Randomized Phase II Study of Nivolumab With or Without Ipilimumab in Patients With Metastatic or Unresectable Sarcoma
Phase: PHASE2
Conditions: Locally Advanced Bone Sarcoma, Locally Advanced Dedifferentiated Liposarcoma, Locally Advanced Gastrointestinal Stromal Tumor, Locally Advanced Soft Tissue Sarcoma, Metastatic Bone Sarcoma, Metastatic Liposarcoma, Metastatic Soft Tissue Sarcoma, Metastatic Undifferentiated Pleomorphic Sarcoma, Metastatic Unresectable Sarcoma, Pleomorphic Liposarcoma, Stage III Bone Sarcoma AJCC v7, Stage III Soft Tissue Sarcoma AJCC v7, Stage IV Bone Sarcoma AJCC v7, Stage IV Soft Tissue Sarcoma AJCC v7, Stage IVA Bone Sarcoma AJCC v7, Stage IVB Bone Sarcoma AJCC v7, Unresectable Bone Sarcoma, Unresectable Dedifferentiated Liposarcoma, Unresectable Liposarcoma, Unresectable Malignant Gastrointestinal Stromal Tumor, Unresectable Soft Tissue Sarcoma
Sponsor: National Cancer Institute (NCI)

 
 
 
1
Update #12 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
PROTOCOL UPDATE TO ALLIANCE A091401 
_________________________________________ 
 
RANDOMIZED PHASE II STUDY OF NIVOLUMAB WITH OR WITHOUT IPILIMUMAB IN PATIENTS WITH 
METASTATIC OR UNRESECTABLE SARCOMA 
 
NCI-supplied agents: Nivolumab (NSC #748726, IND #126336); IND holder: CTEP 
Ipilimumab (NSC #732442, IND #126336), IND holder: CTEP 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
 
Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
X Other: Updated CAEPR for Ipilimumab 
 
 
The changes included in this update to A091401 have been made in response to the NCI Action Letters 
for ipilimumab from Dr. Howard Streicher (streicherh@ctep.nci.nih.gov). The Action Letter is posted 
on the A091401 study page on the Alliance and CTSU websites. A revised CAEPR with new risks has 
been added to the protocol. Therefore, the model consent form has been revised to incorporate these 
new risks consistent with the new NCI Model Consent Template instructions. There are no changes to 
the risk/benefit ratio. 
 
Expedited review is allowed. IRB approval (or disapproval) is required within 90 days. Please follow 
your IRB of record guidelines. 
 
UPDATES TO THE PROTOCOL: 
Section 9.4.2 (Comprehensive Adverse Events and Potential Risks list [CAEPR] for Ipilimumab 
[MDX-010, NSCs 732442, IND #126336]) 
This section has an updated CAEPR for ipilimumab. Version 2.9, December 20, 2017 has been updated to 
Version 2.10, March 29, 2019. Changes from Version 2.9 to Version 2.10 include the following:  
• 
Added New Risk: 
o Rare but Serious: Nervous system disorders - Other (immune-mediated encephalitis) 
• 
Increase in Risk Attribution: 
o Changed to Rare but Serious from Also Reported on Ipilimumab (MDX-010) Trials But With 
Insufficient Evidence for Attribution: Peripheral motor neuropathy; Peripheral sensory 
neuropathy 

 
 
 
2
 
 
 
UPDATES TO THE MODEL CONSENT: 
What possible risks can I expect from taking part in this study? 
This section has updated risks and side effects related to ipilimumab used in Group 2 (and in Group 1 if 
cancer grows and patient is able to receive both drugs): 
• 
Provided Further Clarification: 
o Problem of the muscle, including swelling, which can cause muscle pain and severe muscle 
weakness sometimes with dark urine is now reported as Problem of the muscle, including 
inflammation, which can cause muscle pain and severe muscle weakness sometimes with dark 
urine (under Occasional, Some May be Serious).  
o Heart problems including swelling and heart failure.  Symptoms and signs of heart problem 
may include: Shortness of breath, swelling of the ankle and body is now reported as Heart 
problems including inflammation and heart failure.  Symptoms and signs of heart problem may 
include: Shortness of breath, swelling of the ankle and body (under Rare and Serious) 
o 
Swelling of the brain which may cause headache, blurred vision, stiff neck and/or confusion 
(under Rare) is now reported as Swelling of the brain (meningitis/encephalitis), which may 
cause: headache, confusion, sleepiness, seizures, and stiff neck (under Rare and Serious) and is 
now under the “Ipilimumab (MDX-010) may cause your immune system to attack normal 
organs and cause side effects in many parts of the body.  These problems may include but are 
not limited to” heading.  
 
 
 
 
 
 
 
A replacement protocol document and model consent form have been issued. 
 
____________________________________________________________ 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
___________________________________________________________ 

 
Version Date: 05/22/2019 
 
Update #12 
1
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
ALLIANCE A091401 
 
RANDOMIZED PHASE II STUDY OF NIVOLUMAB WITH OR WITHOUT IPILIMUMAB IN PATIENTS WITH 
METASTATIC OR UNRESECTABLE SARCOMA 
 
NCI-supplied agents: Nivolumab (NSC #748726, IND #126336); IND holder: CTEP 
Ipilimumab (NSC #732442, IND #126336), IND holder: CTEP 
 
ClinicalTrials.gov Identifier: NCT02500797 
Study Chair 
Sandra P. D’Angelo, M.D. 
Memorial Sloan-Kettering Cancer Center 
300 East 66th St. 
New York, NY 10065 
Tel: 646-888-4159 Fax: 646-888-4253 
dangelos@mskcc.org 
 
 
Community Oncology Co-chair 
Study Pathologist 
Balkrishna Jahagirdar, M.D. 
Cristina Antonescu, M.D. 
Tel: 651-254-3505 
Tel: 212-639-5721 
jahag001@umn.edu 
antonesc@mskcc.org 
 
 
Experimental Therapeutics Committee Co-
Chair 
Experimental Therapeutics Committee Co-
Chair 
Pamela Munster, M.D. 
Gary K. Schwartz, M.D. 
415 502-3598 
212-305-2055 
Pmunster@medicine.ucsf.edu 
schwartzg@columbia.edu 
 
 
Primary Statistician 
Michelle R. Mahoney, M.S. 
Tel: 507-266-4456 
mahoney.michelle@mayo.edu 
 
 
Protocol Coordinator 
Data Manager 
Krista L. Garbacz 
Kristin Poe 
Tel: 773-702-9269 Fax: 312-345-0117 
Tel: 507-538-1610 Fax: 507-284-1902 
kgarbacz@uchicago.edu 
poe.kristin@mayo.edu 
 
Participating Organizations: 
ALLIANCE / Alliance for Clinical Trials in Oncology (lead) 
ECOG-ACRIN/ ECOG-ACRIN Cancer Research Group 
NRG / NRG Oncology 
SWOG / SWOG 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
2 
Update #12 
Study Resources: 
Expedited Adverse Event Reporting 
http://eapps-ctep.nci.nih.gov/ctepaers/ 
 Medidata Rave iMedidata portal 
https://login.imedidata.com 
OPEN (Oncology Patient Enrollment Network) 
https://open.ctsu.org 
 Biospecimen Management System 
http://bioms.allianceforclinicaltrialsinoncology.org 
 
Protocol Contacts: 
 
A091401 Nursing Contact 
Lisa Kottschade, RN, MSN, CNP 
Mayo Clinic 
507-538-7888 Email: kottschade.lisa@mayo.edu 
A091401 Pharmacy Contact 
Heidi Finnes, PharmD, BCOP 
Mayo Clinic 
507-538-7066 Email: finnes.heidi@mayo.edu 
Alliance Biorepository at Ohio State 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway, Columbus, OH 43240 
Tel: 614-293-7073  Fax: 614-293-7967 
path.calgb@osumc.edu 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data 
Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
regulatory@allianceNCTN.org 
Questions regarding CTEP-AERS reporting: 
Pharmacovigilance Inbox 
pharmacovigilance@alliancenctn.org 
Questions regarding specimens/specimen 
submissions: 
Alliance Biorepository at Ohio State 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
3 
Update #12 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,  and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-2878 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
at ctsucontact@westat.com. 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password.: Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS.   
 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
4 
Update #12 
RANDOMIZED PHASE II STUDY OF NIVOLUMAB WITH OR WITHOUT IPILIMUMAB IN PATIENTS WITH 
METASTATIC OR UNRESECTABLE SARCOMA 
Pre-Registration Eligibility Criteria (see Section 3.2) 
Central pathology review submission (see § 3.2.1) 
Registration Eligibility Criteria (See Section 3.3) 
Histologically confirmed bone or soft tissue sarcoma by 
central pathology review 
Measureable disease as defined in Section 11.0 
Locally advanced/unresectable or metastatic disease 
≥ 1 prior systemic therapy for sarcoma 
No prior therapy with ipilimumab or nivolumab or other 
agent targeting PD-1, PD-L1 or CTLA-4. 
No treatment with biologic therapy, immunotherapy, 
chemotherapy, investigational agent for malignancy, or 
radiation ≤ 28 days before study registration. No 
treatment with nitrosourea or mitomycin ≤ 42 days 
before study registration. *For GIST, tyrosine kinase inhibitor can be continued for up to 3 days prior to 
initiation of study treatment. 
Resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE, Version 4.0, grade 1 or less. 
No history of the following:  
- 
Active known or suspected autoimmune disease 
- 
Symptomatic, untreated, or uncontrolled brain metastases 
- 
Active autoimmune colitis 
- 
Autoimmune panhypopituitarism 
- 
Autoimmune adrenal insufficiency 
- 
Known active hepatitis B or C (see section 3.3.4 for definition) 
No systemic treatment with corticosteroids or other immunosuppressive medications ≤ 14 days of registration. 
Not pregnant and not nursing (see Section 3.3.6) 
Age ≥ 18 years 
ECOG performance status 0 or 1 
Schema 
1 Cycle = 42 Days 
SLOT RESERVATION 
 
PRE-REGISTRATION 
 
Confirmation 
of Locally 
Advanced/ 
Unresectable 
and/or 
Metastatic 
Sarcoma 
 
 
REGISTRATION/ 
RANDOMIZATION 
 
ARM 1* 
Nivolumab at 3mg/kg IV over 30 
minutes  
Every 2 weeks 
 
RE-
REGISTER 
 
Nivolumab 
+ 
Ipilimumab 
Combination 
 
 
 
 
PD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ARM 2* 
Nivolumab 3mg/kg IV over 30 
minutes combined with 
Ipilimumab 1mg/kg IV over 90 
minutes every 3 weeks for 4 doses, 
followed by Nivolumab 3 mg/kg 
IV over 30 minutes every 2 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* During the first twelve weeks of therapy, patients who progress by imaging may be eligible to continue therapy. See Section 
7.1 for more information. 
 Nivolumab 3mg/kg IV over 30 minutes combined with Ipilimumab 1mg/kg IV over 90 minutes every 3 weeks for 4 doses 
total followed by Nivolumab 3 mg/kg IV over 30 minutes every 2 weeks (See Section 3.4, Section 4.6 and Section 7.2 for 
further instructions). 
Treatment is to continue for 108 weeks or until disease progression or unacceptable adverse events. Patients are followed for a 
maximum of three years post-randomization or until death, whichever comes first. 
Please note that vaccinations should be administered prior to therapy (See Section 8.1). 
Please refer to the full protocol text for a complete description of the eligibility criteria and treatment plan.  
Required Initial Laboratory Values 
Absolute neutrophil  
count (ANC) ≥ 1500/mm3 
Platelet Count ≥ 100,000/mm3 
Creatinine < 1.5 x ULN 
Calc. Creatinine OR 
Clearance (see Alliance 
website) ≥ 45 mL/min* 
Total Bilirubin ≤ 1.5 x ULN* 
AST / ALT  ≤ 3 x ULN 
TSH WNL* 
*See section 3.3.9 

 
Alliance A091401 
Version Date: 05/22/2019 
5 
Update #12 
Table of Contents 
 
Section 
 
Page 
1.0 
BACKGROUND .............................................................................................................................. 7 
1.1 
Endpoints in Sarcoma Studies ........................................................................................................ 7 
1.2 
Immunotherapy in Sarcoma ........................................................................................................... 7 
1.3 
Immunologic Checkpoint Blockade ............................................................................................. 10 
1.4 
CTLA-4 blockade with ipilimumab ............................................................................................. 11 
1.5 
PD-1 blockade with nivolumab .................................................................................................... 11 
1.6 
Combination therapy utilizing ipilimumab and nivolumab .......................................................... 13 
1.7 
Rationale of 2 therapeutic arms of this trial ................................................................................. 14 
1.8 
Rationale for crossover from single agent nivolumab to dual agent nivolumab/ipilimumab upon 
progression ............................................................................................................................................. 14 
1.9 
Rationale for cohort expansion in GIST ....................................................................................... 15 
1.10  Rationale for cohort expansion in UPS/MFH and LPS ................................................................ 16 
1.11 Registration Quality of Life (QOL) Measurements ..................................................................... 16 
1.12 Impact of This Trial ...................................................................................................................... 16 
2.0 
OBJECTIVES ................................................................................................................................ 17 
2.1 
Primary objective ......................................................................................................................... 17 
2.2 
Secondary objectives .................................................................................................................... 17 
2.3 
Correlative science objectives ...................................................................................................... 17 
2.4 
Exploratory Phase II objectives (Crossover Treatment)............................................................... 17 
3.0 
PATIENT SELECTION ............................................................................................................... 18 
3.1 
On-Study Guidelines .................................................................................................................... 18 
3.2 
Pre-Registration Eligibility Criteria ............................................................................................. 19 
3.3 
Registration Eligibility Criteria .................................................................................................... 19 
3.4 
Re-registration Eligibility Criteria (For patients who crossover from arm 1 nivolumab alone to 
dual agent nivolumab and ipilimumab upon progression) ...................................................................... 21 
4.0 
PATIENT REGISTRATION ....................................................................................................... 23 
4.1 
CTEP Investigator Registration Procedures ................................................................................. 23 
4.2 
CTSU Site Registration Procedures ............................................................................................. 24 
4.3 
Patient Pre-registration Requirements (Step 0) ............................................................................ 25 
4.4 
Patient Registration Requirements (Step 1) ................................................................................. 26 
4.5 
Patient Pre-Registration/Registration/Randomization Procedures ............................................... 26 
4.6 
Re-Registration (Step 2) at the time of progression ..................................................................... 27 
4.7 
Registration to Correlative and Companion Studies .................................................................... 27 
4.8 
Grouping Factors .......................................................................................................................... 27 
5.0 
STUDY CALENDAR .................................................................................................................... 28 
6.0 
DATA AND SPECIMEN SUBMISSION .................................................................................... 31 
6.1 
Data collection and submission .................................................................................................... 31 
6.2 
Specimen collection and submission ............................................................................................ 32 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 38 
7.1 
Treatment Decisions within the First Twelve Weeks of Therapy ................................................ 38 
7.2  
Crossover to Dual Agent Nivolumab and Ipilimumab upon Progression on Arm 1 (single agent 
nivolumab) .............................................................................................................................................. 39 
8.0 
DOSE AND TREATMENT MODIFICATIONS........................................................................ 41 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care........................................... 41 

