imaging studies to formulate a treatment plan, including identifying the 
target lesions appropriate for treatment;  the number and type of cryoablation probes 
needed;  and optimal percutaneous access approach.  As the goal of the cryotherapy is 
to enhance systemic immunotherapy, the cryoablation will most commonly be subtotal.  
For lesions that are in close proximity to freeze-sensitive tissues, such as bowel or skin, 
the cryoablation treatment will be performed with a safe distance (≥ 1 cm) between the 
edge of the tissue to be frozen (the “iceball”) and the freeze-sensitive tissue.  
The cryoablation procedure will be performed with moderate sedation or general 
anesthesia in a CT procedure room.  A limited CT will be obtained and the desired 


 
 
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access sites will be marked on the subject’s skin.  After sterile preparation of the 
treatment field and application of local anesthesia, cryoablation probes will be 
sequentially placed percutaneously into the target lesion(s) using CT and/or ultrasound 
guidance.  After all cryoablation probes are positioned appropriately, cryoablation will be 
performed with 1 or more freeze-thaw cycles.  Iceball growth will be monitored by CT.  
The probes will then be removed and sterile dressings applied.  
In brief, a total of 20 minutes of freezing time will be administered to the tumor in 
2 or 3 freeze-thaw cycles.  Care will be taken to avoid off-target ablation of sensitive 
structures such as bowel and skin.  The procedures will be performed under either 
moderate sedation, monitored anesthesia care (conscious sedation), or general 
anesthesia, depending on the subject's ability to tolerate positioning for the anticipated 
duration of the procedure.  The risks of ablation include hemorrhage, infection, 
pneumothorax, and injury to off-target structures.  With any procedure there is a small 
risk of death.  After ablation, the subject can expect discharge to home within 23 hours 
in most circumstances. 
6. 
DOSE MODIFICATIONS 
There will be no dose modifications for the investigational agents.   
Per-subject stopping rule  
Subjects will be monitored for toxicity at every study visit during the treatment phase 
(through 10 weeks).  As defined by the current US package inserts (USPIs) for 
nivolumab and ipilimumab, treatment will be withheld for the related adverse events 
(toxicities) specified therein, and additionally by the discretion of the investigator.  
Treatment may be resumed in accordance with the USPIs.  In the event that toxicity is 
judged to be excessive, treatment will be terminated with one or both agents.  Particular 
attention will be given to events that might be an overlapping toxicity.  
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
7.1.1 Ipilimumab (see appendix D for treatment algorithm) 
Inflammatory Events (Immune-related Adverse Events or Immune-mediated Adverse 
Reactions) 
Blockade of CTLA-4 by ipilimumab leads to T-cell activation, with the potential for 
clinical inflammatory AEs primarily involving the skin (dermatitis/pruritus), GI tract 
(diarrhea/colitis), liver (hepatitis), endocrine glands (eg, hypophysitis and adrenal or 
thyroid abnormalities), and other less frequent organs (eg, uveitis/episcleritis).  The 
majority of these inflammatory AEs initially manifest during treatment; however, a 
minority occur weeks to months after discontinuation of ipilimumab.  The majority of the 
inflammatory AEs are reversible with the guidance issued below.   
 Gastrointestinal Toxicities 
The most common site for ipilimumab-induced GI toxicity was the lower GI tract, and the 
most common presentation was mild to severe diarrhea or colitis with occasional bloody 
stools.  In some cases, diarrhea began as mild and then worsened.  Constipation was 


 
 
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rarely associated with ipilimumab administration.  Delay in corticosteroid treatment may 
be associated with a poor outcome for subjects with high-grade diarrhea. 
 Liver Toxicities 
Subjects receiving ipilimumab may develop elevations in LFTs in the absence of clinical 
symptoms.  Occasionally, subjects may present with symptoms, including right upper 
quadrant abdominal pain or unexplained vomiting.  Most cases of inflammatory hepatitis 
responded to high-dose corticosteroids (IV route recommended). 
 Endocrine Toxicities 
The most common inflammatory endocrine toxicities are hypophysitis and 
hypopituitarism, secondary cortisol deficiency (hypoadrenalism), hypothyroidism or 
thyroiditis.  Symptoms of hypopituitarism and other endocrine toxicities were generally 
controlled with appropriate hormone replacement. 
 Skin Toxicities 
The most common inflammatory skin toxicities are rash and pruritus, mostly mild to 
moderate in severity.  Two cases of fatal treatment-related toxic epidermal necrolysis 
have been reported in clinical trials.   
 Neurological Toxicities 
Neurological manifestations may include motor and/or sensory neuropathy.  Fatal 
Guillain-Barre syndrome and cases of myasthenia gravis have been reported in clinical 
trials.  Unexplained motor neuropathy, muscle weakness, or sensory neuropathy should 
be evaluated, and non-inflammatory causes such as infections, metabolic disorders, 
and medications should be excluded. 
 Other Toxicities 
Ocular inflammation can be manifested as episcleritis or uveitis.  Other presumed 
inflammatory events reported include, arthritis/arthralgia, pneumonitis, pancreatitis, 
autoimmune (aseptic) meningitis, autoimmune nephritis, pure red cell aplasia, 
noninfective myocarditis, polymyositis, eosinophilia, pericarditis, urticaria (2%), large 
intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, infusion 
reactions, and myasthenia gravis. 
7.1.2 Nivolumab (see appendix D for treatment algorithm) 
 Pulmonary toxicities 
Subjects can present with either asymptomatic radiographic changes (eg, focal ground 
glass opacities and patchy infiltrates) or with symptoms of dyspnea, cough, or fever.  
All subjects with Grade 3 to 4 pneumonitis should discontinue nivolumab and initiate 
treatment with high doses of corticosteroids.   
 Gastrointestinal toxicities 
Most cases present with diarrhea.  However diverticular perforation should also be 
considered when subjects present with abdominal pain and fevers.   


 
 
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 Hepatic toxicities 
Early recognition and treatment of elevated LFTs and drug-induces liver injury are 
critical to their management.  The principal treatment for high-grade hepatic AEs is 
corticosteroids. 
 Endocrinopathies 
The events are typically identified through either routine periodic monitoring of specific 
laboratories (eg, TSH) or as part of a work-up for associated symptoms (eg, fatigue).  
Moderate- to high-grade cases were managed with hormone replacement therapy and, 
in some cases, with the addition of corticosteroids.   
 Skin toxicities 
The most common skin toxicities include rash and pruritus.  Rashes are typically focal 
with a maculopapular appearance occurring on the trunk, back, or extremities.  Topical 
corticosteroids can be used for some cases of rash.  Anti-histamines can be used for 
some cases of pruritus.   
 Renal toxicities 
Elevated creatinine and biopsy-confirmed tubulointerstitial nephritis and allergic 
nephritis are seen infrequently. 
 Neurologic toxicities 
Neurologic AEs can manifest as central abnormalities (eg, aseptic meningitis, 
encephalopathy, or encephalitis) or peripheral sensory/motor neuropathies (eg, 
Guillain-Barre Syndrome, myasthenia gravis complicated with sepsis and fatality).  The 
onset has been observed as early as after a single treatment with the nivolumab + 
ipilimumab combination. 
 Infusion Reactions 
Infusion reactions, including high-grade hypersensitivity reactions, following 
administration of nivolumab are uncommon.  Investigators are advised to monitor for 
fever, chills, shakes, itching, rash, hypertension or hypotension, or difficulty in breathing 
during and immediately after administration of nivolumab.  Study protocols provide 
explicit guidance on the management of infusion-related reactions. 
 Lipase/Amylase Elevations 
In studies evaluating the safety of the nivolumab + ipilimumab combination in multiple 
tumor types, lipase and amylase levels were systematically monitored, and elevations in 
any grade of lipase/amylase were consistently noted in approximately 10% to 30% of 
subjects.  Very few subjects reported associated symptoms.   
 Uveitis and Visual Complaints 
Uveitis may occur more frequently with nivolumab + ipilimumab combination therapy 
than with nivolumab monotherapy or nivolumab in combination with other therapies.  An 
ophthalmologist should evaluate visual complaints with examination of the conjunctiva, 
anterior and posterior chambers, and retina.  Topical corticosteroids may be used to 