 
Alliance A091401 
Version Date: 05/22/2019 
6 
Update #12 
8.2 
Dose Modifications ...................................................................................................................... 44 
9.0 
ADVERSE EVENTS ..................................................................................................................... 49 
9.1 
Routine adverse event reporting (solicited) .................................................................................. 49 
9.2 
Routine adverse event reporting (not solicited) ............................................................................ 49 
9.3 
Expedited Adverse event reporting (CTEP-AERS) ..................................................................... 50 
9.4 
CAEPRs ....................................................................................................................................... 53 
10.0 
DRUG INFORMATION ............................................................................................................... 62 
10.1 General Considerations ................................................................................................................ 62 
10.2 Nivolumab (BMS-936558, MDX-1106, ONO-4538 NSC #748726, IND #126336, IND holder: 
CTEP) ..................................................................................................................................................... 62 
10.3 Ipilimumab (BMS-734016, MDX-010, NSC#s 732442 and 720801, IND #126336, IND holder: 
CTEP) ..................................................................................................................................................... 65 
11.0 
MEASUREMENT OF EFFECT .................................................................................................. 69 
11.1 Schedule of Evaluations: .............................................................................................................. 69 
11.2 Definitions of Measurable and Non-Measurable Disease ............................................................ 69 
11.3 Guidelines for Evaluation of Measurable Disease ....................................................................... 70 
11.4 Measurement of Treatment/Intervention Effect ........................................................................... 71 
11.5 Definitions of analysis variables .................................................................................................. 74 
12.0 
END OF TREATMENT/INTERVENTION ............................................................................... 75 
12.1 Duration of Treatment .................................................................................................................. 75 
12.2 Crossover ...................................................................................................................................... 75 
12.3 Managing ineligible patients and registered patients who never receive protocol intervention ... 75 
12.4 Extraordinary Medical Circumstances ......................................................................................... 76 
13.0 
STATISTICAL CONSIDERATIONS ......................................................................................... 77 
13.1 Study Overview ............................................................................................................................ 77 
13.2 Primary Endpoint ......................................................................................................................... 77 
13.3 Study Design ................................................................................................................................ 78 
13.4 Secondary Endpoints .................................................................................................................... 79 
13.5 Exploratory and Correlative Endpoints ........................................................................................ 80 
13.6 Total Sample Size, Accrual Duration, and Anticipated time to study completion ....................... 80 
13.7 AE Stopping Rule ......................................................................................................................... 81 
13.8  Accrual Monitoring Stopping Rule .............................................................................................. 82 
13.9 Primary Endpoint Completion Time Estimation (For clinicaltrails.gov reporting) ..................... 82 
13.10 Descriptive Factors ....................................................................................................................... 82 
13.11 Inclusion of Women and Minorities ............................................................................................. 82 
14.0 
CORRELATIVE AND COMPANION STUDIES ..................................................................... 83 
14.1 Mandatory studies and optional Correlative Science (Alliance A091401-ST1) .......................... 84 
15.0 
GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING ...................... 89 
16.0 
REFERENCES .............................................................................................................................. 90 
APPENDIX I 
REGISTRATION FATIGUE/UNISCALE ASSESSMENTS ................................. 93 
APPENDIX II CRADA ............................................................................................................................ 94 
APPENDIX III TOXICITY ALGORITHMS ........................................................................................ 96 
APPENDIX IV DEFINITION OF ACTIVE AUTOIMMUNE DISEASE ........................................ 103 
APPENDIX V MANAGEMENT OF INFUSION REACTIONS ....................................................... 104 
 

 
Alliance A091401 
Version Date: 05/22/2019 
7 
Update #12 
1.0 
BACKGROUND 
Sarcomas are heterogenous malignant tumors of mesenchymal origin characterized by more than 100 
distinct subtypes.  Approximately 13,000 cases of soft tissue and bone are diagnosed annually in the 
US.  Surgery, often with adjuvant radiation for larger tumors, is the mainstay of treatment.[1]  
Perioperative chemotherapy has proven efficacy only in specific chemosensitive subtypes such as 
rhabdomyosarcoma, osteosarcoma and Ewing sarcoma.[1] Despite primary combined modality 
therapy, between 25-50% of patients develop recurrent and/or metastatic disease, dependent upon 
initial stage and subtype.[2, 3]  Complete responses to chemotherapy for recurrent or metastatic 
sarcoma are rare and median survival in the metastatic setting is 10-15 months.[4, 5] Standard 
cytotoxic chemotherapy agents such as doxorubicin, ifosfamide and dacarbazine have response rates 
10-30%.[6]  The development of novel and effective therapies in sarcoma patient populations is 
urgently needed. 
1.1 
Endpoints in Sarcoma Studies 
Historical data show that the prognosis for advanced sarcoma patients who have failed at least 
one prior therapy is poor, with 90% experiencing disease progression within 6 months (i.e., the 
6-month progression-free survival is 10%).[7]  Thus, we consider the prolonged progression-
free survival in this patient population to be a meaningful result. 
Progression-free survival (PFS) is used increasingly as a metric for comparison of 
chemotherapeutic agents in sarcomas, given that responses rates are relatively low, at least in 
part due to the biology of chemotherapy responses of sarcomas, which die more frequently by 
senescence than by apoptosis. The best available data regarding PFS comes from EORTC 
databases.[7] In this analysis, PFS was estimated in both previously treated and previously 
untreated patients, based on analysis of 12 clinical trials of different agents in which in only two 
cases (ifosfamide and dacarbazine) was there a significant response rate. Comparison was made 
between responses to these two agents vs. inactive agents (all others examined in these studies). 
Response assessment was made by WHO criteria for these studies performed reported between 
1991 and 1999. A total of 1154 patients were examined who had not received prior therapy, 
while 146 cases with prior anthracyclines who then received ifosfamide or dacarbazine 
constituted the responding cohort. 234 patients receiving what were termed inactive 
agents/regimens were used as a comparator.[7]  For patients who had received prior therapy, 
PFS was better with active drugs than inactive drugs in a multivariate analysis. Performance 
status was of borderline significance (p=0.08). For previously treated patients, PFS was 21% at 
3 months for inactive drugs/regimens, and 39% for active drugs; 6 month PFS was 8% with 
inactive regimens, and 14% for active regimens. In patients who had not received prior 
chemotherapy, 3 month PFS varied from 44-77%, depending on histology, and 6 month PFS 
varied between 30% and 56%. 
1.2 
Immunotherapy in Sarcoma 
Immunotherapeutic strategies may be a promising approach to this disease. The role of the 
immune system as a mechanism of cancer therapy was in fact first observed in a sarcoma 
patients.  Dating back to 1866, Wilhelm Busch in Germany observed tumor regressions in 
patients with sarcoma after postoperative wound infections.[8] Coley described a dramatic 
response in a patient with small cell sarcoma after an erysipelas infection, suggesting that that 
the body’s response to infection also had potential anti-tumor effects.[9]   The observation that 
the development of sarcoma is more common in patients that are immunosuppressed also 
supports the relevance of the immune surveillance in this disease.[10]  Perhaps the best example 
of this is the development of in immunosuppressed patients.[11]  The development of sarcomas 
have also been described in allograft transplant recipients.  Thus, the immune system is critical 

 
Alliance A091401 
Version Date: 05/22/2019 
8 
Update #12 
in sarcoma control and progression, and appropriate modulation of the immune system may 
provide an effective therapeutic option for this disease.   
The clinical use of monoclonal antibodies to T-cell inhibitory receptors has provided 
transformative information on the nature of the immune system and cancer.  An emerging picture 
suggests that endogenous immune responses can mediate effective tumor regression and/or 
improved survival even in patients with large volume tumors resistant to other forms of therapy.  
Some of the unique features of this type of therapy, based largely on experience in advanced 
melanoma, include:  improved overall survival (OS) with or without radiographic responses or 
improved progression-free survival (PFS); responses that may be delayed or occur after 
radiographic disease progression; combinations of immune modulators with enhanced or novel 
activities (in the example of ipilimumab and nivolumab); and toxicity that is almost exclusively 
immune or inflammatory in nature.  It is not yet clear what factors determine responses and 
which components of the immune system are needed for this to occur.  It seems likely that both 
memory helper and effector cells would be needed to sustain long-term responses. Increasing 
emphasis has been placed on understanding the relationships of the tumor, celluar infiltrate, and 
immunologic milieu surrounding each tumor. 
The prognostic significance of lymphocyte infiltration of soft tissue sarcomas has been 
investigated.[12]  A tissue microarray from 249 patients with STS was constructed evaluating 
CD3+, CD4+, CD8+ and CD20+ lymphocytes in the tumors.  In a multivariate analysis, CD20+ 
infiltration was found to be an independent positive prognostic factor in patients that underwent 
surgical resection and had wide resection margins, (HR=5.5, CI 95% 1.6-18.6, p=0.006.)[12]   
This suggests the lymphocytes are present in sarcomas and may play a role in the patient 
outcomes.  Therefore, manipulating the immune system in sarcoma may prove to be an effective 
therapeutic intervention in these patients. 
PDL-1 Expression in Sarcoma Cell Lines 
In vitro models using sarcoma cell lines have documented very high PDL1 expression at baseline 
by Western blot (Figure 1) and by flow cytometry (Figure 1) that is also induced by interferon.  
Expression is noted in nearly 65% of the cell lines including synovial sarcoma, Ewing sarcoma, 
rhabdomyosarcoma, liposarcoma, malignant peripheral nerve sheath tumors, desmoplastic small 
round cell, osteosarcoma and chondrosarcoma. 

 
Alliance A091401 
Version Date: 05/22/2019 
9 
Update #12 
 
 
PDL-1 Expression in Sarcoma Tumor Specimens 
PDL-1 expression was evaluated in 50 sarcoma tumor specimens of various subtypes using 
immunohistochemistry with the use of a rabbit monoclonal antihuman PD-L1 antibody (clone 
28-8) and an automated assay developed by Dako. Greater than 1% PDL-1 expression was 
identified in 6/50 (12%) of samples (Table 1). There was evidence of macrophage and 
lymphocyte infiltration in the tumor, outside of the tumor, and both.    
Median age 46 years (range, 22 - 76), 66% male.  Disease status: 70% primary disease/locally 
recurrent, 26% metastatic and 4% unknown. Tumor, lymphocyte and macrophage PD-L1 
expression was noted in 12%, 30% and 58%, respectively.  Lymphocyte and macrophage 
infiltration was present in 98% and 90%, respectively. (Table 1) 
Figure 1 

 
Alliance A091401 
Version Date: 05/22/2019 
10 
Update #12 
Immunohistochemistry 
Immunohistochemical staining for PD-L1 (DAKO, Carpinteria, CA) will be performed on 5 µm 
thick sections obtained from formalin-fixed paraffin embedded tissue of the selected cases.   PD-
L1 positivity was defined as >1% of tumor cells (minimum of 100 evaluable cells) 
demonstrating plasma membrane staining. Macrophage and lymphocyte PD-L1 status was 
determined qualitatively.   Positive macrophage or lymphocyte PD-L1 expression inside and/or 
outside of the tumor expression was defined.   
Immunohistochemical staining for PD1 (mouse clone NAT antibody, LOT#GR81330-2 Abcam 
Cambridge, MA or equivalent. 
Table 1: PD-L1 expression 
Histology  
n  
% Tumor 
PD-L1  +   
% Lymphocyte 
PD-L1 +  
% Macrophage 
PD- L1 +  
Angiosarcoma  
3  
 0  
100  
100  
GIST  
14  
27  
100  
100  
Leiomyosarcoma  
4  
0  
0  
25  
Liposarcoma  
5  
0  
20  
60  
Synovial Sarcoma  
3  
0  
33  
0  
Radiation associated pleomorphic 
sarcoma  
1  
100  
100  
100  
Other  
20  
5  
10  
70  
Overall  
50  
12  
30  
58  
PD-L1 expression is not an established biomarker predictive of response  
The significance of PD-L1 expression as a biomarker of response to checkpoint blockade with 
PD-1 inhibitors remains a controversial topic.  PD-L1 expression remains a dynamic marker, 
that can change over time and under different conditions in the microenvironment.  Tumor 
heterogeneity can also contribute to varied PD-L1 expression.(30)    Based on the initial phase 
I clinical data of the combination of ipilimumab and nivolumab in melanoma patients, patients 
with PD-L1 expression may be more likely to respond, however, lack of expression did not 
exclude responses. (29)   These data suggest that either PD-L1 expression may change as a result 
of therapy with checkpoint blockade such as ipilimumab or nivolumab.   Therefore, it remains 
pertinent to explore this biomarker as an integral part of the study. 
1.3 
Immunologic Checkpoint Blockade 
T cell activation requires dual signaling.[13, 14] The binding of the T cell receptor to antigens 
presented by antigen presenting cells via major histocompatibility complex I and II is the first 
required signal in T cell activation.  Subsequently, the second signal is generated when the B7 
ligand bind to CD28 which is a co-stimulatory receptor.  This signaling leads to T cell 
proliferation, cytokine release and upregulation of the immune response.  As a result, CTLA-4 
is upregulated and competes with B7 for CD28 binding. Ultimately, CTLA4 has higher affinity 
for the CD28 receptor and the T cell response is down-regulated.  CTLA-4 is a negative regulator 
of T cell responses that prevents autoimmunity and allows tolerance to self antigens.[13]   
PD-1 is a member of the CD28 family of T-cell costimulatory receptors that also includes CD28, 
CTLA-4, ICOS and BTLA.[15]  PD-1 is expressed on activated T cells, B cells and myeloid 
cells.[16]  There are 2 ligands, PD-L1 and PD-L2 that are specific for PD-1.  Once they bind to 
PD-1, down-regulation of T-cell activation occurs.[17, 18]  When the PD-1 ligand binds to the 
receptor, T cell activation is blocked.  If this interaction is interrupted, the checkpoint is turned 
off and antitumor T-cell activation maybe enhanced. I 

 
Alliance A091401 
Version Date: 05/22/2019 
11 
Update #12 
1.4 
CTLA-4 blockade with ipilimumab  
Ipilimumab (BMS-734016, MDX010, MDX-CTLA4, YervoyTM) is a fully human monoclonal 
immunoglobulin (Ig) G1κ specific for human cytotoxic T lymphocyte antigen 4 (CTLA-4, 
CD152), which is expressed on a subset of activated T cells (Ipilimumab Investigator Brochure, 
2014).  CTLA-4 is a negative regulator of T-cell activation.  Ipilimumab binds to CTLA-4 and 
inhibits its interaction with ligands on antigen-presenting cells (APCs).  The proposed 
mechanism of action for ipilimumab’s effects in subjects with melanoma is indirect, possibly 
through T-cell potentiation and mediation of antitumor immune responses. 
Ipilimumab has been FDA approved for the treatment of melanoma, demonstrating an 
improvement in overall survival.[19]  The response rate of ipilimumab is about 10%-20%.[20]  
Since clinical responses can be delayed, many patients do not demonstrate disease regression 
for until weeks after therapy is complete and some patients can have initial progressive disease 
and subsequent disease stabilization.  Therefore, one must consider inclusion of alternate 
endpoints such as improvement in immune-related progression-free survival as well as overall 
survival.  A set of novel response criteria termed immune-related response criteria (irRC) have 
been developed to capture these unique response patterns.[21]  With the irRC, progressive 
disease is defined as total disease growth up to 25% from baseline or total disease burden (new 
lesions + target) greater than 25%.   In addition, using this therapy earlier in the metastatic 
setting, when patients are asymptomatic and perhaps have less disease burden may be more 
effective.  This will allow for sufficient time to see a potential immune response. 
Ipilimumab in sarcoma 
In a small phase II study, patients with synovial sarcoma were treated with ipilimumab 3mg/kg 
every 3 weeks and re-staged after 3 cycles.[22]   Serum and peripheral blood was collected 
before and during therapy to assess NY-ESO-1 specific immunity. The primary endpoint of the 
study was RECIST 1.0 response rate.   A response rate of at least 25% would be considered 
worthy of activity and further evaluation. Secondary endpoints included determination of the 
clinical benefit rate (CR + PR+ SD) and evaluation of NY-ESO-1 specific immunity.  Six 
patients received 1 to 3 cycles of ipilimumab.  Four patients completed 3 doses of ipilimumab, 
while 2 patients each received 1 and 2 doses due to clinical or radiologic progression.  There 
were no documented responses, and the time to progression ranged from 0.47 months- 2.1 
months.  There was no evidence of serologic or delayed type hypersensitivity to NY-ESO-1.   
1.5 
PD-1 blockade with nivolumab 
PD-1 and PD-L1 
Programmed death 1 (PD-1) receptor is another promising potential immunological target.  PD-
1, a 55-kDa type 1 transmembrane protein, is a member of the CD28 family of T-cell co-
stimulatory receptors that include Ig super family member CD28, CTLA-4, inducible co-
stimulator (ICOS), and B and T lymphocyte attenuator (BTLA) (Investigator Brochure, 2014).  
PD-1 is transiently but highly expressed on activated T cells functioning to limit immune 
effectors at the site of activation.  Chronic stimulation may prevent the re-methylation of the 
PD-1 gene leading to continuous expression and characterizes a state of “exhausted” T cells that 
lose function and proliferative capacity while enhancing a suppressive tumor microenvironment.  
PD-1 may act together with other T-cell modulating molecules, including CTLA-4, TIM-3, 
lymphocyte-activation gene 3 (LAG-3) as well as indoleamine-pyrrole 2,3-dioxygenase 1 (IDO-
1), cytokines, and transforming growth factor beta (TGF-beta).   
Two ligands specific for PD-1 have been identified:  PD-ligand 1 (PD-L1, also known as B7-
H1 or CD274, expressed on tumor, antigen-presenting cells [APCs], and dendritic cells [DCs]) 
and PD-L2 (also known as B7-DC or CD273, expressed on endothelial cells).  The interaction 
of PD-1 with PD-L1 and PD-L2 results in negative regulatory stimuli that down-modulate the 

 
Alliance A091401 
Version Date: 05/22/2019 
12 
Update #12 
activated T-cell immune response through SHP-1 phosphastase PD-1 knockout mice develop 
strain-specific lupus-like glomerulonephritis (C57BL/6) and cardiomyopathy (BALB/c).  In 
transplantable tumor models that expressed PD-1 and LAG-3 on tumor-infiltrating CD4+ and 
CD8+ T cells dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established 
tumors that were largely resistant to single antibody treatment.[23]  Despite minimal 
immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice 
abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to 
eventual lethality. 
PD-L1 expression is found on a number of tumors, and is associated with poor prognoses based 
on OS in many tumors, including melanoma[24], renal[25-27], esophageal[28], gastric[29], 
ovarian[30], pancreatic[31], lung[32], and other cancers (Investigator Brochure, 2014). 
The PD-1/PD-L1 axis plays a role in human infections, particularly in hepatitis C virus (HCV) 
and human immunodeficiency virus (HIV).  In these cases, high expression levels of PD-1 were 
found in viral-specific CD8+ T cells that also display a non-responsive or exhausted phenotype.  
Non-responsive PD-1-high T cells were observed in simian immunodeficiency virus (SIV) 
infection in rhesus macaques.  Treatment of SIV-infected macaques with an anti-PD-1 mAb (3 
mg/kg x4) resulted in decreased viral loads and increased survival along with expanded T cells 
with increased T-cell functionality.   
Nivolumab 
Nivolumab (BMS-936558, MDX-1106, and ONO-4538) is a fully human monoclonal 
immunoglobulin G4 (IgG4) antibody (HuMAb) that is specific for human programmed death-1 
(PD-1, cluster of differentiation 279 [CD279]) cell surface membrane receptor (Investigator 
Brochure, 2014).  PD-1 is a negative regulatory molecule that is expressed transiently following 
T-cell activation and on chronically stimulated T cells characterized by an “exhausted” 
phenotype.   
Nivolumab is being evaluated as monotherapy and in combination with cytotoxic chemotherapy, 
other immunotherapy (such as ipilimumab), anti-angiogenesis therapy, and targeted therapies in 
completed and ongoing BMS-sponsored clinical trials in NSCLC, melanoma, RCC, 
hepatocellular carcinoma (HCC), gastrointestinal (GI) malignancies including microsatellite 
instability (MSI) in colorectal cancer, and triple-negative breast cancer (TNBC) with an 
expanding group of indications (Investigator Brochure, 2014).   
Seven nivolumab studies were conducted in Japan, including six studies in advanced solid 
tumors and recurrent or unresectable stage III/IV melanoma sponsored by Ono Pharmaceuticals 
Co. Ltd., and one IST in recurrent or advanced platinum-refractory ovarian cancer.   
In a phase 1 (1, 3, and 10 mg/kg nivolumab doses) dose-escalation study the 3 mg/kg dose was 
chosen for expanded cohorts. Among 236 patients, objective responses (ORs) (complete or 
partial responses [CR or PR]) were seen in NSCLC, melanoma, and RCC.  ORs were observed 
at all doses.[33]  Median OS was 16.8 months across doses and 20.3 months at the 3 mg/kg dose.  
Median OS across all dose cohorts was 9.2 months and 9.6 months for squamous and non-
squamous NSCLC, respectively.[34]  In the RCC cohort, median duration of response was 12.9 
months for both doses with 5 of the 10 responses lasting ≥1 year.[35]   
In a study that enrolled and treated 296 patients with nivolumab, an antibody to PD-1, response 
rates were 18%, 28% and 27% in patients with non-small cell lung cancer, melanoma and renal 
cell carcinoma, respectively.[36]  PD-L1 expression has been demonstrated in many tumors and 
has correlated with decreased immune system function and worse prognosis.[25, 28, 37-39]  
Further, there was initial suggestion that PD-L1 expression may correlate with clinical activity 
of PD-1 blockade.  An immunohistochemistry assay was used to measure PD-L1 expression in 
42 patients treated with nivolumab.  There were 18 patients that lacked expression and all of 

 
Alliance A091401 
Version Date: 05/22/2019 
13 
Update #12 
them did not have any evidence of benefit to the drug.  In a subgroup of patients with melanoma, 
the positive predictive value was 40%.[36]   
In a phase 1 study of nivolumab plus platinum-based doublet chemotherapy (PT-doublet) in 
chemotherapy-naïve NSCLC patients, 43 patients were treated with nivolumab + PT-
doublet.[40]  No dose-limiting toxicities (DLTs) were reported and total/confirmed ORRs were 
43/33%, 
40/33%, 
and 
31/31% 
in 
nivolumab/gemcitabine/cisplatin, 
nivolumab/pemetrexed/cisplatin, and nivolumab/carboplatin/paclitaxel arms, respectively. 
A maximum tolerated dose (MTD) of nivolumab was not defined.[36]  Serious adverse events 
(SAEs) occurred in 32 of 296 patients (11%) similar to the immune-related inflammatory events 
seen with ipilimumab:  pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis 
(with noted pulmonary toxicity resulting in 3 deaths. Renal failure, symptomatic pancreatic and 
DM, neurologic events, and vasculitis have also been reported.).   In combination with 
ipilimumab in the concurrent-regimen group[41], grade 3 or 4 treatment-related events were 
noted in 53% of patients.  Skin rash represents the majority of these events.   
1.6 
Combination therapy utilizing ipilimumab and nivolumab 
While the toxicity and clinical responses overlap, mechanisms of immune activation and range 
of responses appear to be different for ipilimumab and nivolumab. Preclinical data support the 
combinations of nivolumab and ipilimumab.[42]   
The combination of nivolumab and ipilimumab (anti-cytotoxic T lymphocyte associated 
antigen-4 [anti-CTLA-4]) in a phase 1/2 trial showed markedly enhanced clinical activity with 
an acceptable safety profile in melanoma patients.[41]  In the phase 1 study, nivolumab and 
ipilimumab were administered IV every 3 weeks for 4 doses followed by nivolumab alone every 
3 weeks for 4 doses (concurrent regimen).[41]  The combined treatment was subsequently 
administered every 12 weeks for up to 8 doses.  In a sequenced regimen, patients previously 
treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.  In the concurrent 
regimen (53 patients), 53% of patients had an OR at doses 1 mg/kg nivolumab and 3 mg/kg 
ipilimumab, with tumor reduction of 80% or more (modified World Health Organization 
[mWHO] criteria).  In the sequenced-regimen (33 patients), the objective response rate (ORR) 
was 20%. 
Tumor-cell expression (melanoma) of PD-L1 was characterized in combination with ipilimumab 
with the use of IHC staining and pharmacodynamics changes in the peripheral-blood absolute 
lymphocyte count.[41] With PD-L1 positivity defined as expression in at least 5% of tumor 
cells, biopsy specimens from 21 of 56 patients (38%) were PD-L1–positive.  Among patients 
treated with the concurrent regimen of nivolumab and ipilimumab, ORs were observed in 
patients with either PD-L1–positive tumor samples (6 of 13 patients) or PD-L1–negative tumor 
samples (9 of 22).  In the sequenced regimen cohorts, a higher number of overall responses was 
seen among patients with PD-L1–positive tumor samples (4 of 8 patients) than among patients 
with PD-L1–negative tumor samples (1 of 13) suggesting the possibility that these tumors have 
higher response rates to the combination. The relationship between PDL-1 expression and 
responses may not be present in patients treated with the combination.  Tissue expression of 
PDL-2, interferon-γ (IFN- γ), IDO, and T cell CD8+ are of current interest.  Until more reliable 
data based on standardized procedures for tissue collection and assays are available, PD-L1 
status cannot be used to select patients for treatment at this time.   
For RCC results have been reported.[43] Pts were randomized to nivolumab 3mg/kg + 
ipilimumab 1mg/kg (n=21) and nivolumab 1mg/kg + ipilimumab 3mg/kg (n=23). Most pts 
(n=34; 77%) had prior systemic therapy (N3 + I1: 16; N1 + I3: 18). Objective response rate 
(ORR) was 29% (nivolumab 3mg/kg + ipilimumab 1mg/kg) and 39% (nivolumab 1mg/kg+ 
ipilimumab 3mg/kg.) Duration of response was 4.1to 22.1 weeks (all 6 responses ongoing) in 

 
Alliance A091401 
Version Date: 05/22/2019 
14 
Update #12 
nivolumab 3mg/kg + ipilimumab 1mg/kg, and 6.1 yo 18.3 weeks (8/9 responses ongoing) in 
nivolumab 1mg/kg+ ipilimumab 3mg/kg. Responses occurred by first tumor assessment at week 
6 in 67% of responding patients in both patient cohorts. Stable disease was seen in 7 (33%) 
patients (nivolumab 3mg/kg + ipilimumab 1mg/kg) and 9 (39%) patients (nivolumab 1mg/kg + 
ipilimumab 3mg/kg).  Treatment-related adverse events (AEs) were seen in 89% of patients with 
16% discontinuation due to any-grade related AEs. Grade 3–4 related AEs 43%, most commonly 
↑ lipase (16%, n=7), ↑ ALT (11%, n=5), diarrhea (9%, n=4), colitis (5%, n=2), ↑ amylase (5%, 
n=2). No grade 3–4 pneumonitis was seen.  Based on the above background trials, the 
combination is being evaluated in other disease settings typically with 3mg/kg nivolumab and 
1mg/kg ipilimumab q 3 weeks during induction, for 4 doses. This is the induction dosing we 
have chosen for the combination arm of the trial. 
1.7 
Rationale of 2 therapeutic arms of this trial 
There is interest in conducting 2 concurrent phase II studies exploring single agent nivolumab 
as well as the combination of nivolumab and ipilimumab.  In metastatic melanoma, published 
data has demonstrated promising results with single agent nivolumab but the combination has 
been even more promising.   
By conducting this study single agent efficacy of nivolumab will be determined.  In addition, it 
will be explored if the combination arm leads to higher responses.  This will be important to 
plan future clinical studies. 
1.8 
Rationale for crossover from single agent nivolumab to dual agent 
nivolumab/ipilimumab upon progression 
Recently published data has demonstrated superiority of responses with combination therapy 
with nivolumab and ipilimumab [49-52].  This data has shown near doubling of overall response 
rates across multiple diseases including, but not limited to melanoma, non-small cell lung cancer 
and renal cell carcinoma.  
 
Given the high overall activity, the combination of nivolumab and ipilimumab was FDA 
approved for the treatment of metastatic melanoma.  It was shown that the complete response 
rate with the combination was 17% versus none with nivolumab monotherapy for patients with 
melanoma. Further, ORR with the combination was found to be independent of PD-L1 status. 
In PD-L1–positive and –negative tumors, respectively, ORR was 58% and 55% with 
nivolumab/ipilimumab.   More recently, frontline combination therapy with nivolumab and 
ipilimumab was demonstrated to be active in patients with non-small cell lung cancer receiving 
one of four dosing regimens of nivolumab and ipilimumab.    It was noted that the ORR ranged 
from 13% to 39%, regardless of PD-L1 status.  Further, in renal cell carcinoma, single agent 
nivolumab has demonstrated an ORR in 20% of patients while the combination of nivolumab 
and ipilimumab has demonstrated responses ranging from 43-48%. 
 