 
 
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manage low-grade events.  Low-grade events that do not resolve and high-grade 
events should be managed with systemic corticosteroids.  Rare cases of granulomatous 
panuveitis with exudative retinal detachment have been observed and are often 
associated with neurologic and cutaneous manifestations. 
 Other Immune-mediated Adverse Events 
Rare cases of myotoxicity (myositis, myocarditis, and rhabdomyolysis), some with fatal 
outcome, have been reported with nivolumab or nivolumab in combination with 
ipilimumab.   
For Grade 3 myocarditis, nivolumab or nivolumab in combination with ipilimumab should 
be permanently discontinued. 
7.2 
Adverse Event Reporting 
Adverse events will be graded according to CTCAE v5.  Adverse events will be 
recorded from the time the subject signs informed consent and for 30 days after the last 
dose of study drug.  Adverse Events will be clearly noted in source documentation and 
listed on study specific Case Report Forms (CRFs).  The Protocol Director (PD) or 
designee will promptly assess each Adverse Event (AE) to determine whether it is 
unexpected according to the Investigator’s Brochure;  this protocol,  and/or the informed 
consent document, and related to the both the study drug and the investigation itself.  
All Serious Adverse Events (SAEs) will be tracked until resolution, or until 100 days 
after the last dose of the study drug.  
Reporting Serious Adverse Events (SAEs)  
Any adverse event meeting the definition of a 21CFR§312.32 serious adverse event 
(SAE) that occurs during the clinical study and for 100 days after the last dose of study 
drug must be recorded as an on-study SAE.  Attribution of the SAE to study drug should 
follow the standard attribution and grading system as specified by CTEP 
(http://ctep.cancer.gov/reporting/adeers.html, see table below).   
Attribution of Adverse Events  
Code Descriptor 
Definition  
1  
Unrelated 
The adverse event is clearly not related to the investigational agent(s)  
2  
Unlikely 
The adverse event is doubtfully related to the investigational agent(s)  
3  
Possible 
The adverse event may be related to the investigational agent(s)  
4  
Probable 
The adverse event is likely related to the investigational agent(s)  
5  
Definite 
The adverse event is clearly related to the investigational agent(s)  
FDA 
Events that meet the 21CFR§312.32 definition of a serious, unexpected, suspected 
adverse reaction (SUSAR, ie, serious, unexpected, and related SAE) will be reported to 
the investigator’s IND as a serialized submission on the Form FDA 3500A (MedWatch 


 
 
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form for Mandatory Reporting), in accordance with the timelines defined at 
21CFR§312.32.  
Drug Manufacturer (Bristol Myers Squib) 
SAEs, whether related or not related to study drug, and any on-study pregnancies, will 
be reported within 24 hours to Bristol-Myers Squibb (SAE Email Address:  
Worldwide.Safety@BMS.com;  SAE Facsimile Number:  +1-609-818-3804).  The 
SAE will be reported on the Form FDA 3500A (MedWatch form for Mandatory 
Reporting) if used per the above;  or the Form FDA 3500 (MedWatch form for Voluntary 
Reporting) or the Council for International Organizations of Medical Sciences (CIOMS) 
form. 
Stanford Cancer Institute (SCI) Data Safety Monitoring Committee (DSMC) 
SAEs, CTCAE Grade 3 and above, whether related or not related to study drug;  all 
on-study pregnancies;  and all subsequent follow-ups must be reported to the Stanford 
Cancer Institute Data and Safety Monitoring Committee (DSMC) via 
CCTO-Safety@Stanford.edu within 24 hours (1 business day) of becoming aware of 
the event.  The SAE will be reported using the CCTO SAE CRF plus the 
Form FDA 3500A (MedWatch form) if prepared per above.  
Institutional Review Board (IRB) 
Events that meet the 21CFR§312.32 definition of a serious, unexpected, suspected 
adverse reaction (SUSAR) which occurred as a result of the study intervention(s) or 
protocol-specific procedures, including diagnostic procedures, will be reported to the 
local IRB of record.  If a Form FDA 3500A (MedWatch form) was prepared per the 
above, this should be part of the report.  
Following review by the SCI DSMC, the committee may issue an assessment that an 
event met the criteria of an IRB definition of “Unanticipated Problem (UP).”  Upon 
notification of such determination, the investigator will, if not previously reported to the 
IRB as a UP, submit a UP report of the event within 10 working days of DSMC 
notification, or within 5 working days for deaths or life-threatening events. 


 
 
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8. 
CORRELATIVE/SPECIAL STUDIES  
8.1  
Archival tumor samples: 
Histology, immunohistochemistry for lymphocyte subsets (include multi-marker studies 
such as MIBI or other) and for Gene Expression profiling  with additional analysis of 
immune subsets by Cibersort and for Gene Expression profiling within the immune cells 
by CibersortX.  The latter dataset can be validated by performing LCM-SMART-3SEQ. 
8.2  
Tumor samples collected throughout study:   
Histology, immunohistochemistry for lymphocyte subsets (include multi-marker studies 
such as MIBI or other) and for gene expression profiling (GEP) with additional analysis 
of immune subsets by Cibersort and for GEP within the immune cells by CibersortX.  
The latter dataset can be validated by performing LCM-SMART-3SEQ. 
8.3 
Blood collection:  
a) Determine ctDNA levels  
 Draw blood into two Streck Cell-free DNA BCT tubes (10 mL each)  
 Cell-free DNA will be extracted from plasma using QIAamp Circulating 
Nucleic Acid kit (Qiagen), according to the manufacturer’s protocol.  
Germline DNA will be extracted from peripheral blood cells using DNeasy 
Blood & Tissue kit (Qiagen), following the manufacturer’s protocol.  
Depending on the histological subtype of sarcoma, cell-free DNA will be 
analyzed for the presence of tumor-type specific point mutations and/or 
DNA copy number alterations.  For the point mutation analysis, we will 
apply deep targeted sequencing by Cancer Personalized Profiling by deep 
Sequencing (CAPP-Seq).  For detection of DNA copy number alterations, 
we will perform shallow whole genome sequencing.  We have previously 
successfully applied both methods to profile tumor-derived genomic 
aberrations in cell-free DNA extracted from plasma of subjects diagnosed 
with leiomyosarcoma (Przybyl J, Chabon JJ, et al.  Combination Approach 
for Detecting Different Types of Alterations in Circulating Tumor DNA in 
Leiomyosarcoma.  Clin Cancer Res.  2018 Jun 1;24(11):2688-2699.) 
b) Gene expression profiling on blood lymphocytes, followed by CibersortX to 
assess subsets.  This data can then be compared to c) 
 For gene expression profiling of blood cells, collect blood into two PAXgene 
Blood RNA tubes (2.5 mL each) manufactured by BD biosciences that are 
specifically optimized for RNA extraction from the blood cells.   
c) Perform flow with purification of T-cells, followed by Gene Expression profiling  
d) Perform proteomic analysis for cytokines 


 
 
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8.3.1 Blood Specimen Handling Instructions: 
 
a) Prior to Collection: 
 Using a permanent marker pen, record the required information (subject 
number) on the blood collection tube label. 
b)  Sample Collection and Handling: 
 Draw blood into two Streck BCT tubes (10 mL each), and draw blood into 
two PAXgene Blood RNA tubes (2.5 mL each).  Invert gently 10 times to 
mix. 
 Blood drawn into PAXgene tubes should be frozen at -80C and sent 
directly to van de Rijn lab on dry ice in batches of 40 tubes (so not each 
one separately). 
 Blood drawn in the Streck BCT tubes should be sent to van de Rijn 
laboratory of the Stanford University Medical Center for processing. 