Given the now known promise and overall higher degree of activity with the combination of 
nivolumab and ipilimumab, regardless of PD-L1 status in many other disease types- there is now 
rationale to allow a cross-over to dual therapy, for patients with locally advanced/metastatic 
sarcoma that have progressed on single agent nivolumab.  Overall the 2-drug regimen appears 
to be more effective therapy than single agent, and while there is limited data in sarcoma, 
performing this crossover will provide access to dual agent therapy without affecting the 
integrity of the primary endpoint of the study and scientific design.  Many of these patients will 
be excluded from future clinical trials with checkpoint blockade, as most trials will exclude 
patients with prior exposure to nivolumab.  Also, sarcoma currently has minimal FDA approved 

 
Alliance A091401 
Version Date: 05/22/2019 
15 
Update #12 
therapies and clinical trials are a mainstay of treatment. Therefore, with Update #04 of the 
protocol, the option of allowing re-registration and crossover to dual agent therapy, upon 
progression on single agent nivolumab, was added to the protocol. 
1.9 
Rationale for cohort expansion in GIST 
GIST are the most common sarcomas of the digestive tract and are thought to arise from or share 
a common ancestor with the interstitial cells of Cajal, the autonomic pacemaker cells of the gut 
that coordinate peristalsis.  Approximately 4000 to 6000 new cases of GIST are diagnosed in 
the US each year.1,2  Between 75% and 80% of these tumors contain activating mutations of KIT 
or PDGFR-alpha,3,4 providing oncogenic signaling and driving tumor growth.5  Given this, 
multiple small molecule tyrosine kinase inhibitors (TKI) against KIT and PDGFRA, such as 
imatinib, sunitinib, sorafenib and dasatinib, have been evaluated for the treatment of this disease. 
Advanced GIST is refractory to conventional chemotherapy or radiotherapy, but multiple TKIs 
have been shown to have antitumor activity in this disease.  Imatinib mesylate, a multi-targeted 
TKI with activity against PDGFR, KIT, BCR-ABL, ABL and LCK, has become the first line 
standard of care in advanced GIST achieving disease control in 70% to 85% of patients, with a 
median progression free survival of 20 to 24 months.6,7  Although treatment with imatinib has 
greatly increased survival and quality of life for patients with advanced GIST, a subset of 
patients acquire kinase mutations in KIT or PDGFR-alpha that interfere with imatinib activity 
and ultimately lead to imatinib resistance.8-10 
At time of progression, the currently accepted treatment strategies include dose escalation of 
imatinib11 or transition to treatment with sunitinib.12  Sunitinib is a multi-targeted TKI with a 
kinase spectrum including VEGF as well as PDGFR and KIT, among others.  In an international 
phase III trial of imatinib refractory patients, sunitinib showed a median time to tumor 
progression of 27.3 weeks compared to 6.4 weeks in those on placebo.13  Based on this and other 
data, sunitinib has been FDA approved for the treatment of imatinib-refractory or intolerant 
advanced GIST.   
Although treatment of GIST with tyrosine kinase inhibitors results in demonstrated clinical 
benefit, this efficacy is not indefinite and treatment with KIT inhibition does not result in the 
cure of patients with advanced disease.  Alternate options are necessary to improve outcomes 
for patients with TKI resistant GIST. 
An attractive potential therapy for GIST is immunotherapy. There is pre-clinical evidence of 
benefit from immunotherapy in GIST. A study of 50 sarcoma patients treated at Memorial Sloan-
Kettering Cancer Center consented to a tissue procurement protocol and collected correlative 
clinical information.  Immunohistochemistry staining of tumor specimens was performed with 
the use of a rabbit monoclonal antihuman PD-L1 antibody (clone 28-8) and an automated assay 
developed by Dako. Findings were the following: there was >1% PDL-1 expression in 6/50 
(12%) of samples that included all sarcoma subtypes.  Positive PD-L1 expression was noted in 
27% of GIST samples.  Of all tested histologies, the highest level of expression was noted in 
GIST. 
The high PD-L1 expression noted in GIST tumor samples prompted further pre-clinical work in 
this disease.  In collaboration with the DeMatteo lab, PD-L1 expression in tumor samples was 
re-explored as well as the efficacy of PD-1 blockade and sunitinib in mouse models.   Over half 
of resistant GIST specimens contain intratumoral CD8 T cells that express substantial levels of 
PD-L1. 
GIST is a malignancy with a marked difference in pathogenesis and treatment, compared to 
other sarcomas.  The standard cytotoxic agents that are utilized in sarcoma are ineffective in 
GIST, and tyrosine kinase inhibitors are the standard of care. As described above, pre-clinical 
data suggests that PD-L1 expression is much higher in GIST compared to other sarcomas, 

 
Alliance A091401 
Version Date: 05/22/2019 
16 
Update #12 
therefore, there is rationale to evaluate these agents in GIST, as separate cohorts given the overall 
different biology. 
1.10  Rationale for cohort expansion in UPS/MFH and LPS 
Recent data from ASCO 2016 by Hussein Tawbi et al. noted efficacy of pembrolizumab in 
selected sarcomas. In a trial that enrolled 80 sarcoma patients, 40 bone (Ewing’s, Osteosarcoma, 
Chondrosarcoma) and 40 soft tissue (leiomyosarcoma [LMS], undifferentiated pleomorphic 
sarcoma 
[UPS]/malignant 
fibrous 
histiocytoma[MFH], 
dedifferentiated/pleiomorphic 
liposarcoma [LPS], synovial sarcoma), the overall response rate was 19.5%. There were higher 
responses in the MFH/UPS and LPS subtypes, tumors thought to be characterized by high 
mutational burden and high tumor infiltrating lymphocytes. Given the promising activity in 
these subtypes there is rationale to expand the trial in these 2 histologies. 
1.11 
Registration Quality of Life (QOL) Measurements 
QOL measurements of fatigue and overall perception of QOL are routinely included in Alliance 
studies and will be assessed upon registration in this study.  Evidence has arisen indicating that 
baseline single-item assessments of fatigue and overall QOL are strong prognostic indicators for 
survival in cancer patients, independent of performance status. This evidence was derived from 
two separate meta-analyses recently presented at ASCO, the first involving 23 NCCTG and 
Mayo Clinic Cancer Center oncology clinical trials, the second involving 43 clinical trials. 
Routine inclusion of these measures should be considered similar to that of including 
performance status, either as stratification or prognostic covariates. It will take approximately 
one minute to complete this measure. [44] 
1.12 
Impact of This Trial 
Sarcomas represent a heterogeneous group of neoplasms with a limited number of therapeutic 
options in metastatic disease. There is indirect evidence from preclinical analysis of markers 
such as PDL-1 and characterization of immune infiltrates in human tissue samples that certain 
sarcomas may benefit from immune checkpoint blockade. This trial will represent one of the 
first Phase II studies of immune checkpoint blockade in sarcomas, and the first to combine 
CTLA-4 and PD-1 blockade in sarcoma. Planned correlates will investigate retrospective 
biomarkers that may predict which patients will respond to these therapies. 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
17 
Update #12 
2.0 
OBJECTIVES  
As of Update #06, the study objectives will be evaluated within the initial cohort of patients enrolled, as 
well as within 3 cohorts of patients defined by the following histologic subtypes:  LPS, UPS/MFH, and 
GIST.  
2.1 
Primary objective  
To evaluate the confirmed response rate of single agent nivolumab and dual agent nivolumab 
plus ipilimumab in patients with locally advanced/unresectable or metastatic soft tissue sarcoma.  
2.2 
Secondary objectives 
2.2.1 To evaluate adverse event rates (NCI CTCAE v4.0) within each treatment arm. 
2.2.2 To evaluate duration of response, clinical benefit rate, time to progression, progression-free 
survival, and overall survival within each treatment arm. 
2.3 
Correlative science objectives  
2.3.1 To potentially detect an early signal of confirmed response rate within a histologically 
defined patient cohort. 
2.3.2 To assess the potential association between PD-L1 expression (by IHC) and clinical 
outcome, within each treatment. 
2.3.3 To evaluate associations between selected biomarker measured in serial peripheral blood 
and with clinical efficacy, within each treatment. 
2.3.4 To evaluate the association between selected biomarker measured in tumor tissue with 
clinical efficacy, within each treatment. 
2.3.5 To evaluate the association between baseline tumor mutational burden and neoantigen 
production with clinical efficacy within each treatment. 
2.4 
Exploratory Phase II objectives (Crossover Treatment) 
2.4.1 To evaluate secondary endpoints within patients crossing over to dual agent nivolumab plus 
ipilimumab after experiencing progressive disease while receiving single agent nivolumab. 
2.4.2 To evaluate correlative science objectives endpoints within patients crossing over to dual 
agent nivolumab plus ipilimumab after experiencing progressive disease while receiving 
single agent nivolumab. 

 
Alliance A091401 
Version Date: 05/22/2019 
18 
Update #12 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Although they will not be considered formal eligibility (exclusion) criteria, physicians should 
recognize that the following may seriously increase the risk to the patient entering this protocol, 
and the following patients will not be enrolled: 
• 
Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac 
disease which, in the opinion of the treating physician, would make this protocol 
unreasonably hazardous for the patient. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin 
cancers. Patients are not considered to have a “currently active” malignancy if they have 
completed therapy and are free of disease for ≥ 1 year. 
In addition: 
• 
Women and men of reproductive potential should agree to use an appropriate method of 
birth control throughout their participation in this study and continue for 5 months (women) 
and 7 months (men) after the last dose of study drugs, even if oral contraceptives are also 
used, due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods 
of birth control include abstinence, oral contraceptives, implantable hormonal 
contraceptives or double barrier method (diaphragm plus condom). 
• 
Patients with a history of CHf or at risk because of underlying cardiovascular disease or 
exposure to cardiotoxic drugs as clinically indicated should be assessed as per the study 
calendar (see Section 5.0) for appropriateness for participation on this trial.  
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
19 
Update #12 
3.2 
Pre-Registration Eligibility Criteria  
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following pages. 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday four weeks later 
would be considered Day 28. 
A female of childbearing potential is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 
12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive 
months). 
___ 
3.2.1 Central pathology review submission 
Patients must have a FFPE tumor block OR 1 representative H&E and 20 unstained sarcoma 
tissue slides available for submission for central pathology review. This review is mandatory 
prior to registration to confirm eligibility. See Section 6.2 for details on slide/block 
submission. 
3.3 
Registration Eligibility Criteria  
___ 
3.3.1 Documentation of Disease 
Histologic Documentation:  
Prior to Update #06: Patients must have histologically confirmed bone or soft tissue 
sarcoma by central pathology review.  
 
 
Effective with Update #06: Patients must have histologically confirmed LPS (only 
dedifferentiated and pleomorphic. Well differentiated not eligible), UPS/MFH, or GIST.  
___ 
3.3.2 
Disease Status 
Measurable disease as defined in Section 11.0. 
Locally advanced/unresectable or metastatic disease. 
___ 
3.3.3 Prior Treatment  
 • 
≥ 1 prior systemic therapy for sarcoma, including adjuvant systemic therapy. 
• 
No prior therapy with ipilimumab or nivolumab, or any agent targeting PD-1, PD-L1 or 
CTLA-4. 
• 
No treatment with biologic therapy, immunotherapy, chemotherapy, investigational 
agent for malignancy, or radiation ≤ 28 days before study registration. No treatment 
with nitrosourea or mitomycin ≤ 42 days before study registration. For GIST, tyrosine 
kinase inhibitor can be continued for up to 3 days prior to initiation of study treatment. 
• 
Patients should have resolution of any toxic effects of prior therapy (except alopecia) to 
NCI CTCAE, Version 4.0, grade 1 or less. 
___ 
3.3.4 
No history of the following: 
• 
Active known or suspected autoimmune disease. See Appendix IV for details.  
• 
Patients with HIV are eligible if the lymphocytes > 350 CD4+ cells and no detectable 
viral load 
• 
Symptomatic, untreated, or uncontrolled brain metastases present. 

 
Alliance A091401 
Version Date: 05/22/2019 
20 
Update #12 
• 
Active autoimmune colitis  
• 
Autoimmune panhypopituitarism 
• 
Autoimmune adrenal insufficiency 
• 
Known active hepatitis B or C 
Hepatitis B Can be defined as:  
1. HBsAg > 6 months 
2. Serum HBV DNA 20,000 IU/ml (105copies/ml), lower values 2,000-20,000 IU/ml 
(104-105 copies/ml) are often seen in HBeAg-negative chronic hepatitis B 
3. Persistent or intermittent elevation in ALT/AST levels 
4. Liver 
biopsy 
showing 
chronic 
hepatitis 
with 
moderate 
or 
severe 
necroinﬂammation 
Hepatitis C can be defined as: 
1. Hepatitis C AB positive 
2. Presence of HCV RNA 
• 
Known active pulmonary disease with hypoxia defined as  
1. Oxygen saturation < 85% on room air or  
2. Oxygen saturation <88% despite supplemental oxygen 
___ 
3.3.5 
Concomitant Medications: 
No systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or 
other immunosuppressive medications within 14 days of registration. 
___ 
3.3.6 Not pregnant and not nursing, because this study involves an agent that has known 
genotoxic, mutagenic and teratogenic effects. 
Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 
days prior to registration is required. 
___ 
3.3.7 Age ≥ 18 years  
 
___ 
3.3.8 ECOG Performance Status 0 or 1. 
 
___ 
3.3.9 Required Initial Laboratory Values:  
Absolute Neutrophil Count (ANC) 
≥ 1,500/mm3 
Platelet Count 
≥ 100,000/mm3 
Creatinine 
≤ 1.5 x upper limit of normal (ULN) OR 
Calc. Creatinine Clearance 
> 45 mL/min* 
Total Bilirubin 
≤ 1.5 x upper limit of normal (ULN)** 
AST / ALT  
≤ 3 x upper limit of normal (ULN) 
TSH 
WNL*** 
* 
Using the lean body mass formula only (Modified Cockcroft and Gault; Shargel and 
Yu 1985) 
**  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 
***  Supplementation is acceptable to achieve a TSH WNL. In patients with abnormal TSH 
if Free T4 is normal and patient is clinically euthyroid, patient is eligible.  
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
21 
Update #12 
3.4 
Re-registration Eligibility Criteria (For patients who crossover from arm 1 nivolumab 
alone to dual agent nivolumab and ipilimumab upon progression) 
___ 
3.4.1 
Disease Status 
• 
Measurable disease as defined in Section 11.0. 
• 
Locally advanced/unresectable or metastatic disease. 
• 
Patient MUST have had progressive disease (radiographic or clinical) while on arm 1 
single agent nivolumab while registered to A091401.  
___ 
3.4.2 Prior Treatment  
 • 
Patients removed from any immunotherapy for reasons other than progressive disease, 
including arm 1 single agent nivolumab of A091401, are NOT eligible for re-
registration 
• 
Patients must have completed a minimum of 10 weeks of single agent nivolumab on 
arm 1 of A091401 to be eligible for re-registration 
• 
Patients must have completed study drug on arm 1 of A091401 (i.e., last dose of 
nivolumab)  12 months of re-registration to crossover dual agent therapy 
• 
No treatment with immunotherapy  21 days before re-registration. No treatment with 
biologic therapy, chemotherapy, investigational agent for malignancy, or radiation ≤ 28 
days before re-registration. No treatment with nitrosourea or mitomycin ≤ 42 days 
before re-registration. 
• 
Patients should have resolution of any toxic effects of prior therapy (except fatigue and 
alopecia) to NCI CTCAE, Version 4.0, grade 1 or less, including immune toxicity. 
___ 
3.4.3 
Concomitant Medications: 
No systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or 
other immunosuppressive medications within 14 days of re-registration. 
___ 
3.4.4 Not pregnant and not nursing, because this study involves an agent that has known 
genotoxic, mutagenic and teratogenic effects. 
Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 
days prior to re-registration is required. 
 
___ 
3.4.5 ECOG Performance Status 0 or 1. 
 
___ 
3.4.6 Required Laboratory Values:  
Absolute Neutrophil Count (ANC) 
≥ 1,500/mm3 
Platelet Count 
≥ 100,000/mm3 
Creatinine 
≤ 1.5 x upper limit of normal (ULN) OR 
Calc. Creatinine Clearance 
> 45 mL/min* 
Total Bilirubin 
≤ 1.5 x upper limit of normal (ULN)** 
AST / ALT  
≤ 3 x upper limit of normal (ULN) 
TSH 
WNL*** 
* 
Using the lean body mass formula only (Modified Cockroft and Gault; Shargel and Yu 
1985) 

 
Alliance A091401 
Version Date: 05/22/2019 
22 
Update #12 
**  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 
***  Supplementation is acceptable to achieve a TSH WNL. In patients with abnormal TSH 
if Free T4 is normal and patient is clinically euthyroid, patient is eligible. 

 
Alliance A091401 
Version Date: 05/22/2019 
23 
Update #12 
4.0 
PATIENT REGISTRATION 
4.1 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per 
registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov>. 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
24 
Update #12 
4.2 
CTSU Site Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can be approved to enroll patients.  Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
4.2.1 Downloading Site Registration Documents 
Site registration forms may be downloaded from the A091401 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the Alliance link to expand, then select trial protocol # A091401 
• 
Click on LPO Documents, select the Site Registration Documents link, and 
download and complete the forms provided. 
4.2.2 Requirements for A091401 Site Registration 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted). 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
25 
Update #12 
4.2.3 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab → 
Regulatory Submission. 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
      
1818 Market Street, Suite 3000 
       
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
4.2.4 Checking Your Site’s Registration Status 
You can verify your site registration status on the members’ section of the CTSU website  
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol 
or the enrolling investigator’s status with the NCI or their affiliated networks. 
4.3 
Patient Pre-registration Requirements (Step 0) 
• 
Informed consent: The patient must be aware of the neoplastic nature of his/her disease 
and willingly consent after being informed of the procedure to be followed, the experimental 
nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. 
Current human protection committee approval of this protocol and a consent form is 
required prior to patient consent and registration. 
• 
Slot reservation: As of Update #06, patient enrollment will be facilitated using the Slot  
Reservation System in conjunction with the Registration system on Oncology Patient 
Enrollment Network (OPEN). Prior to discussing protocol entry with the patient, all site 
staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on the 
correct cohort is available to the patient. Once a slot reservation confirmation is obtained, 
site staff may then proceed to consent and pre-register the patient. Once a patient is pre-
registered, specimens should be submitted for central pathology review. There will be no 
renewal of slots for this protocol. Therefore, pre-registration must be completed within 7 
calendar days of slot reservation. 
• 
Central pathology: Patients who meet the pre-registration eligibility criteria will be pre-
registered using the OPEN registration system (see Section 4.5) in order to submit 
specimens for central pathology review. Once a patient is pre-registered, the archival FFPE 
tumor block OR 1 representative H&E and 20 unstained sarcoma tissue slides (thickness of 
4-5 microns) from diagnostic biopsy should be sent to the Alliance Biorepository at Ohio 
State (OSU) along with a completed “Central Pathology Review Form”, per Section 6.2.3. 
Failure to submit this form with the specimens will delay turnaround time for central 

 
Alliance A091401 
Version Date: 05/22/2019 
26 
Update #12 
pathology review. The specimen will be centrally reviewed to confirm the patient meets 
the pathology criteria.  
• 
For all Investigators: Patients should be encouraged to verify that their medical insurance 
will cover the costs associated with the frequency of the scanning schedule (see Section 5.0, 
Study Calendar).  
4.4 
Patient Registration Requirements (Step 1) 
• 
Confirmation of eligibility by central pathology review: Sites will be notified via e-mail 
within 10 business days of receipt, whether or not the patient is eligible based on the central 
pathology review. The results section of the “Central Pathology Review Form” will be 
completed by the pathologist, scanned and sent via e-mail to the Responsible CRA listed on 
the form. The form will indicate whether or not the patient is eligible, and if a discrepancy 
was found in central vs. local pathology review. If the central review disagrees with local 
review, then the following may occur: 
• 
Complete discordance: the patient is ineligible for the trial. The treating physician 
should inform the patient and determine next steps.  
• 
Partial discordance: the patient is eligible (as this trial allows all sarcoma subtypes), 
but the treating physician at the site may determine whether not they would like to 
register the patient to the trial. The patient should be informed of the discordance. 
After receiving the results form via e-mail, the institution must forward the form to the 
Alliance Patient Registration office at random01@mayo.edu in order to register the patient. 
Once the form is forwarded to the Alliance Patient Registration Office and the Registration 
and Randomization Eligibility Criteria have been met, the patient can be registered using 
the OPEN system per Section 4.5. Registration must occur within 40 days of specimen 
submission. The same patient ID number obtained at pre-registration from the OPEN system 
should be used to register the patient. Please contact Alliance Patient Registration office at 
random01@mayo.edu or 507-284-4130 if registration problems occur.  
4.5 
Patient Pre-Registration/Registration/Randomization Procedures 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available on a 24/7 basis.  To access OPEN, the site 
user must have an active CTEP-IAM account (check at < https://ctepcore.nci.nih.gov/iam >) and 
a 'Registrar' role on either the LPO or participating organization roster.  Registrars must hold a 
minimum of an AP registration type. 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient in 
the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the 
CTSU members’ side of the website at https://www.ctsu.org.  To assign an IVR or NPIVR as 
the treating, crediting, consenting, drug shipment (IVR only), or investigator receiving a transfer 
in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR the IRB number used 
on the site’s IRB approval. 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes. 
• 
As of Update #06, tumor histology (local diagnosis) is one of the following:  
1. LPS 
2. UPS/MFH 
3. GIST 

 
Alliance A091401 
Version Date: 05/22/2019 
27 
Update #12 
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of 
the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any additional 
questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
4.6 
Re-Registration (Step 2) at the time of progression 
Upon confirmation of progression, patients who were initially assigned to nivolumab alone 
(Arm 1) will be allowed to cross over to the dual agent arm (Arm 2). 
Re-registration procedures: 
• 
Call (507-284-4130) or email (random01@mayo.edu) the Alliance Registration Office. 
• 
After Registration Office confirms progression and ensures all data is up-to-date with 
Data Manager, the patient will be allowed to re-register to the trial.  
Follow the OPEN enrollment procedures as detailed in Section 4.5. 
4.7 
Registration to Correlative and Companion Studies 
4.7.1 Registration to Substudy described in Section 14.1 
There is one substudy within Alliance A091401. This correlative science study must be 
offered to all patients enrolled on Alliance A091401 (although patients may opt to not 
participate). This substudy does not require separate IRB approval. The substudy included 
within Alliance A091401 is: 
• 
Correlative Science, Alliance A091401-ST1 (Section 14.1) 
If a patient answers “yes” to “I agree to have my specimen collected and I agree that my 
specimen sample(s) and related information may be used for the laboratory study(ies) 
described above,” they have consented to participate in the substudy described in Section 
14.1. The patient should be registered to Alliance A091401-ST1 at the same time they are 
registered to the treatment trial (A091401). Samples should be submitted per Section 6. 
4.8 
Grouping Factors  
• 
Enrollment Group: 
1. Initial Cohort (enrollment closed as of 02/02/2017) 
2. LPS 
3. UPS/MFH 
4. GIST 
 

 
Alliance A091401 
Version Date: 05/22/2019 
28 
Update #12 
5.0 
STUDY CALENDAR 
Laboratory and clinical parameters during treatment are to be followed using individual institutional 
guidelines and the best clinical judgment of the responsible physician. It is expected that patients on 
this study will be cared for by physicians experienced in the treatment and supportive care of patients 
on this trial.  
Pre-Study and Pre-Crossover (re-registration) Testing Intervals  
• 
To be completed ≤ 16 DAYS before registration and re-registration: All laboratory studies, history 
and physical. 
• 
To be completed ≤ 28 DAYS before registration: Any X-ray, scan of any type or ultrasound which is 
utilized for tumor measurement per protocol  
• 
To be completed ≤ 42 DAYS before registration and re-registration: Any baseline exams used for 
screening, or any X-ray, scan of any type or ultrasound of uninvolved organs which is not utilized for 
tumor measurement. 
 
Prior to 
Registration 
AND Prior to 
Re-Registration 
* 
Arm 1 
(Nivolumab 
alone): 
Every 2 weeks  
Arm 2 AND 
Crossover 
Patients 
Every 3 weeks 
x 12 weeks, 
then every 2 
weeks 
Post 
treatment 
follow up** 
At PD, 
withdrawal, or 
removal*** 
Tests & Observations 
 
 
 
 
 
History and physical, weight, PS**** 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
Pulse, Blood Pressure 
X 
X 
X 
 
 
Oxygen Saturation † 
X 
X 
X 
X 
 
Adverse Event Assessment π 
X 
X 
X 
X 
 
EKG, Echo or MUGA, CPK, 
troponin 
X (F) 
 
 
 
 
Registration Fatigue/Uniscale 
Assessment 
X(1) 
 
 
 
 
Laboratory Studies 
 
 
 
 
 
Complete Blood Count, Differential, 
Platelets 
X 
X (2) 
X (2) 
X 
 
Chemistry Ψ 
X 
X (2) 
X (2) 
X 
 
TSH 
X 
A(2) 
A(2) 
 
 
Lipase 
 
B(2) 
B(2) 
 
 
Serologic Hepatitis B Surface Ag and 
Hepatitis C ab (physician discretion, 
not required) 
X 
 
 
 
 
Serum or Urine HCG 
X(3) 
 
 
 
 
Urinalysis 
 
B(2) 
B(2) 
 
 
Staging 
 
 
 
 
 
Central Pathology review for 
eligibility  
X(4) 
 
 
 
 
CT or MRI of chest and of regions of 
tumor involvement 
X(5) 
C, D 
C, D,E 
C 
X 
 
Correlative studies: For patients who consent to participate 
Tissue samples (4) 
Baseline, and end of cycle 1. See Section 6.2 
Blood samples (4) 
Weeks 1-16, PD/withdrawal/removal. See Section 6.2 

 
Alliance A091401 
Version Date: 05/22/2019 
29 
Update #12 
* 
Labs completed prior to registration may be used for day 1 of cycle 1 tests if obtained ≤ 16 days prior 
to treatment. Labs completed prior to re-registration may be used for day 1 of cycle 1 if obtained  16 
days prior to treatment. 
** 
Physical examination, adverse event assessment, labs (CBC and chem), and staging scans (if due per 
footnote C) are required 4 weeks (+/- 7 days) after the end of treatment.  
*** 
Patients who do not progress on treatment (i.e. removal for toxicity or withdrawal of consent) are 
followed every 6 months for both survival and disease status for at least three years post-randomization 
or until death, whichever comes first. Upon progressive disease (at any time), survival information is 
required every 6 months for 3 years. See also Section 12.  
**** Drug dosages need not be changed unless the calculated dose changes by ≥ 10%. 
† 
Oxygen saturation should be assessed at rest and after 1 minute walk. 
π  
Solicited AEs are to be collected starting at baseline until off treatment (See Section 9.1). Routine AEs 
are to be collected starting after registration. See Section 9.3 for expedited reporting of SAEs. 
Ψ  
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
1 
To be completed after pre-registration and prior to registration (≤ 21 days prior to treatment), see 
Section 1.9 and Appendix I. NOT required for re-registration. 
2 
Labs may be performed +/- 3 days from date required. 
3 
For women of childbearing potential (see Section 3.2). Must be done ≤ 7 days prior to registration. 
Also, must be done  7 days prior to re-registration. 
4 
See Section 6.2. Central pathology review is only required for registration, not required for re-
registration. 
5 
Baseline scans can include either: 1) a CT, spiral CT, or MRI, or 2) an FDG-PET scan and diagnostic 
CT performed with both IV and oral contrast, and the CT acquired with 5 mm or less slice thickness. 
Supporting documentation is to be submitted, per Section 6.1.1. 
A 
Every 6 to 8 weeks. 
B 
Perform every 4 weeks x 4 in arm 1 (nivolumab alone). Perform every 3 weeks x 4, then every 2 weeks 
x 1 in arm 2 and crossover to dual agent therapy (nivolumab + ipilimumab). 
C 
Every 6 weeks for 12 weeks, then every 8 weeks until evidence of progression or relapse. Scans may be 
performed +/- 7 days from scheduled date. During the first 12 weeks of therapy, patients can be 
considered for continuation of treatment (see Section 7.1 for further details and footnote D below). 
Confirmatory scans to be obtained at least 4 weeks following documentation of objective response (see 
Section 11.0). Response assessment should include assessment of all sites of disease and use the same 
imaging method as was used at baseline. For patients receiving initial treatment beyond 2 years from 
randomization date; scans may be performed every 3 months for year 3, every 4 months for year 4, 
every 6 months for year 5 and then yearly thereafter.  One confirmatory scan continues to be required if 
patient achieves a response for the first time and during this period. Thereafter, returning to the 
assessment schedule. 
D 
If there is evidence of progression in the first 12 weeks, treatment is allowed to be continued.  
 