 
 
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9. 
STUDY CALENDAR 
 
Pre-Study/ 
Baseline Wk 1 
Wk 4 
(± 3 d) 
Wk 7 
(± 3 d) 
Wk 10 
(± 3 d) 
Maintenance 
Every 4W± 1W 
Off-study   
(post-30 dy ± 1 wk) Follow-up i 
Investigational Agents 
 
X 
X 
X 
X 
X 
 
 
Cryoablation 
 
 
X 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
 
Performance status 
X 
X 
X 
X 
X 
X 
X 
 
PRO-CTCAE Questionnaire a 
 
X 
X 
X 
X 
X 
X 
 
CBC with differential and platelets b 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistry b 
X 
X 
X 
X 
X 
X 
X 
 
EKG  
X 
(as clinically indicated) 
 
 
Adverse event evaluation c 
X 
X 
X 
X 
X 
X 
X 
 
Tumor measurements d 
X 
 
 
 
X 
X 
 
 
Radiologic evaluation 
(CT, MRI, X-ray) d 
X 
 
 
 
X 
X d 
 
 
β-HCG e 
X 
X 
X e 
X 
X 
X e 
 
 
Other tests, as appropriate f 
X 
 
X 
 
 
 
 
 
Other correlative studies g 
 
X 
X 
X 
X 
 
X 
 
a.  PRO-CTCAE Questionnaire will be completed by patients at each study visit before any assessments are performed.  Questionnaires 
in English, Spanish, and traditional Chinese are attached in Appendix F.  
b.  Metabolic comprehensive includes:  albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), urea nitrogen, calcium, chloride, CO2, 
creatinine, glucose, globulin, potassium, sodium, total bilirubin, total protein.  These labs should be done at baseline within 14 days of 
first treatment, and within 72 hours of day 1 of each subsequent treatment.  
c.  Adverse events are based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Publish Date:  27 November 2017.  
Adverse events will be recorded from the time the subject signs informed consent through and including 30 days after the last dose of 
study drug.  All serious adverse events will be tracked until resolution, or until 100 days after the last dose of study drug. 
d.  Tumor measurements are based on RECIST v1.1 and irRECIST criteria (Appendices C & D).  Scans will be done at baseline within 
28 days of 1st treatment and then after dose 4 of immunotherapy (W 10 dose).  This scan should be done at week 14 ± 1 week and 
every 12 weeks ± 1 week, once subjects start maintenance nivolumab.  Ablated tumors will not be included as part of the treatment 
response assessment, ie, disease response;  measurable disease;  or tumor progression, by either RECIST or irRECIST.  The 
baseline measurements will be done before treatment, and follow-up measurements will be done after 4 doses of ipilimumab and 
nivolumab (12 weeks), then every 12 weeks thereafter.  At Investigator’s discretion, imaging of known sites of disease is 
recommended.  
e.  Serum β-HCG:  Women of child-bearing potential are required to have a negative pregnancy test within 24 hours (eligibility criteria) 
prior to the initial administration of study drug, then every 3 to 4 weeks (± 1 week) during the study (this test can be omitted if subject is 
post-menopausal by either surgery or elevated FSH).  
f.  ACTH, serum cortisol, TSH, free T4, CRP, ESR.  
g.  Archival tumor sample must be available at baseline.  All subsequent biopsies will be collected in paraffin for research purposes and 
standard diagnostics.  Blood will be collected at baseline, and prior to treatment dose on weeks 1, 4, 7, 10 and during the off-study 
visit.  Off study visit with a ± 1 week. 
h.  Per protocol cryoablation is required to be performed before Week 4 administration of ipilimumab and nivolumab.  (between Cycle 1 
and Cycle 2), at the discretion of the of the investigator.  
i.  Safety follow-up:  After the off-study visit, there will be two additional follow-up phone call/or retrieval of medical records that occur 
every 35 days ± 1 week to collect information on participants’ health status. 


 
 
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10. 
MEASUREMENTS 
10.1  Primary and Secondary Outcome measures 
Primary Outcome 
 Outcome 1 (Primary) Title:  Clinical Response  
 Outcome Description:  Clinical response was assessed per the Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. 
o Complete response (CR) = Disappearance of all target lesions; all lymph 
nodes < 10 mm on the short axis; no new lesions. 
o Partial response (PR) = ≥ 30% decrease in the sum of the longest 
diameter of target lesions; no new lesions. 
o Stable disease (SD) = Small changes that do not meet any of the above 
criteria; no new lesions. 
o Progressive disease (PD) = 20% increase in the sum of the longest 
diameter of target lesions, and/or the appearance of one or more new 
lesion(s). 
The outcome is expressed as the total number of participants who achieve a 
RECIST clinical response, defined as CR + PR, by 16 weeks, a number 
without dispersion.  The outcome is expressed as the total number of 
participants who achieve a clinical response by 16 weeks, a number without 
dispersion.   
 Outcome Timeframe:  16 weeks 
Note:  Per guidance from ClinicalTrials.gov, a single Primary Outcome is declared.  
Other primary and secondary objectives are reflected as secondary outcomes.  


 
 
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Secondary Outcomes 
 Outcome 2 (Secondary) Title:  Partial Response (PR) Rate   
o Outcome Description:  Clinical response was assessed per the Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. 
 Complete response (CR) = Disappearance of all target lesions; no new 
lesions. 
 Partial response (PR) = ≥ 30% decrease in the sum of the longest 
diameter of target lesions; no new lesions. 
 Stable disease (SD) = Small changes that do not meet any of the 
above criteria; no new lesions. 
 Progressive disease (PD) = 20% increase in the sum of the longest 
diameter of target lesions, and/or the appearance of one or more new 
lesion(s) 
The outcome is expressed as the total number of participants who achieve 
PR by 16 weeks, a number without dispersion.  
o Outcome Timeframe:  16 weeks 
 Outcome 3 (Secondary) Title:  Stable Disease (SD) Rate   
o Outcome Description:  Clinical response was assessed per the Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. 
 Complete response (CR) = Disappearance of all target lesions; no new 
lesions. 
 Partial response (PR) = ≥ 30% decrease in the sum of the longest 
diameter of target lesions; no new lesions. 
 Stable disease (SD) = Small changes that do not meet any of the 
above criteria; no new lesions. 
 Progressive disease (PD) = 20% increase in the sum of the longest 
diameter of target lesions, and/or the appearance of one or more new 
lesion(s) 
The outcome is expressed as the total number of participants with SD at 
16 weeks, a number without dispersion.  
o Outcome Timeframe:  16 weeks 
 Outcome 4 (Secondary) Title:  Related Adverse Events (Toxicity)  
o Outcome Description:  Adverse events were assessed per CTCAE 
version 5.  The outcome is expressed as the total number of possibly, 
probably, or definitely-related adverse events experienced by participants, 
a number without dispersion.  
o Outcome Timeframe:  24 months  


 
 
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 Outcome 5 (Secondary) Title:  Immune-related Clinical Response (irRECIST)  
 Outcome Description:  The Immune-related Response Evaluation Criteria 
in Solid Tumors (irRECIST) vary from the RECIST criteria in order to 
distinguish cellular anti-tumor responses from tumor progression.  This is 
primarily accomplished by specifying the minimum size to be considered a 
new tumor lesion.  Clinical response was assessed per the irRECIST 
criteria. 
o Complete response (CR) = Disappearance of all target lesions; no new 
lesions > 5 × 5 mm in size. 
o Partial response (PR) = ≥ 30% decrease in the sum of the longest 
diameter of target lesions; no new lesions > 5 × 5 mm in size. 
o Stable disease (SD) = Small changes that do not meet any of the 
above criteria; no new lesions > 5 × 5 mm in size. 
o Progressive disease (PD) = 20% increase in the sum of the longest 
diameter of target lesions, and/or the appearance of one or more new 
lesion(s). 
The outcome is expressed as the total number of participants who achieve 
an irRECIST clinical response, defined as CR + PR, by 16 weeks, 
a\ number without dispersion.   
 Outcome Timeframe:  16 weeks 
 Outcome 6 (Secondary) Title:  Progression-free survival (PFS)   
o Outcome Description:  6-month Progression-free survival (PFS) as 
measured from the time of consent until death or disease progression.  
The outcome is expressed as the total number of participants remaining 
alive without disease progression at 6 months after consent, a number 
without dispersion.  
o Outcome Timeframe:  6 months  
11. 
REGULATORY CONSIDERATIONS 
11.1 Regulatory Oversight 
The US Food and Drug Administration (FDA) has not approved ipilimumab nor 
nivolumab for the treatment of soft tissue sarcoma, however ipilimumab and nivolumab 
are approved for use in combination by the FDA for several tumor settings.  Although 
the investigator will submit an IND for this study, the FDA may deem the study to be 
IND-exempt.  
This study will only be initiated and conducted after review and approval by the local 
IRB of record. 


 
 
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11.2 Monitoring plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be 
the monitoring entity for this study. 
The DSMC will audit study-related activities approximately once per year to determine 
whether the study has been conducted in accordance with the protocol, local standard 
operating procedures, FDA regulations, and Good Clinical Practice (GCP).  This may 
include review of the following types of documents participating in the study:  regulatory 
binders, case report forms, eligibility checklists, and source documents.  In addition, the 
DSMC will regularly review serious adverse events and protocol deviations associated 
with the research to ensure the protection of human subjects.  Results of the DSMC 
audit will be communicated to the IRB and the appropriate regulatory authorities at the 
time of continuing review, or in an expedited fashion, as needed.  
11.3  Protocol Review and Amendments 
The protocol, the proposed informed consent and all forms of participant information 
related to the study (eg, advertisements used to recruit participants) will be reviewed 
and approved by the Stanford IRB and Stanford Cancer Institute Scientific Review 
Committee (SRC).  Any changes made to the protocol will be submitted as a 
modification and will be approved by the IRB prior to implementation.  
11.4  Data management  
The research coordinator will be responsible for database records of subject data.  The 
data will be kept in an OnCore online database, under password protection with access 
limited to specific areas of the database.  A chart with all of the relevant research 
subject information will be maintained for each subject by the research coordinator.  
Subject charts will be reviewed by Stanford PI and Study Coordinator for yearly audits.  
11.5 Study Documentation  
The Protocol Director must maintain adequate and accurate participant case histories 
with observations and other data pertinent to the study.  Original source documents 
should be transcribed to Case Report Forms (CRFs).  Source documents include 
hospital records, clinical charts, laboratory and pharmacy records, and recorded 
electronic data.   
The Principal Investigator will be responsible for maintaining the clinical protocol and 
subjects’ study charts, reporting adverse events, assuring that consent is obtained and 
documented, and reporting the status of the trial in continuing renewals submitted to 
their IRB and trial monitoring group(s).  
12. 
STATISTICAL CONSIDERATIONS 
We anticipate enrolling no more than 30 subjects to achieve our aims and this is 
feasible.  Specifically, it is anticipated that 3 to 4 subjects per month may be enrolled 
onto this trial.  Thus, it is expected that 12 months will be required to accrue the number 
of subjects necessary to complete the trial.  
More specifically, clinical benefit (CR/PR/SD) will be assessed for each subject at 
16 weeks.  Our null hypothesis is that the response rate is ≤ 30%, and our alternative 


 
 
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hypothesis is that the response rate is ≥ 60%.  The selection of 60% as a threshold for 
determining the treatment is worthy of further study is due to recent trials of sarcoma 
FDA-approved drugs showing ~60% PFS rate at 3 months (ie, pazopanib, trabectedin, 
eribulin).  
We will employ a Simon 2-stage design to address our primary objective.  The type 1 
error rate assumed for the Simon 2-stage design is 0.04.  The null hypothesis that the 
true response rate (ie, sum of CR and PR) is 30% or less will be tested against a 
one-sided alternative.  Our decision rule works as follows.  In the first stage, we will 
accrue and assess 10 subjects.  If 3 or fewer subjects (< 30% of 10 subjects) achieve a 
clinical response, the trial will be stopped for futility.  If more than 3 subjects achieve a 
clinical response, we will enroll and treat an additional 18 subjects.  If 12 or fewer of the 
28 treated subjects (< 42.8%) demonstrate a clinical response (either CR or PR), we will 
conclude the treatment is not worthy of further study.  If, however, more than 12 of the 
28 treated subjects (≥ 42.8%) responds, we will claim the treatment promising.  
Assuming a true response rate of 60%, we have 90% power to correctly conclude the 
treatment promising.  In contrast, if the true response rate is only 30%, we have a low 
probability (0.04) of incorrectly continuing to study the treatment.  
Additionally, we will characterize rates of toxicity by level of toxicity as well as by other 
subject-level characteristics.  
To address secondary objectives, we will use Kaplan-Meier methods to graphically 
depict progression-free survival.  This tool will also be used to demonstrate survival 
across various sub-groups of interest.  Generalized linear regression methods (with a 
logit link) will be utilized to characterize relationships between features such as mutation 
burden, PDL1 expression, and tumor infiltrating lymphocytes and response.  


 
 
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13. 
REFERENCES 
1. D'Angelo SP, Mahoney MR, Van Tine BA, et al.  Nivolumab with or without 
ipilimumab treatment for metastatic sarcoma (Alliance A091401):  two open-label, 
non-comparative, randomised, phase 2 trials.  Lancet Oncol.  2018 
Mar;19(3):416-426. 
2. Nomura M, Otsuka A, Yoshimura M, et al.  Efficacy and safety of concurrent 
immunoradiotherapy in subjects with metastatic melanoma after progression on 
nivolumab.  Cancer Chemother Pharmacol.  2018 May;81(5):823-827.   
3. Twyman-Saint Victor C, Rech AJ, Maity A et al (2015) Radiation and dual 
checkpoint blockade activate non-redundant immune mechanisms in cancer.  
Nature 520:373–377 
4. Liniker E, Menzies AM, Kong BY et al (2016) Activity and safety of radiotherapy 
with anti-PD-1 drug ther apy in subjects with metastatic melanoma.  
Oncoimmunology 5:e1214788 
5. Aboudaram A, Modesto A, Chaltiel L et al (2017) Concurrent radiotherapy for 
subjects with metastatic melanoma and receiving anti-programmed-death 1 
therapy:  a safe and effective combination.  Melanoma Res 27:485–491 
6. Abdo J, Cornell DL, Mittal SK, et al.  Immunotherapy Plus Cryotherapy:  Potential 
Augmented Abscopal Effect for Advanced Cancers.  Front Oncol.  2018 Mar 
28;8:85. 
7. Sheng JY, et al.  Systemic Therapy for Advanced Soft Tissue Sarcoma.  Surg Clin 
N Am.  2016; 96:1141-1156.   
8.   Riedel RF, et al.  Systemic therapy for advanced soft tissue sarcomas:  highlighting 
novel therapies and treatment approaches, Cancer.  2012; 118:1474-1485.   
9.   Spira AI, et al.  The use of chemotherapy in soft-tissue sarcomas.  The Oncologist; 
2002; 7:348-359.   
10.  Sordillo PP, et al.  Cisplatin.  A phase II evaluation in previously untreated subjects 
with soft tissue sarcomas.  Cancer.  1987; 59:  884-886.   
11.  Garcia-Carbonero R, et al.  Ecteinascidin-743 (ET-743) for chemotherapy-naïve 
subjects with advanced soft tissue sarcomas:  multicenter phase II and 
pharmacokinetic study.  J Clin Oncol.  2005 Aug 20; 24:  5484-5492.   
12.  Beck AH, Weng Z, Witten DM, Zhu S, Foley JW, et al.  (2010) 39-End Sequencing 
for Expression Quantification (3SEQ) from Archival Tumor Samples.  PLoSONE 
5(1):  e8768.  doi:10.1371/journal.pone.0008768 
13.  Foley JW, Zhu C, Jolive P, et al.  Gene-expression pro ling of single cells from 
archival tissue with laser-capture microdissection and Smart-3SEQ.  bioRxiv  
207340;doi:  https://doi.org/10.1101/207340 
14.  Guo X, Jo VY, Mills AM, et al.  Clinically Relevant Molecular Subtypes in 
Leiomyosarcoma.  doi:  10.1158/1078-0432.CCR-14-3141 


 
 
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APPENDICES 
APPENDIX A:  Participant Eligibility Checklist  
A Participant Eligibility Checklist must be completed in its entirety for each subject prior to 
registration.  The completed, signed, and dated checklist must be retained in the subject’s study 
file and the study’s Regulatory Binder.   
Protocol Title: 
Phase II Study of Ipilimumab Plus Nivolumab in Combination 
with Cryotherapy in Metastatic or Locally Advanced Soft 
Tissue Sarcoma  
Protocol Number: 
IRB-50853 
Principal Investigator: 
Kristen Ganjoo, MD 
II.  Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
III.  Study Information: 
SRC Approved 
 IRB Approved 
  