The patient’s baseline assessment is now the 1st assessment showing progression (not the pre-study 
disease assessment) and is used for the remainder of the patient’s initial treatment assignment (not 
crossover).  Contact the Data Manager or Study Chair for questions. If this occurs, an additional scan is 
to be scheduled 4 weeks from the regular scan (i.e. at week 10 or 16). Thereafter, the patient will have a 
scan every 8 weeks. See also section 7.1 for further information.  
E. 
Crossover Patients Only: For patients who crossover to dual agent therapy, a baseline scan is required 
< 28 days prior to re-registration. After initiation of dual agent therapy scans are every 6 weeks for 12 
weeks, then every 8 weeks until evidence of progression or relapse (scans may be done +/- 7 days from 
due date). During the first 12 weeks of therapy, patients can be considered for continuation of treatment 
(see Section 7.1 for further details and footnote D above with the appropriate reset for baseline disease 
measurement.  Contact the Data Manager or Study Chair for questions). Confirmatory scans are to be 
obtained at least 4 weeks following documentation of objective response (see Section 11.0). Response 
assessment should include assessment of all sites of disease and use the same imaging method as was 
used at the baseline measurements associated with crossover. For patients receiving crossover 

 
Alliance A091401 
Version Date: 05/22/2019 
30 
Update #12 
treatment beyond 2 years from date of crossover, scans may be performed every 3 months for year 3, 
every 4 months for year 4, every 6 months for year 5 and then yearly thereafter. One confirmatory scan 
continues to be required if patient achieves a response for the first time and during this period. 
Thereafter, returning to the assessment schedule. 
F. 
For patients with evidence of CHF, MI, cardiomyopathy, or myositis a cardiac evaluation including lab 
tests and cardiology consultations as clinically indicated are required prior to study including EKG, 
CPK, troponin, ECHO or MUGA. 

 
Alliance A091401 
Version Date: 05/22/2019 
31 
Update #12 
6.0 
DATA AND SPECIMEN SUBMISSION  
6.1 
Data collection and submission 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to 
all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access 
Rave via iMedidata, the site user must have an active CTEP-IAM account (check at 
<https://ctepcore.nci.nih.gov/iam>) and the appropriate Rave role (Rave CRA, Read-Only, CRA 
[Lab Admin, SLA, or Site Investigator]) on either the LPO or participating organization roster 
at the enrolling site. To hold the Rave CRA role or CRA Lab Admin role, the user must hold a 
minimum of an AP registration type. To hold the Rave Site Investigator role, the individual must 
be registered as an NPIVR or IVR. Associates can hold read-only roles in Rave. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed. Trainings will be 
in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in 
the upper right pane of the iMedidata screen. 
Users who have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 
1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
A Schedule of Forms is available on the Alliance study webpage, within the Case Report Forms 
section. The Schedule of Forms is also available on the CTSU site within the study-specific 
Education and Promotion folder, and is named Time & Events. 
6.1.1 Supporting documentation 
This study requires supporting documentation for screening, on study, response and 
progression. Supporting documentation will include “Central Pathology Review Form,” 
radiology report, pathology report, clinic note. These must be submitted at the following 
time points: 
• 
Screening: Site will be required to upload the “Central Pathology Review Form” 
confirming eligibility onto the screening form. 
• 
On study: clinic note, radiology report of baseline study scan only, and pathology 
report establishing diagnosis  
• 
Response: radiology report 
• 
Progression: radiology report and pathology report (if applicable); clinic note for 
patients deemed to have progressive disease by virtue of symptomatic deterioration 
(see section 11.4.5) 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
32 
Update #12 
6.2 
Specimen collection and submission  
6.2.1 Overview of specimen collection and submission 
For patients registered to substudy A091401-ST1: All participating institutions must ask 
patients for their consent to participate in the correlative substudy planned for Alliance 
A091401-ST1, although patient participation is optional. Serum studies, tumor and 
peripheral blood mononuclear cell (PBMC) genetic analysis and PBMC flow cytometry will 
be performed. Rationale and methods for the scientific components of these studies are 
described in Section 14.0. For patients who consent to participate, tissue and blood will be 
collected at the following time points for these studies: 
* 
Correlative time points for blood should be drawn on the visit and day of treatment for each 
arm. See Section 5.0 for dates of clinical assessments. All correlative time points have a 
window of ±1 week. Correlates obtained outside these windows may be included in 
analysis after discussion with the Study Chair. 
** 
Tumor block is preferred. If site does not have 20 slides, send as many as possible, up to 
20. This is for mandatory pathology review, PD-L1 expression in tumor and tumor 
infiltrating lymphocytes (TIL) and TIL expression by IHC. For patients who opt into tissue 
bank (Model Consent Question#2 SAMPLES FOR FUTURE RESEARCH STUDIES). 
Left over tissues will be stored at the Alliance Biorepository at OSU for future unspecified 
research. 
 
Pre-
treatment 
(not 
applicable 
to 
crossover 
to dual 
agent 
therapy) 
Arm 1: 
Weeks 
3,5,9, 
11,13* 
Arm 2:  
Weeks 
4,7,10, 
13,15* 
Crossover 
to dual 
agent 
therapy 
Weeks 
1,4,7,10,13 
& 15 
End of 
Cycle 1 
(6 weeks): 
Includes 
crossover 
to dual 
agent 
therapy 
 
End of 
Treat-
ment 
PD, 
withdrawal, 
or removal 
Storage/ 
Shipping 
conditions 
Submit 
to: 
Mandatory for all patients pre-registered to A091401: 
Archival FFPE 
tumor block OR 
1 representative 
H&E and 20 
unstained tissue 
slides ** 
X(1) 
 
 
 
 
 
 
See Section 
6.2.3 
OSU 
For patients registered to A091401-ST1, submit the following: 
Fresh tumor 
biopsy 
X(2) 
 
 
X (3) 
X 
 
 
See Section 
6.2.4 
OSU 
Peripheral whole 
blood (EDTA)*** 
1 x 10 mL  
 
 
 
 
 
 
See Section 
6.2.5 
OSU 
Peripheral whole 
blood (non-
additive red top) 
Ω 
1 x 10 mL  
1 x 10 mL 
1 x 10 mL  
1 x 10 mL 
 
1 x 10 mL  
1 x 10 mL  
See Section 
6.2.5 
OSU 
Peripheral whole 
Blood (green top 
heparin) Ψ 
 2 x 10 mL  2 x 10 mL  2 x 10 mL  
2 x 10 mL 
 
2 x 10 mL  
2 x 10 mL  
See Section 
6.2.5 
OSU 

 
Alliance A091401 
Version Date: 05/22/2019 
33 
Update #12 
*** Germline DNA to be used for analysis described in Section 14.0. It is strongly encouraged 
that the whole blood sample for germline DNA is collected prior to the initiation of study 
treatment. However, this sample collection may take place during later clinical visit while 
the patient is on study. 
Ω 
Serum to be used for biomarker analyses described in Section 14.0. Plasma isolated from 
heparin green top tubes processed for PMBC’s can substitute for serum if necessary. 
Ψ 
PBMCs to be used for flow cytometry and/or genomic analysis described in Section 14.0. 
1 
Collect/submit within 3 days from pre-registration. 
2 
Blocks/cores to be used for biomarker/TMA analyses described in Section 14.1. If 
sufficient archival tissue (block, unstained slides) is available from a metastatic or 
unresectable lesion, baseline tumor biopsy may be foregone after discussion with the Study 
and/or Correlate Chair. Baseline biopsy can be performed anytime between registration 
and first day of study therapy. Archival block or unstained slides may suffice for baseline 
biopsy if at least 80% tumor (based on local histopathology review) and adequate sample 
is available for analysis. See Section 6.2.4 for instructions. 
3 
Collect tissue at baseline (prior to initiation of dual agent therapy, after progression on 
single agent nivolumab. 
6.2.2 Specimen submission using the Alliance Biospecimen Management System  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials.  Authorized individuals may access BioMS at the following URL:  
http://bioms.allianceforclinicaltrialsinoncology.org using most standard web browsers 
(Safari, Firefox, Internet Explorer).  For information on using the BioMS system, please 
refer to the ‘Help’ links on the BioMS webpage to access the on-line user manual, FAQs, 
and training videos.  To report technical problems, such as login issues or application errors, 
please contact: 1-855-55-BIOMS or Bioms@alliancenctn.org.  For assistance in using the 
application or questions or problems related to specific specimen logging, please contact: 1-
855-55-BIOMS or Bioms@alliancenctn.org. 
After logging collected specimens in BioMS, the system will create a shipping manifest.  
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
All submitted specimens must be labeled with the protocol number (A091401), Alliance 
patient number, patient’s initials and date and type of specimen collected (e.g., serum, whole 
blood). 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in the 
shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a method 
of shipping that is secure and traceable. Extreme heat precautions should be taken when 
necessary.  
Shipment on Monday through Thursday by overnight service to assure receipt is 
encouraged. Do not ship specimens on Fridays or Saturdays. 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
34 
Update #12 
All specimens should be sent to the following address: 
Alliance Biorepository at Ohio State University (OSU) 
Department of Pathology 
Polaris Innovation Centre 
2001 Polaris Parkway 
Columbus, OH  43240 
Tel: 614-293-7073  Fax: 614-293-7967 
6.2.3 Collection and processing for histopathology review (Mandatory for all patients)) 
Consistent and accurate histologic grading is important for this study. Archival FFPE tumor 
block (preferred) OR 1 representative H&E and 20 unstained tissue slides (thickness of 4-5 
microns) from the diagnostic biopsy must be submitted. The submission should be taken 
from the highest grade area as identified by your local pathologist/investigator. This will be 
used for central pathology review and PD-L1 testing in tumor, tumor infiltration 
lymphocytes (TILs) and TIL expression. 
Blocks which contain minimal amounts of tissue specimen based on local review or that are 
very thin should not be submitted unless the block is the only representative tissue for the 
case. A de-identified surgical pathology report should be sent with all specimens. Usually, 
this is generated by obscuring all PHI (names and dates) with white-out or a black magic 
marker, labeling each page of the report with the Alliance patient ID, and photocopying the 
report.  
In addition to the pathology report, the institution must complete and submit the 
“Central Pathology Review Form” with the tumor block or slides to the Alliance 
Biorepository at OSU. Failure to submit this form with the specimens will delay 
turnaround time for central pathology review. The top portion of the form must be 
completed by typing and cannot be handwritten. For Alliance members, the form may be 
found on the A091401 study page on the Alliance website under the “Supplemental 
Materials” tab. For non-Alliance institutions, the form can be found under “Miscellaneous” 
documents section of the CTSU A091401 study page (www.ctsu.org). 
When shipping blocks and /or FFPE slides, it is important to avoid extreme heat. If 
environmental conditions indicate, specimens may be shipped in containers containing cold 
packs. The diagnostic slides must be appropriately packed to prevent damage (e.g. slides 
should be placed in appropriate slide container) and placed in an individual plastic bag. It is 
also important that blocks are shipped in appropriately padded and secure containers to 
avoid physical damage.  Do not wrap blocks or slides in tissue or paper toweling that is in 
direct contact with the paraffin. 
The Alliance has instituted special considerations for the small percentage of hospitals 
whose policy prohibits long-term storage of blocks, and the smaller percentage of hospitals 
whose policies prohibit release of any block. 
The goal of the Alliance is to provide investigators with quality histology sections for their 
research while maintaining the integrity of the tissue. All slides/blocks may be returned with 
written request by the site. 
6.2.4 Collection of fresh biopsy specimen (A091401-ST1) 
From patients who consent to A091401-ST1, fresh biopsy samples will be used for the 
analyses described in Section 14.1 (Objective 2). Core biopsy samples will be taken at the 
following time points: 
• 
Prior to start of treatment (anytime between registration and first day of study 
therapy). An archival block or unstained slides may suffice for fresh baseline biopsy 

 
Alliance A091401 
Version Date: 05/22/2019 
35 
Update #12 
if at least 80% tumor (based on local histopathology review) and adequate sample 
is available for analysis.  
• 
End of cycle 1 of therapy (week 6 of initial treatment assignment AND in addition 
week 6 of crossover dual agent therapy). This biopsy specimen is optional but 
encouraged.  
• 
Prior to start of crossover to dual agent therapy after progression on single agent 
nivolumab. A fresh biopsy must be obtained for arm 1 patients who progress and 
are proceeding with crossover to dual agent therapy 
The same metastatic tumor site should be biopsied at both time points, if feasible. Cores 
should be representative of tumor (preferably >80% tumor based on local histopathology 
review). A goal of 3-4 cores should be obtained, with 1-2 flash frozen in liquid nitrogen. 
But it is acceptable to send less if is not possible to obtain all of these: 
• 
If 1 core is obtained, it should be placed in formalin and paraffin-embedded. 
• 
If 2 cores are obtained, 1 should be placed in formalin and 1 should be flash frozen 
in liquid nitrogen 
• 
If 3 cores are obtained, 2 cores should be flash frozen in liquid nitrogen and 1 should 
be placed in formalin 
• 
If 4 cores are obtained, 2 cores should be flash frozen in liquid nitrogen and 2 should 
be placed in formalin 
Label samples with the following identification: 
1) Procurement date 
2) Alliance patient number 
3) Alliance study number (i.e. A091401-ST1) 
4) Time point (baseline or week 6) 
5) Tumor type (primary vs metastasis) 
Ensure that the label adheres to the vial and does not come off when placed in liquid 
nitrogen.  Labels cannot be adequately affixed to the vials after freezing. 
Immediately place the freshly obtained tissue into the labelled cryogenic vial.  Place the vial 
with tissue in liquid nitrogen for 2 minutes or longer to snap-freeze the tissue.  Tumor cores 
should be frozen individually in separate cryovials as collected in order to minimize the time 
between removal and freezing. 
Remove the cryovial from liquid nitrogen and store the sample in a -80oC freezer (-65oC to 
-80oC acceptable) until ready for shipping on dry ice. Flash frozen samples must be 
shipped overnight on dry ice. 
If at least 80% tumor and adequate sample (based on local histopathology review) is 
available for analysis, then an archival block or unstained slides may suffice for fresh 
baseline biopsy (archival tissue is not applicable for baseline biopsy for patients 
crossing over to dual agent therapy, this requires fresh tissue). Paraffin blocks of 
primary and, when available, metastatic tissue obtained from archival sarcoma tumor 
specimens should be sent to the Alliance Biorepository at Ohio State University. Paraffin-
embedded samples can be sent in ambient temperature. Please specify the source of the 
tumor block (primary or metastatic site) and accompany it with a deidentified pathology 
report.  
If, due to institutional policy, a block cannot be sent, 15 unstained slides (in addition to those 
sent for central pathology review) will suffice (thickness of 4-5 microns). Unstained slides 

 
Alliance A091401 
Version Date: 05/22/2019 
36 
Update #12 
should be cut within 1 week of shipment. Charged slides are required. After cutting, the 
slides should be refrigerated at 2-4oC and sent in ambient temperature. 
The goal of the Alliance Biorepository at OSU is to provide investigators with quality 
histology sections for their research while maintaining the integrity of the tissue. All paraffin 
blocks that are to be stored at the OSU will be vacuum packed to prevent oxidation and will 
be stored at 4º C to minimize degradation of cellular antigens. For these reasons it is 
preferred that the Alliance Biorepository at OSU bank the block until the study investigator 
requests thin sections. Please contact the Alliance Biorepository at OSU if additional 
assurances with your hospital pathology department are required.  
6.2.5 Blood sample submission (A091401-ST1) 
For patients who consent to A091401-ST1, whole blood samples will be used for the 
analyses described in Section 14.1. From consenting patients: 
• 
Collect 10 mL of venous blood in lavender top (EDTA anticoagulant) vacutainer 
tube(s) at baseline. The tubes should be inverted approximately 8-10 times to mix 
the EDTA. Refrigerate sample until shipping. The sample should be placed in a 
biohazard bag shipped according to IATA guidelines the same day as the blood is 
drawn on a cold pack by overnight courier service to the Alliance Biorepository at 
OSU for germline DNA extraction. 
• 
Collect 10 mL of peripheral venous blood in red top vacutainer tube(s) at the 
following time points: 
- 
Arm 1: Baseline, Weeks 3,5,9, 11, 13; End of treatment; PD, withdrawal or 
removal from study.  
- 
Arm 2: Baseline, Weeks 4, 7, 10, 13, 15; End of Treatment; PD, withdrawal, 
or removal from study.  
- 
Crossover to dual agent therapy upon progression on Arm 1: Weeks 1, 4, 
7, 10, 13, 15; End of Treatment; PD, withdrawal, or removal from study. 
Gently invert approximately 5 times to mix clot activator with blood. Let blood clot 
for 30 minutes. Observe a dense clot. Refrigerate the sample until shipping. The 
sample should be placed in a biohazard bag and shipped according to IATA 
guidelines the same day as the blood is drawn on cold pack by overnight courier 
service to the Alliance Biorepository at OSU for serum preparation. 
• 
Collect 2 x 10 mL of peripheral venous blood into green top (sodium heparin) 
vacutainer tubes at the following time points:  
- 
Arm 1: Baseline, Weeks 3, 5, 9, 11, 13; End of treatment; PD, withdrawal 
or removal from study.  
- 
Arm 2: Baseline, Weeks 4, 7, 10, 13, 15; End of Treatment; PD, withdrawal, 
or removal.  
- 
Crossover to dual agent therapy upon progression on Arm 1: Weeks 1, 4, 7, 
10, 13, 15; End of Treatment; PD, withdrawal, or removal from study. 
Invert tubes approximately 8-10 times to mix the sodium heparin solution. 
Specimens should be kept at room temperature until shipping. Samples should be 
placed in a biohazard bag and shipped according to IATA guidelines the same day 
as the blood is drawn and shipped at ambient temperature by overnight courier 
service to the Alliance Biorepository at OSU for PBMC isolation. Please do NOT 
use cold pack during shipping for the whole blood sodium heparin (green top) 
samples. 

 
Alliance A091401 
Version Date: 05/22/2019 
37 
Update #12 
Label samples with the following identification: 
1) Procurement date 
2) Alliance patient ID number 
3) Alliance study number (i.e., A091401-ST1) 
4) Time point (baseline, Week 1, etc) 
5) Patient initials 
6) Sample type 

 
Alliance A091401 
Version Date: 05/22/2019 
38 
Update #12 
7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 14 days of registration or of re-registration.  
It is acceptable for individual therapy doses to be delivered ≤ a 24-hour (business day) window before 
and after the protocol-defined date for a scheduled dose. For example, if the treatment due date is a 
Friday, the window for treatment includes the preceding Thursday through the following Monday. In 
addition, patients are permitted to have a new cycle of immunotherapy delayed up to 7 days for major 
life events (e.g., serious illness in a family member, major holiday, vacation that cannot be 
rescheduled) without this being considered a protocol violation. Documentation to justify this delay 
should be provided. 
Patients with locally advanced/unresectable and/or metastatic sarcoma of will be randomized in a 1:1 
fashion to receive either nivolumab single agent or combination nivolumab + ipilimumab. Upon 
progression on a minimum of 10 weeks of nivolumab single agent, patients may crossover to dual 
agent therapy. See Section 7.2 for further information. 
Though treatment is every 2 or 3 weeks depending on the treatment arm, a cycle will consist of 6 
weeks in length and therapy can be continued until patient develops progressive disease or 
unacceptable toxicity or withdraws from treatment. In the absence of these 3 events, treatment will 
continue for a maximum of 108 weeks (i.e. 18 cycles) on either arm. See Section 7.1 for further 
information. 
To determine response via RECIST v1.1, patients will undergo radiographic imaging every 6 weeks 
for 12 weeks, then every 8 weeks thereafter while on study treatment.  
Duration of treatment in both arms: Up to 2 years. 
 
ARM 1 
Agent 
Dose & Route 
Frequency 
 Cycle Length (ReRx) 
Nivolumab 
3mg/kg IV over 30 minutes 
Every 2 weeks 
42 days 
 
ARM 2** 
Administer nivolumab prior to ipilimumab (follow institutional standard for timing between agents) 
as specified below: 
Agent 
Dose & Route 
Frequency 
 Cycle Length (ReRx) 
nivolumab 
3mg/kg IV over 30 minutes 
Every 3 weeks 
42 days 
ipilimumab 
1mg/kg IV over 90 minutes 
Every 3 weeks 
42 days 
 
**The above regimen will be followed for 4 doses, followed by: 
 
Agent 
Dose & Route 
Frequency 
 Cycle Length (ReRx) 
nivolumab 
3mg/kg IV over 30 minutes 
Every 2 weeks 
42 days 
 
7.1 
Treatment Decisions within the First Twelve Weeks of Therapy 
Note: This section is applicable to initial treatment assignment, and to patients who are crossing 
over from the single agent nivolumab to combination treatment. 
Patients who progress by imaging (See Section 11.4.3.2) during the first 12 weeks of therapy 
may continue treatment, at the discretion of the patient and treating investigator. These patients 
must meet all of the following in order to be eligible to continue therapy: 

 
Alliance A091401 
Version Date: 05/22/2019 
39 
Update #12 
• 
No more than 4 new lesions. The sum of the longest diameter (SHORT diameter for LN) 
of target lesions and the new lesions are less than 40% increase from the baseline.   
• 
Patients must be clinically stable with no change in performance status due to disease 
progression 
• 
No indication for immediate alternative treatment 
• 
Patient [assessed by the investigator] is showing clinical benefit and tolerates study drug.  
The assessment of clinical benefit should take into account whether the subject is 
clinically stable or deteriorating and likely or unlikely to receive further benefit from 
continued treatment.  
• 
The time of progression is noted from the first assessment that exceeds standard criteria 
New lesions are considered measurable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm).  Any new lesion considered non-measurable at the time of initial progression may 
become measurable and therefore included in the tumor burden measurement if the longest 
diameter increases to at least 10 mm (except for pathological lymph nodes, which must have an 
increase in short axis to at least 15 mm). 
If the decision is made to continue treatment after progressive disease is identified within the 
initial 12 weeks (and criteria above are met), then the patient may continue therapy for a 
maximum of 4 weeks. Note: At this time, the baseline scan to use for further assessments of 
disease status is reset to this assessment.  After 4 weeks a scan is to be repeated. If the scan 
shows progression compared to the scan 4 weeks prior, they should be removed from protocol 
therapy. If the scan shows stable disease or response, compared to the scan 4 weeks prior, they 
can remain on protocol therapy should they choose to and the suspected initial progression date 
and assessment is considered the baseline scan to use for until further PD is evident. See section 
11.4.3.2 for more information for determining objective status and section 12.1 for information 
regarding duration of therapy. Scan schedule will resume routine schedule, as per Section 5.0 
footnote D. 
Patients who have progression AFTER the initial 12-week period will be removed from protocol 
therapy in arm 2 (arm 1 patients may elect to cross over to dual agent therapy with progression 
after a minimum of 10 weeks of single agent nivolumab). 
7.2  
Crossover to Dual Agent Nivolumab and Ipilimumab upon Progression on Arm 1 (single 
agent nivolumab)  
Upon documentation of progression on arm 1 and confirmation of eligibility criteria as per 
Section 3.4, patients may be re-registered and initiate dual-agent therapy. All parameters 
outlined in section 7.0 are applicable. NOTE: Treatment beyond progression in the first 12 
weeks, as per section 7.1, is applicable to patients receiving crossover dual agent therapy. 
Administer nivolumab prior to ipilimumab (follow institutional standard for timing between 
agents) as specified below: 
Agent 
Dose & Route 
Frequency 
 Cycle Length (ReRx) 
nivolumab 
3mg/kg IV over 30 minutes 
Every 3 weeks 
42 days 
ipilimumab 
1mg/kg IV over 90 minutes 
Every 3 weeks 
42 days 
 
**The above regimen will be followed for 4 doses, followed by: 
 
Agent 
Dose & Route 
Frequency 
 Cycle Length (ReRx) 
nivolumab 
3mg/kg IV over 30 minutes 
Every 2 weeks 
42 days 

 
Alliance A091401 
Version Date: 05/22/2019 
40 
Update #12 
Though treatment is every 2 or 3 weeks, a cycle will consist of 6 weeks in length and therapy 
can be continued until patient develops progressive disease or unacceptable toxicity or 
withdraws from treatment. In the absence of these 3 events, treatment will continue for a 
maximum of 108 weeks (i.e. 18 cycles) including the single agent nivolumab received prior 
to crossover to dual agent therapy.  
To determine response via RECIST v1.1, patients will undergo radiographic imaging every 8 
weeks while on study treatment.  

 
Alliance A091401 
Version Date: 05/22/2019 
41 
Update #12 
8.0 
DOSE AND TREATMENT MODIFICATIONS 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care.  
Please refer to the Nivolumab Investigator Brochure or Appendix III to the protocol for toxicity 
management algorithms which include recommended treatment guidelines for toxicity 
associated with nivolumab and ipilimumab.  These algorithms provide recommended guidelines 
for treating physicians.  
8.1.1 Patients should not receive any other agent which would be considered treatment for 
the primary neoplasm or impact the primary endpoint. 
8.1.2 Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent 
medical conditions.  All blood products and concomitant medications such as antidiarrheals, 
analgesics, and/or antiemetics received from the first day of study treatment administration 
until 30 days after the final dose will be recorded in the medical records. 
8.1.3 Treatment with hormones or other chemotherapeutic agents may not be administered 
except for steroids given for adrenal failure (steroid supplementation should be at 
physiologic dosing or as described in section 8.1.10); hormones administered for non-
disease-related conditions (e.g., insulin for diabetes); and intermittent use of dexamethasone 
as an antiemetic in solid tumor protocols.  
8.1.4 Antiemetics may be used at the discretion of the attending physician. 
8.1.5 Diarrhea: Please see Section 8.1.10 for further description of immune mediated colitis. All 
therapies for diarrhea are allowed on this protocol at the discretion of the treating 
investigator. 
8.1.6 Radiation therapy  
Patients who require radiation therapy during protocol treatment will be removed from 
protocol therapy due to disease progression. 
8.1.7 Alliance Policy Concerning the Use of Growth Factors 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations.  The use of growth factors should follow 
published guidelines of the American Society of Clinical Oncology 2006 Update of 
Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based, 
Clinical Practice Guideline.  J Clin Oncol 24(19): 3187-3205, 2006. 
Epoetin (EPO): Use of epoetin in this protocol is permitted at the discretion of the treating 
physician. 
Filgrastim (G-CSF) and sargramostim (GM-CSF) 
1. Filgrastim (G-CSF)/pegfilgrastim and sargramostim (GM-CSF) treatment for patients 
on protocols that do not specify their use is discouraged. 
2. Filgrastim/pegfilgrastim and sargramostim may not be used: 
a. To avoid dose reductions, delays or to allow for dose escalations specified in the 
protocol. 
b. For the treatment of febrile neutropenia the use of CSFs should not be routinely 
instituted as an adjunct to appropriate antibiotic therapy. However, the use of CSFs 
may be indicated in patients who have prognostic factors that are predictive of 
clinical deterioration such as pneumonia, hypotension, multi-organ dysfunction 

 
Alliance A091401 
Version Date: 05/22/2019 
42 
Update #12 
(sepsis syndrome) or fungal infection, as per the ASCO guidelines.  Investigators 
should therefore use their own discretion in using the CSFs in this setting.  The use 
of CSF (filgrastim/pegfilgrastim or sargramostim) must be documented and 
reported. 
c. If filgrastim/pegfilgrastim or sargramostim are used, they must be obtained from 
commercial sources. 
8.1.8 Surgery: Patients who require surgery during protocol treatment may proceed as such, 
unless the surgery involves resection of sarcoma. Study drug should be held for a maximum 
of 42 days. If the patient requires an interruption of > 42 days, then they will be removed 
from protocol therapy. 
8.1.9 Infusion reactions: See Appendix V for management.  
8.1.10 Immune related toxicity: Both ipilimumab and nivolumab can lead to a variety of immune 
manifestations. The following supporting care guidelines are given for specific toxicities: 
• 
Colitis: Typical symptoms of immune-mediated enterocolitis are diarrhea, abdominal 
pain, mucus or blood in stool, with or without fever. Consider evaluation to ensure that 
there is not an infectious etiology. Consider treatment with anti-diarrheals or 
corticosteroids at the discretion of the treating physician. Evaluation by GI should be 
considered. Treating physicians should consider the risk of perforation with colitis and 
utilize anti-diarrheals with this in mind. Recommend evaluation for all patients for 
additional causes including C. diff, acute and self-limited infectious and foodborne 
illness, ischemic bowel, diverticulitis, and IBD. 
• 
Pneumonitis: Patients with suspected pneumonitis should undergo full evaluation, 
which may include CT scan, PFTs, O2 saturation, bronchoscopy. Treatment may 
involve steroids (any grade pneumonitis) and possibly empiric antibiotics, at the 
discretion of the treating physician. Distinguishing inflammatory pneumonitis is often 
a diagnosis of exclusion for patients who do not respond to antibiotics and have no 
causal organism identified including influenza. Most patients with respiratory failure or 
hypoxia will be treated with steroids. Bronchoscopy may be required and analysis of 
lavage fluid for lymphocytic predominance may be helpful. Consider that new lung 
nodules may represent sarcoid like granuloma.  Please consider recommending seasonal 
influenza killed vaccine, as per the bullet below (“vaccinations”). 
• 
Nephritis: For suspected nephritis, the patient should be evaluated by nephrology and 
considered for renal biopsy.  
• 
Hepatitis: For hepatitis, close monitoring with serial LFTs should be instituted. 
Continued treatment of active immune mediated hepatitis may exacerbate ongoing 
inflammation. Holding drug to evaluate LFT changes and early treatment are 
recommended. LFT changes may occur during steroid tapers from other events and may 
occur together with other GI events including gall bladder inflammation/pancreatitis. 
• 
Endocrinopathy: At the discretion of the treating physician: consider endocrine 
consult, draw all appropriate labs (such as cortisol, ACTH, TSH and T4), perform any 
appropriate imaging (such as pituitary MRI), and supplement any deficiency. It is 
recommended to perform any clinically indicated laboratory evaluation of pituitary 
function before beginning steroid therapy or replacement therapy of any kind. 
• 
Gastritis: In patients with nausea or vomiting consider evaluation for upper GI 
inflammation and other immune related events.   