III.  Inclusion/Exclusion Criteria 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Unresectable or metastatic soft tissue sarcoma 
 
 
      
2. ≥ 1 prior systemic therapy for sarcoma, including 
adjuvant systemic therapy 
 
 
      
3. Age ≥ 18 years 
 
 
      
4. Life expectancy > 3 months 
 
 
      
5. Eastern Cooperative Oncology Group (ECOG) 
performance status 0 or 1 
 
 
      
6. Absolute neutrophil count (ANC) ≥ 1,000/mm3 
 
 
      
7. Platelet count ≥ 75,000/mm3 
 
 
      
8. Creatinine ≤ 1.5 x upper limit of normal (ULN) OR 
calculated (calc.) creatinine clearance 
> 45 mL/min using the lean body mass formula 
only 
 
 
      
9. Total bilirubin ≤ 1.5 x ULN in absence of Gilbert 
disease (total bilirubin ≤ 3 x ULN with Gilbert); 
also, if hyperbilirubinemia is clearly attributed to 
liver metastases total bilirubin ≤ 3 x ULN is 
permitted 
 
 
      
10. AST/ALT ≤ 3 x ULN 
 
 
      


 
 
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11. Thyroid stimulating hormone (TSH) within normal 
limits (WNL); supplementation is acceptable to 
achieve a TSH WNL; in subjects with abnormal 
TSH if free T4 is normal and subject is clinically 
euthyroid, subject is eligible 
 
 
      
12. Any toxic effects of prior therapy (except alopecia) 
must be resolved to NCI CTCAE, version 5.0, 
Grade 1 or less 
 
 
      
13. Ability to understand and the willingness to sign a 
written informed consent document 
 
 
      
14. Women of childbearing potential (WOCBP) 
receiving nivolumab must be willing to adhere to 
contraception for a period of 5 months after the 
last dose of nivolumab.  Men receiving nivolumab 
and who are sexually active with WOCBP will be 
instructed and must be willing to adhere to 
contraception for a period of 7 months after the 
last dose of nivolumab 
 
 
      
Exclusion Criteria 
(From IRB approved protocol) 
 
1. Prior therapy with ipilimumab or nivolumab, or any 
agent targeting programmed cell death 1 (PD-1), 
PD-L1 or cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) 
 
 
      
2. Active known or suspected autoimmune disease 
 
 
      
3. Subjects with known human immunodeficiency 
virus (HIV) (Subjects with lymphocytes > 350 
cluster of differentiation (CD)4+ cells and no 
detectable viral load are eligible) 
 
 
      


 
 
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4. Active known Hepatitis B.  Testing is unrequired 
in the absence of history. 
Hepatitis B can be defined as: 
 Hepatitis B surface antigen (HBsAg) 
> 6 months.   
 Serum hepatitis B virus (HBV) deoxyribonucleic 
acid (DNA) 20,000 IU/mL (105 copies/mL), 
lower values 2,000 to 20,000 IU/mL 
(104 to 105 copies/mL) are often seen in 
hepatitis B-e antigen (HbeAg)-negative chronic 
hepatitis B 
 Persistent or intermittent elevation in alanine 
aminotransferase (ALT)/alanine 
aminotransferase (AST) levels.   
 Liver biopsy showing chronic hepatitis with 
moderate or severe necroinflammation 
 
 
      
5. Active Known Hepatitis C.  Testing is unrequired 
in the absence of history.  
 Hepatitis C antibody (Ab) positive 
 Presence of hepatitis C virus (HCV) 
ribonucleic acid (RNA) 
 
 
      
6. Known active pulmonary disease with hypoxia 
defined as: 
 Oxygen saturation < 85% on room air or  
 Oxygen saturation < 88% despite 
supplemental oxygen 
 
 
      
7. Systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 7 days of 
registration 
 
 
      
8. Received any live/attenuated vaccine 
(eg, varicella, zoster, yellow fever, rotavirus, 
oral polio and measles, mumps, rubella 
(MMRI) within 30 days before initiation of 
treatment on this protocol 
 
 
      
9. If female, pregnant or lactating.  (Women of 
childbearing potential are required to have a 
negative pregnancy test within 24 hours prior to 
the initial administration of study drug)  
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  The method of 
confirmation can include, but is not limited to, laboratory test results, radiology test results, subject 
self-report, and medical record review.   


 
 
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IV.  Statement of Eligibility 
By signing this form of this trial, I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study.  This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
Study Coordinator Signature: 
Date: 
Printed Name: 


 
 
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APPENDIX B:  Revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1  
1. 
Measurability of tumor at baseline 
1.1.  Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows: 
1.1.1.  Measurable 
Tumor lesions:  Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of 10 mm 
by CT scan (CT scan slice thickness no greater than 5 mm).  10 mm caliper 
measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable).  20 mm by chest X-ray. 
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.   
1.1.2.  Non-measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions.  
Lesions considered truly non-measurable include:  leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, abdominal masses/abdominal organomegaly identified by physical exam 
that is not measurable by reproducible imaging techniques.  
1.1.3.  Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions:  Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions.  However, these techniques can be used to 
confirm the presence or disappearance of bone lesions.  Lytic bone lesions or mixed 
lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by 
cross sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability 
described above.  Blastic bone lesions are non-measurable. 
Cystic lesions:  Lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts.  ‘Cystic lesions’ thought to 
represent cystic metastases can be considered as measurable lesions, if they meet the 
definition of measurability described above.  However, if non-cystic lesions are present 
in the same subject, these are preferred for selection as target lesions. 
Lesions with prior local treatment:  Tumor lesions situated in a previously irradiated 
area, or in an area subjected to other loco-regional therapy, are usually not considered 


 
 
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measurable unless there has been demonstrated progression in the lesion.  Study 
protocols should detail the conditions under which such lesions would be considered 
measurable. 
1.2.  Specifications by methods of measurements 
1.2.1.  Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
1.2.2.  Method of assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  
Imaging based evaluation should always be done rather than 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 and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules).  
For the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.  As noted above, when lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should be undertaken 
since it is more objective and may also be reviewed at the end of the study.   
Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.   
CT, MRI:  CT is the best currently available and reproducible method to measure 
lesions selected for response assessment.  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less.  
When 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 (eg, for body scans).   
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, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following complete response or surgical resection is an endpoint.   


 
 
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2.  Tumor response evaluation 
2.1.  Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Only subjects with measurable disease at baseline should be included.  
Measurable disease is defined by the presence of at least one measurable lesion (as 
detailed above in Section 3).   
2.2.  Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total (and a maximum of 2 lesions per organ) representative of 
all involved organs should be identified as target lesions and will be recorded and 
measured at baseline (this means in instances where subjects have only 1 or 2 organ 
sites involved a maximum of 2 and 4 lesions respectively will be recorded).   
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. 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor.  As noted in Section 3, 
pathological nodes which are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short 
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor.  
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal).  The smaller of these measures is the 
short axis.  For example, an abdominal node which is reported as being 20 mm × 
30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node.  In 
this example, 20 mm should be recorded as the node measurement.  All other 
pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered 
non-target lesions.  Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed. 
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 as noted above, only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the 
disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline.  


 
 
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Measurements are not required, and these lesions should be followed as ‘present’, 
‘absent’, or in rare cases ‘unequivocal progression’ (more details to follow).  In addition, 
it is possible to record multiple non-target lesions involving the same organ as a single 
item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’). 
2.3.  Response criteria 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
2.3.1.  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 diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD):  At least a 20% increase in the sum of 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). 
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. 
2.3.2.  Special notes on the assessment of target lesions 
Lymph nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero 
even if complete response criteria are met, since a normal lymph node is defined as 
having a short axis of < 10 mm.  Case report forms or other data collection methods 
may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm.  For 
PR, SD and PD, the actual short axis measurement of the nodes is to be included in the 
sum of target lesions. 
Target lesions that become ‘too small to measure’ 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their 
actual measurements recorded at each subsequent evaluation, even when very small 
(eg, 2 mm).  However, sometimes lesions or lymph nodes which are recorded as target 
lesions at baseline become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measure and may report them as being ‘too small to 
measure’.  When this occurs, it is important that a value be recorded on the case report 
form.  If it is the opinion of the radiologist that the lesion has likely disappeared, the 


 
 
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measurement should be recorded as 0 mm.  If the lesion is believed to be present and 
is faintly seen but too small to measure, a default value of 5 mm should be assigned 
(Note:  It is less likely that this rule will be used for lymph nodes since they usually have 
a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well).  This default value is derived from the 5 mm CT slice thickness 
(but should not be changed with varying CT slice thickness).  The measurement of 
these lesions is potentially non-reproducible, therefore providing this default value will 
prevent false responses or progressions based upon measurement error.  To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions 
should be added together to calculate the target lesion sum.  Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion.  If the lesions have truly coalesced 
such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
2.3.3.  Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor 
response for the group of non-target lesions.  While some non-target lesions may 
actually be measurable, they need not be measured and instead should be assessed 
only qualitatively at the time points specified in the protocol. 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (< 10 mm short 
axis). 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
Progressive Disease (PD):  Unequivocal progression (see comments below) of existing 
non-target lesions.  (Note:  the appearance of one or more new lesions is also 
considered progression). 
2.3.4  New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, 
some comments on detection of new lesions are important.  There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new 
lesion should be unequivocal:  i.e.  not attributable to differences in scanning technique, 
change in imaging modality or findings thought to represent something other than tumor 
(for example, some ‘new’ bone lesions may be simply healing or flare of pre-existing 
lesions).  This is particularly important when the subject’s baseline lesions show partial 
or complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan report as a ‘new’ cystic lesion, which it is not. 


 
 
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A lesion identified on a follow-up study in an anatomical location that was not scanned 
at baseline is considered a new lesion and will indicate disease progression.  An 
example of this is the subject who has visceral disease at baseline and while on study 
has a CT or MRI brain ordered which reveals metastases.  The subject’s brain 
metastases are considered to be evidence of PD even if he/she did not have brain 
imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease.  If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the initial scan. 
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. 
2.4.  Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for 
confirmation.  The subject’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions.   
2.4.1.  Time point response 
Table 1 on provides a summary of the overall response status calculation at each time 
point for subjects who have measurable disease at baseline. 


 
 
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Table 1.  Overall Response Status Calculation by Time point 
 
2.4.2.  Missing assessments and non-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the subject is 
not evaluable (NE) at that time point.  If only a subset of lesion measurements are made 
at an assessment, usually the case is also considered NE at that time point, unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response.  This would be most likely 
to happen in the case of PD.  For example, if a subject had a baseline sum of 50 mm 
with three measured lesions and at follow-up only two lesions were assessed, but those 
gave a sum of 80 mm, the subject will have achieved PD status, regardless of the 
contribution of the missing lesion. 
2.4.3.  Best overall response:  all time points 
The best overall response is determined once all the data for the subject is known. 
Best response determination in this trial where confirmation of complete or partial 
response IS NOT required:  Best response in these trials is defined as the best 
response across all time points (for example, a subject who has SD at first assessment, 
PR at second assessment, and PD on last assessment has a best overall response of 
PR).  When SD is believed to be best response, it must also meet the protocol specified 
minimum time from baseline.  If the minimum time is not met when SD is otherwise the 
best time point response, the subject’s best response depends on the subsequent 
assessments.  For example, a subject who has SD at first assessment, PD at second 
and does not meet minimum duration for SD, will have a best response of PD.  The 
same subject lost to follow-up after the first SD assessment would be considered 
non-evaluable. 


 
 
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2.4.4.  Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that subjects with CR may not have a total sum of ‘zero’ on the case 
report form (CRF). 
Subjects 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 
objective progression even after discontinuation of treatment.  Symptomatic 
deterioration is not a descriptor of an objective response:  it is a reason for stopping 
study therapy.  The objective response status of such subjects is to be determined by 
evaluation of target and non-target disease as shown in Table 1, Table 2, and Table 3. 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends upon this determination, it 
is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) 
before assigning a status of complete response.  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. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment.  If at the next scheduled assessment, progression is confirmed, 
the date of progression should be the earlier date when progression was suspected. 
 


 
 
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APPENDIX C:  Immune-related Response Evaluation Criteria in Solid Tumors 
(Immune-related RECIST, irRECIST)  
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents, which can produce delayed responses that may 
be preceded by initial apparent radiographic progression, including the appearance of 
new lesions.  Therefore, immune-related response criteria have been developed to 
incorporate new lesions into the assessment of total tumor burden and allow 
radiographic progression to be confirmed at a subsequent assessment.  
Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), as described 
within this appendix, were adapted from RECIST, Version 1.1 (v1.1) (Eisenhauer, et al.  
2009), in the same manner that immune-related response criteria were adapted from 
WHO criteria (Wolchok et al.  2009) and RECIST v1.0 (Nishino et al.  2014).  When not 
otherwise specified, RECIS  v1.1 conventions will apply.  
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment time points.  Additional assessments may be performed as clinically 
indicated for suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions: 
Tumor lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size as 
follows: 
 10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (CT/MRI scan slice thickness/interval ≤ 5 mm) 
 10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
≥ 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be ≤ 5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is 
provided below (see "Identification of Target and Non-Target Lesions," "New Lesions," 
and "Calculation of Sum of Diameters"). 
DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis ≥ 10 mm but < 15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 


 
 
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mass/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
 Technetium-99m bone scans, sodium fluoride positron emission tomography 
scans, and plain films are not considered adequate imaging techniques for 
measuring bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such 
as CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
Cystic Lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
 Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same subject, these are preferred 
for selection as target lesions. 
Lesions with Prior Local Treatment: 
 Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there 
has been demonstrated progression in the lesion. 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
≥ 10 mm in diameter as assessed using calipers (eg, skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 


 
 
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CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is ≤ 5 mm.  When CT 
scans have slice thickness of > 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a subject is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
subject at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For subjects who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease, and should 
be optimized to allow for comparison with the prior studies if possible.  Each case 
should be discussed with the radiologist to determine if substitution of these other 
approaches is possible and, if not, the subject should be considered not evaluable from 
that point forward.  Care must be taken in measurement of target lesions and 
interpretation of non-target disease or new lesions on a different modality, since the 
same lesion may appear to have a different size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, CYTOLOGY, 
HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation. 
ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which subjects have only 
1 or 2 organ sites involved, a maximum of 2 lesions (1 site) and 4 lesions (2 sites), 
respectively, will be recorded.  Other lesions (albeit measurable) in those organs will be 
considered non-target lesions. 


 
 
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Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should 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 that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must 
meet the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short axis of these 
nodes will contribute to the baseline sum.  The short axis of the node is the diameter 
normally used by radiologists to judge if a node is involved by solid tumor.  Lymph node 
size is normally reported as two dimensions in the plane in which the image is obtained 
(for CT, this is almost always the axial plane; for MRI, the plane of acquisition may be 
axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For 
example, an abdominal node that is reported as being 20 mm × 30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions.  Nodes that 
have a short axis of < 10 mm are considered non-pathological and should not be 
recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (eg, "multiple enlarged pelvic lymph nodes" or "multiple 
liver metastases"). 
NEW LESIONS 
New lesions identified after baseline will be evaluated for measurability with use of the 
same criteria applied to prospective target lesions at baseline per RECIST 
(eg, non−lymph node lesions must be ≥ 10 mm on the longest diameter; new lymph 
nodes must be ≥ 15 mm on the short axis [see note below]).  All new lesions 
(measurable or non-measurable) must be assessed and recorded at the time of 
identification and at all subsequent tumor assessment time points. 
Up to a maximum of five measurable new lesions total (and a maximum of two lesions 
per organ) can be included in the calculation of tumor burden that is performed as part 
of the tumor response evaluation.  New lesion types that would not qualify as target 
lesions per RECIST cannot be included in the calculation of tumor burden and thus will 
not affect overall tumor response evaluation.  New lesions that are not measurable at 
first appearance but meet measurability criteria at a subsequent time point can be 
included in the tumor response evaluation from that point on, if the maximum number of 
measurable new lesions has not been reached.   


 
 
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Note regarding new lymph node lesions:  If at first appearance the short axis of a lymph 
node lesion is ≥ 15 mm, it will be considered a measurable new lesion.  If at first 
appearance the short axis of a lymph node lesion is ≥ 10 mm and < 15 mm, the lymph 
node will not be considered measurable but will still be considered a new lesion and 
should be identified as a non-measurable new lesion.  If at first appearance the short 
axis of a lymph node is < 10 mm, the lymph node should not be considered pathological 
and should not be considered a new lesion.  A lymph node can subsequently become 
measurable, when the short axis is ≥ 15 mm. 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for non−lymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline as a measure of 
tumor burden.  At each subsequent tumor assessment, a sum of the diameters (longest 
diameter for non-lymph node lesions, short axis for lymph node lesions) will be 
calculated for all target lesions plus measurable new lesions (up to five new lesions, 
with a maximum of two new lesions per organ) that have emerged after baseline.  
Hence, each net percentage change in tumor burden per assessment accounts for the 
size and growth kinetics of both old lesions and new lesions as they appear.   
Measuring Lymph Nodes 
If at first appearance the short axis of a new lymph node lesion is ≥ 15 mm, it will be 
considered a measurable new lesion and may be included in the sum of the diameters. 
If the new lymph node lesion is included in the sum of diameters, it will continue to be 
measured and included in the sum of diameters at subsequent time points, even if the 
short axis decreases to < 15 mm (or even < 10 mm).  However, if it subsequently 
decreases to < 10 mm and all other lesions are no longer detectable or have also 
decreased to a short axis of < 10 mm (if lymph nodes), a response assessment of 
complete response may be assigned. 
Lymph nodes should always have the actual short axis measurement recorded 
(measured in the same anatomical plane as the baseline examination), even if the node 
regresses to < 10 mm during the study.  Thus, when lymph nodes are included in the 
sum of diameters, the sum may not be zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions and up to five measurable new lesions (lymph node 
and non−lymph node) should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes lesions 
or lymph nodes become so faint on CT scan that the radiologist may not feel 
comfortable assigning an exact measurement and may report them as being too small 
to measure.  When this occurs, it is important that a value be recorded on the CRF, as 
follows: 
 If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 


 
 
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 If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned in this circumstance as well and "too small to measure" should also be 
ticked). 
To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is < 5 mm, and in that case "too small to measure" should 
not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When non−lymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS AND NON-MEASURABLE NEW LESIONS 
Measurements are not required for non-target lesions or non-measurable new lesions. 
Non-target lesions should be noted at baseline, and non-measurable new lesions 
should be noted at the time of identification.  At subsequent evaluations, non-target 
lesions and non-measurable new lesions will be categorized as "present" or "absent." 
After baseline, changes in non-target lesions or non-measurable new lesions (or 
measurable new lesions in excess of five total or two per organ) will contribute only in 
the assessment of complete response (ie, a complete response is attained only with the 
complete disappearance of all tumor lesions, including non-target lesions and 
non-measurable new lesions) and will not be used to assess progressive disease. 
RESPONSE CRITERIA 
Definitions of the criteria used to determine objective tumor response are provided 
below: 
 Complete response (CR):  Disappearance of all lesions.  Any pathological lymph 
nodes must have reduction in short axis to < 10 mm. 
 Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions plus measurable new lesions (up to a maximum of five total or two per 
organ), taking as reference the baseline sum of diameters, in the absence of CR 
 Progressive disease (PD):  At least a 20% increase in the sum of diameters of all 
target lesions plus measurable new lesions (up to a maximum of five total or two per 
organ), taking as reference the smallest sum of diameters on study (including 
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 In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of ≥ 5 mm.  New lesions alone do not qualify as 
progressive disease.  However, their contribution to total tumor burden is factored 
into the sum of the diameters, which is used to determine the overall irRECIST 
tumor response. 
 Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular time point, the subject is 
not evaluable at that time point.  If measurements are made on only a subset of target 
or measurable new lesions at a time point, usually the case is also considered not 
evaluable 
at that time point, unless a convincing argument can be made that the contribution of 
the individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a subject had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the subject will have achieved 
PD status, regardless of the contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Subjects with a global deterioration in 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 
objective progression even after discontinuation of treatment.  Symptomatic 
deterioration is not a descriptor of an objective response; it is a reason for stopping 
study therapy.  The objective response status of such subjects is to be determined by 
evaluation of target and non-target lesions, as well as new lesions, as shown in Table 2. 


 
 
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APPENDIX D:  Toxicity Management 
(From Investigator Brochure nivolumab:  BMS-936558/MDX1106/ONO-4538, pg 
283-290) 
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 subjects with low-grade toxicity.  The lower bioavailability of oral 
corticosteroids should be taken into account when switching to the equivalent dose of 
oral corticosteroids. 
GI Adverse Event Management Algorithm 
Rule out non-inflammatory causes.  If non-inflammatory cause is identified, treat 
accordingly and continue I-O therapy.  Opiates/narcotics may mask symptoms of 
perforation.  Infliximab should not be used in cases of perforation or sepsis. 
 
Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed.  Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 


 
 
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Renal Adverse Event Management Algorithm 
Rule out non-inflammatory causes.  If non-inflammatory cause, treat accordingly and 
continue I-O therapy. 
 
Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed.  Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 


 
 
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Pulmonary Adverse Event Management Algorithm 
Rule out non-inflammatory causes.  If non-inflammatory cause, treat accordingly and 
continue I-O therapy.  Evaluate with imaging and pulmonary consultation. 
 
Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed.  Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids 


 
 
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Hepatic Adverse Event Management Algorithm 
Rule out non-inflammatory causes.  If non-inflammatory cause, treat accordingly and 
continue I-O therapy.  Consider imaging for obstruction. 
 
Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed.  Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
*The recommended starting dose for Grade 4 hepatitis is 2 mg/kg/day 
methylprednisolone IV. 


 
 
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Endocrinopathy Adverse Event Management Algorithm 
Rule out non-inflammatory causes.  If non-inflammatory cause, treat accordingly and 
continue I-O therapy.  Consider visual field testing, endocrinology consultation, and 
imaging. 
 
Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed.  Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 


 
 
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Skin Adverse Event Management Algorithm 
Rule out non-inflammatory causes.  If non-inflammatory cause, treat accordingly and 
continue I-O therapy. 
 
Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed.  Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
*Refer to NCI CTCAE v5 for term-specific grading criteria. 
^If SJS/TEN is suspected, withhold I-O therapy and refer subject for specialized care for 
assessment and treatment.  If SJS or TEN is diagnosed, permanently discontinue I-O 
therapy. 


 
 
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Neurological Adverse Event Management Algorithm 
Rule out non-inflammatory causes.  If non-inflammatory cause, treat accordingly and 
continue I-O therapy. 
 
Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(eg, prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed.  Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 


 
 
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Appendix E:  Definitions and Adverse Event Collection and Reporting Information 
for Interventional Protocols: 
DEFINITIONS 
ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a preexisting medical condition in a clinical investigation participant 
administered study drug and that does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (such as 
an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of investigational product, whether or not considered related to the investigational 
product. 
A non-serious adverse event is an AE not classified as serious.  
The protocol must include a definition for Serious Adverse Events (SAE). 
SERIOUS ADVERSE EVENTS 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:   
 results in death 
 is life-threatening (defined as an event in which the participant was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe) 
 requires in-subject hospitalization or causes prolongation of existing hospitalization 
(see NOTE below) 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect  
 is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.)  
 Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) 
via the study drug is an SAE.   
 Unusual Failure in Efficacy (for Phase IV Canadian studies) 
Although pregnancy and potential drug-induced liver injury (DILI), are not always 
serious by regulatory definition, however, these events must be reported within the 
SAEs timeline. 


 
 
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Any component of a study endpoint that is considered related to study therapy should 
be reported as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, 
anaphylaxis must be reported). 
The following hospitalizations are not considered SAEs in BMS clinical studies:   
 a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening 
event) 
 elective surgery, planned prior to signing consent 
 admissions as per protocol for a planned medical/surgical procedure 
 routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy) 
 Medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study.  Appropriate documentation is required in these cases. 
 Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason). 
 Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols) 
ADVERSE EVENT Collection and REPORTING INFORMATION: 
 All Serious Adverse Events (SAEs) that occur following the subject’s written consent 
to participate in the study through 100 days of discontinuation of dosing must be 
reported to BMS Worldwide Safety, whether related or not related to study drug.  If 
applicable, SAEs must be collected that relate to any later protocol-specified 
procedure (eg, a follow-up skin biopsy). 
 Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, are collected, including those thought to be 
associated with protocol-specified procedures.  The investigator should report any 
SAE occurring after these aforementioned time periods, which is believed to be 
related to study drug or protocol-specified procedure. 
 An SAE report should be completed for any event where doubt exists regarding its 
seriousness;  
 If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy or a 
complication of a study procedure), the relationship should be specified in the 
narrative section of the SAE Report Form. 
An appropriate SAE form (Medwatch form) should be used to report SAEs to BMS.  If 
you prefer to use your own Institutional form, it must be reviewed by the BMS Protocol 
Manager prior to study initiation to ensure that at a minimum all of the data elements on 


 
 
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the CIOMS form are present.  Note:  Please include the BMS Protocol number on the SAE 
form or on the cover sheet with the SAE form transmission.   
 The CIOMS form is available at:  
http://www.cioms.ch/index.php/cioms-form-i  
 The MedWatch form is available at:  MedWatch 3500 Form  
 The Sponsor will reconcile the clinical database AE cases (case level only) 
transmitted to BMS Global Pharmacovigilance (Worldwide.Safety@bms.com).   
 The Investigator will request from BMS GPV&E, 
aepbusinessprocess@bms.com the SAE reconciliation report and include the 
BMS protocol number every 3 months and prior to data base lock or final data 
summary 
 GPV&E will send the investigator the report to verify and confirm all SAEs 
have been transmitted to BMS GPV&E. 
 The data elements listed on the GPV&E reconciliation report will be used for 
case identification purposes.  If the Investigator determines a case was not 
transmitted to BMS GPV&E, the case should be sent immediately to BMS 
(Worldwide.Safety@bms.com). 
 In addition to the Sponsor Investigator’s responsibility to report events to their local 
HA, suspected serious adverse reactions (whether expected or unexpected) shall 
be reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate 
reports). 
 In accordance with local regulations, BMS will notify sponsor investigators of all 
reported SAEs that are suspected (related to the investigational product) and 
unexpected (ie, not previously described in the IB).  An event meeting these 
criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR).  
Sponsor investigator notification of these events will be in the form of either a 
SUSAR Report or a Semi-Annual SUSAR Report.   
 Other important findings which may be reported by BMS as an Expedited 
Safety Report (ESR) include:  increased frequency of a clinically significant 
expected SAE, an SAE considered associated with study procedures that 
could modify the conduct of the study, lack of efficacy that poses significant 
hazard to study subjects, clinically significant safety finding from a nonclinical 
(eg, animal) study, important safety recommendations from a study data 
monitoring committee, or sponsor or BMS decision to end or temporarily halt a 
clinical study for safety reasons. 
 Upon receiving an ESR from BMS, the investigator must review and retain the 
ESR with the IB.  Where required by local regulations or when there is a 
central IRB/IEC for the study, the sponsor will submit the ESR to the 
appropriate IRB/IEC.  The investigator and IRB/IEC will determine if the 


 
 
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informed consent requires revision.  The investigator should also comply with 
the IRB/IEC procedures for reporting any other safety information.   
SAEs, whether related or not related to study drug, and pregnancies must be reported 
to BMS within 24 hours \ 1 Business Day of becoming aware of the event.  SAEs must 
be recorded on either CIOMS, MedWatch, or approved site SAE form.   
Pregnancies must be reported and submitted to BMS.  BMS will perform due diligence 
follow-up using the BMS Pregnancy Form which the investigator must complete.   
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1-609-818-3804 
If only limited information is initially available, follow-up reports are required.  (Note:  
Follow-up SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours \ 
1 Business Day to BMS using the same procedure used for transmitting the initial SAE 
report.   
All SAEs should be followed to resolution or stabilization. 
The causal relationship to study drug is determined by a physician and should be used 
to assess all adverse events (AE).  The casual relationship can be one of the following: 
Related:  There is a reasonable causal relationship between study drug administration 
and the AE. 
Not related:  There is not a reasonable causal relationship between study drug 
administration and the AE.   
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.   
Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject.  (In order to prevent reporting bias, 
subjects should not be questioned regarding the specific occurrence of one or more 
AEs.) 
NONSERIOUS ADVERSE EVENT 
 Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via 
interim or final study reports as specified in the agreement or, if a regulatory 
requirement [eg, IND US trial] as part of an annual reporting requirement.   
 Non-serious AE information should also be collected from following the subject’s 
written consent to participate in the study.   
Non-serious Adverse Event Collection and Reporting 
The collection of non-serious AE information should begin following the subject’s written 
consent to participate in the study.  All non-serious adverse events (not only those 


 
 
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deemed to be treatment-related) should be collected continuously during the treatment 
period and for a minimum of 30 days following the last dose of study treatment.   
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if 
they become serious.  Follow-up is also required for non-serious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study 
treatment as appropriate.   
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures.  Test results that constitute SAEs should be documented and 
reported to BMS as such. 
The following laboratory abnormalities should be documented and reported 
appropriately: 
 any laboratory test result that is clinically significant or meets the definition of an 
SAE 
 any laboratory abnormality that required the participant to have study drug 
discontinued or interrupted 
 any laboratory abnormality that required the subject to receive specific corrective 
therapy.   
It is expected that wherever possible, the clinical rather than laboratory term would be 
used by the reporting investigator (eg, anemia versus low hemoglobin value). 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a 
study participant is pregnant or may have been pregnant at the time of investigational 
product exposure, including during at least 5 half-lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for participant).   
The investigator must immediately notify Worldwide.Safety@bms.com of this event and 
complete one of the following forms within 24 hours of awareness of the event via either 
the CIOMS, MedWatch or appropriate Pregnancy Surveillance Form in accordance with 
SAE reporting procedures.   
Protocol-required procedures for study discontinuation and follow-up must be performed 
on the participant. 
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the 
CIOMS, MedWatch, BMS Pregnancy Surveillance Form, or approved site SAE form.  A 
BMS Pregnancy Surveillance Form may be provided upon request. 
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS.  Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.  In order for Sponsor or designee to collect any pregnancy 


 
 
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surveillance information from the female partner, the female partner must sign an 
informed consent form for disclosure of this information.   
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded as a 
non-serious or serious AE, as appropriate, and reported accordingly.   


 
 
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Appendix F:  Patient-reported Outcome (PRO) Questionnaires: 
Provided on the following pages: 
 
National Cancer Institute (NCI) patient-reported outcomes (PRO) questionnaire 
(PRO-CTCAE), English 
 
National Cancer Institute (NCI) patient-reported outcomes (PRO) questionnaire 
(PRO-CTCAE), Spanish 
 
National Cancer Institute (NCI) patient-reported outcomes (PRO) questionnaire 
(PRO-CTCAE), Chinese (traditional) 


 
 
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APPENDIX REFERENCES 
Appendix B:  Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation 
criteria in solid tumors:  revised RECIST guideline (version 1.1).  Eur J Cancer 
2009;45:228−47. 
Appendix C:  Nishino M, Gargano M, Suda M, et al.  Optimizing immune-related tumor 
response assessment:  does reducing the number of lesions impact response 
assessment in melanoma subjects treated with ipilimumab? J Immunother Can 
2014;2:17. 
Appendix C:  Wolchok JD, Hoos A, O'Day S, et al.  Guidelines for the evaluation of 
immune therapy activity in solid tumors:  immune-related response criteria.  Clin Can 
Res 2009;15:7412−20. 
Appendix D:  Bristol-Myers Squibb Research and Development.  Investigator Brochure 
nivolumab:  BMS-936558/MDX1106/ONO-4538, version no:  17, Version date:  
27Jun2018; pg 283-290. 
Appendix E:  Bristol-Myers Squibb.  ISR Protocol and AE Reporting 
Guidance_v8_November2018; pg 9-13.