 
Alliance A091401 
Version Date: 05/22/2019 
43 
Update #12 
• 
Rash: Consider dermatology consult and skin biopsy, at the discretion of the treating 
physician. Patients with purpuric or bullous lesions must be evaluated for vasculitis, 
Steven-Johnson syndrome, TEN, and autoimmune bullous disease including oral lesions 
of bullous pemphigus/pemphigoid. Pruritus may occur with or without skin rash and 
should be treated symptomatically. Please be aware of the possibility that additional 
autoimmune events that may occur shortly after the appearance of skin rashes or pruritus 
and during the steroids withdrawal period. 
• 
Neuropathy: Consider neurology consult for any grade 3 or 4 neuropathy, at the 
discretion of the treating physician. 
• 
Pancreatitis: Patients may develop symptomatic and radiologic evidence of 
pancreatitis as well as DM and DKA. Lipase elevation may occur with other immune 
mediated events including colitis, hepatitis, and gall bladder inflammation. 
• 
Immunosuppressive agents: Steroids are recommended as first line intervention for 
the immune related toxicity of these drugs. Steroids should be started prior to obtaining 
results of any testing, based on clinical indications for steroid initiation. Specifically: 
Prior to starting corticosteroids or hormone replacement for any reason, appropriate 
endocrine testing including cortisol, ACTH, TSH and T4 should be obtained to 
document baseline pituitary function which may be suppressed on treatment. Steroids 
should be tapered over 1 month if clinically appropriate, while monitoring for any return 
of toxicity. Potential second line agents are mycophenolate, cyclophosphamide, 
infliximab, IVIG, etc., at the discretion of the treating physician.  
• 
Vaccination: Flu vaccine, pneumococcal vaccine, and any other relevant vaccines are 
recommended PRIOR to initiation of protocol therapy, at the discretion of the treating 
physician.  
8.1.11 Fatigue: Fatigue is the most common adverse event associated with immune checkpoint 
therapy. Consider evaluation for associated or underlying organ involvement including 
pituitary disease, thyroid disease, and liver disease, or muscle inflammation 
8.1.12 Fever: Patients may experience isolated fever during infusion reactions or up to several days 
after infusion.  Continued fever over the course of 1-2 weeks may represent autoimmune 
events, or infection. Appropriate workup should be initiated, at the discretion of the treating 
physician. 
8.1.13 Supplementation: Electrolyte abnormalities should be adequately corrected with 
appropriate supplementation upon discovery. 
 

 
Alliance A091401 
Version Date: 05/22/2019 
44 
Update #12 
8.2 
Dose Modifications 
• 
If study drug/s is(are) held for >6 weeks, study drug/s will be discontinued. 
• 
Any patients with autoimmune toxicity who require additional immune suppressive 
treatment beyond steroids should go off study drug/s.  
• 
Patients may be dose-delayed for toxicity evaluation and restarted depending on results.  
• 
Any patient started on corticosteroids initially for a presumed autoimmune adverse event, 
and subsequently found to not have an autoimmune etiology of their adverse event, may 
resume therapy after a 2 week observation period without recurrence of symptoms.  
• 
Study drug/s should not be restarted until steroids have been tapered down to 5mg of 
prednisone equivalent.  
• 
Patients requiring > two dose delays for the same event should go off study drug. 
• 
Descriptors below utilize CTCAE version 4.03. AERs reporting may be required for some 
adverse events (See Section 9.0) 
8.2.1 Dose Levels 
See Section 7.0 and Section 7.2 for the dosing schema for both arms. No dose reductions 
will be made during this study, only dose delays. Therefore there is only 1 dose level. 
The following tables provide protocol specific instructions for continuing administration 
of the investigational agent.  
 
Generally we strongly encourage early evaluation, withholding drug, and appropriate 
treatment as indicated in the management tables and following event specific guidelines. 
 
8.2.2 Dose Modification 
 
Skin Rash and Oral 
Lesions 
 
Management/Next Dose for Nivolumab and Ipilimumab 
Grade 1 
Continue on protocol therapy* 
Grade 2 
Continue on protocol therapy.*  
Grade 3 
Hold** until ≤ Grade 1. Resume nivolumab/ipilimumab at same level*  
Grade 4 
Off protocol therapy 
*Steroid use does not require discontinuation of protocol therapy.  
**Any grade Steven Johnson syndrome requires discontinuation of protocol therapy.   
Recommended management: See Skin AE management algorithm  
 
Liver Function ALT 
AST Bilirubin 
Management/Next Dose for Nivolumab and Ipilimumab 
Grade 1 
Continue protocol therapy* 
Grade 2 
Hold therapy until ≤ grade 1 then restart nivolumab/ipilimumab at same dose.* 
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy 
*Steroid use does require discontinuation of protocol therapy. 
Recommended management:  see Hepatitis AE  management algorithm 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
45 
Update #12 
Colitis**  
Management/Next Dose for Nivolumab and Ipilimumab 
Grade 1 
Continue protocol therapy*  
Grade 2 
Hold therapy until ≤ Grade 1*, then restart nivolumab at same dose. 
Discontinue ipilimumab.  
Grade 3 
Off protocol therapy. 
Grade 4 
Off protocol therapy. 
See GI AE Algorithm for management of symptomatic colitis.  
*Steroid use does not require discontinuation of protocol therapy.  
**Follow this table for diarrhea when the workup shows objective evidence of autoimmune colitis. 
Recommended management:  see GI AE management Algorithm 
 
Diarrhea** 
Management/Next Dose for Nivolumab and Ipilimumab 
 
Grade 1 
Continue protocol therapy 
 
Grade 2 
Hold until ≤ Grade 1*, then restart nivolumab/ipilimumab at same dose.  
 
Grade 3 
Hold until ≤ Grade 1*, then restart nivolumab/ipilimumab at same dose.  
 
Grade 4 
Hold until ≤ Grade 1*, then restart nivolumab/ipilimumab at same dose.  
 
*Steroid use does not require discontinuation of protocol therapy. 
**Follow this table for diarrhea when the workup shows no objective evidence of autoimmune colitis 
 
Pancreatitis** 
 
Management/Next Dose for Nivolumab and Ipilimumab 
Grade 2 
Continue on protocol therapy*  
Grade 3 
Hold therapy until ≤ grade 2 then restart nivoloumab/ipilimumab at same 
dose.*  
Grade 4 
Off protocol therapy  
*Steroid use does require discontinuation of protocol therapy. 
**Patients who have asymptomatic amylase or lipase elevation may have a self-limited course and may 
continue therapy.  
 
Pneumonitis 
Management/Next Dose for Nivolumab and Ipilimumab 
Grade 1 
Hold dose pending evaluation. Resume nivolumab/ipilimumab if lymphocytic 
pneumonitis is excluded.*  
Grade 2 
Hold until ≤Grade 1*, then restart nivolumab/ipilimumab at same dose.  
Grade 3 
Off protocol therapy.  
Grade 4 
Off protocol therapy 
*Steroid use does require discontinuation of protocol therapy.  
Recommended management:  See Pulmonary Adverse Event Management Algorithm  

 
Alliance A091401 
Version Date: 05/22/2019 
46 
Update #12 
 
Gastritis, nausea, 
vomiting  
Management/Next Dose for Nivolumab and Ipilimumab 
Grade 1 
Continue protocol therapy*  
Grade 2 
Hold pending evaluation for gastritis duodenitis and other immune adverse 
events or other causes.  Resume nivolumab/ipilimumab at same dose level 
after resolution to Grade ≤ 1.*   
Grade 3 
Hold pending evaluation until ≤ Grade 1. Resume nivolumab at same dose 
level.* If symptoms do not resolve within 7 days with symptomatic treatment, 
patients should go off nivolumab. Discontinue ipilimumab.  
Grade 4 
Off protocol therapy 
*Steroid use does not require discontinuation of protocol therapy. 
 
Fatigue  
Management/Next Dose for Nivolumab and Ipilimumab 
Grade 1 
Continue protocol therapy. 
Grade 2 
Continue protocol therapy. 
Grade 3 
Hold until ≤ Grade 2. Resume nivolumab/ipilimumab at same dose level.* 
*Steroid use does not require discontinuation of protocol therapy. 
 
Neurologic events ** 
 
Management/Next Dose for Nivolumab and Ipilimumab 
Grade 1 
Hold dose pending evaluation. Once evaluation is complete, resume 
nivolumab/ipilimumab at same dose level.* 
Grade 2 
Hold dose pending evaluation and observation. Hold until ≤ Grade 1 and then 
resume nivolumab/ipilimumab at same dose level.*  
Grade 3 
Off protocol therapy  
Grade 4 
Off protocol therapy  
*Steroid use does require discontinuation of protocol therapy. 
**Patients with any grade CNS events of aseptic meningitis, encephalitis, symptomatic hypophysitis, or 
myopathy, polymyositis. rhabdomyolysis, peripheral demyelinating neuropathy, cranial neuropathy 
(other than peripheral n. VII), GB syndrome, myasthenia gravis should be off study once diagnosed.  
Recommended management:  See Neurologic Adverse Event Management Algorithm  
 
Endocrine Toxicity**  
 
Management/Next Dose for Nivolumab and Ipilimumab 
Grade 1 
Continue protocol therapy.*  
Grade 2 
Hold until ≤ Grade 1 and patients are on a stable replacement hormone 
regimen, then resume nivoloumab/ipilimumab at same dose level.*  
Grade 3 
Off protocol therapy.*** 
Grade 4 
Off protocol therapy 
*Steroid use for isolated thyroid disease or testosterone deficiency does not require discontinuation of 
protocol therapy. Steroid use for any other form of endocrine toxicity does require discontinuation of 
therapy. 
**Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, but 
including severe headache or enlarged pituitary on MRI should be considered grade 3 events and 
removed from protocol therapy. Also, note patients with thyroiditis may be retreated with 
immunotherapy while on replacement therapy. 
***Isolated thyroid or testosterone deficiency may be treated as grade 2 if there are no other associated 
deficiencies and adrenal function is monitored.  
Recommended management: See Endocrine Management Algorithm  

 
Alliance A091401 
Version Date: 05/22/2019 
47 
Update #12 
 
Fever  
Management/Next Dose for Nivolumab 
Grade 1 
Continue protocol therapy. May hold if needed for evaluation, then resume 
nivolumab/ipilimumab at same dose level.*  
Grade 2 
Hold until ≤ Grade 1.  Resume nivolumab/ipilimumab at same dose level.* 
Grade 3 
Hold until ≤ Grade 1.  Resume nivolumab/ipilimumab at same dose level.* 
Grade 4 
Off treatment 
*Steroid use does not require discontinuation of protocol therapy. 
See Appendix V regarding infusion reactions.  
 
 
Renal toxicity: 
Creatinine increased, 
hematuria  
Management/Next Dose for Nivolumab and Ipilimumab 
Grade 1 
Continue protocol therapy.* 
Grade 2 
 
Hold until ≤ Grade 1.  Resume nivolumab/ipilimumab at same dose level.* 
Grade 3 
Off protocol therapy.  
Grade 4 
Off protocol therapy 
*Steroid use does require discontinuation of protocol therapy. 
Recommended management: AE management guidelines 
 
Infusion Reaction 
Management/Next Dose for Nivolumab and Ipilimumab 
Grade 1 
Continue protocol therapy.* 
Grade 2 
Hold until ≤ Grade 1. Resume nivolumab/ipilimumab at same dose level.*  
Grade 3 
Off protocol therapy.  
Grade 4 
Off protocol therapy 
*Steroid use does not require discontinuation of protocol therapy. 
Recommended management: see Section 8.1.9 and Appendix V management guidelines 
 
 
Cardiac *   
Management/Next Dose for BMS-936558 (Nivolumab) + Ipilimumab Cardiac Toxicities  
≤ Grade 1  
Hold dose pending evaluation and observation.**  Evaluate for signs and symptoms of CHF, ischemia, 
arrhythmia or myositis.  Obtain history EKG, CK (for concomitant myositis), CK-MB.  Repeat troponin, CK 
and EKG 2-3 days.  If troponin and labs normalize may resume therapy.  If labs worsen or symptoms develop 
then treat as below.  Hold pending evaluation.  
Grade >2 with 
suspected 
myocarditis 
 Hold dose.**  Admit to hospital.  Cardiology consult.  Rule out MI and other causes of cardiac disease.  Cardiac 
Monitoring.  Cardiac Echo.  Consider cardiac MRI and cardiac biopsy.  Initiate high dose methylprednisolone.  
If no improvement within 24 hours, add either infliximab, ATG or tacrolimus. Consult algorithm for more 
details.  Resume therapy if there is a return to baseline and myocarditis is excluded or considered unlikely. 
Grade >2 with 
confirmed 
myocarditis   
Off protocol therapy.  Admit to CCU (consider transfer to nearest Cardiac Transplant Unit).  Treat as above.  
Consider high dose methylprednisolone.   
Add ATG or tacrolimus if no improvement.  Off treatment. 
 
 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as “other event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has not been established.  
Since this toxicity has caused patient deaths, an aggressive approach is recommended.   
 

 
Alliance A091401 
Version Date: 05/22/2019 
48 
Update #12 
 
ALL OTHER 
EVENTS 
(Note 1) 
Management/Next Dose for Nivolumab and Ipilimumab 
≤ Grade 1 
No change in dose  
Grade 2 
Hold until ≤ Grade 1, then resume nivolumab/ipilimumab at same dose 
level.  
Grade 3 
Off protocol therapy (exceptions noted below in note 2)  
Grade 4 
Off protocol therapy 
 
Note: 1. Modifications are applicable to toxicity that is deemed related to study drug (attribution of 
possible, probable, or definite).  
Note 2. For any grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment, nivolumab and ipilimumab should be discontinued. 
 
Recommended management:  As clinically indicated  
 
All other Grade ≥ 3 events including anemia, hyponatremia, hypernatremia, hypokalemia, 
hyperkalemia, hypocalcemia, hypercalcemia, hypomagnesemia, hypermagnesemia, 
hypoglycemia, hyperglycemia, elevated amylase or lipase that is deemed unrelated to drug 
(attribution of unrelated or unlikely) does not require change in dose. 
 
Lymphopenia of any grade does not require change in dose.  
8.2.3 Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when dosing 
is performed according to actual body weight. Therefore, all dosing is to be determined 
solely by actual weight without any modification unless explicitly described in the protocol. 
This will eliminate the risk of calculation error and the possible introduction of variability 
in dose administration. Failure to use actual body weight in the calculation of drug dosages 
will be considered a major protocol deviation. Physicians who are uncomfortable with 
calculating doses based on actual body weight should recognize that doing otherwise would 
be a protocol violation. Physicians may consult the published guidelines of the American 
Society of Clinical Oncology Appropriate Chemotherapy Dosing for Obese Adult Patients 
with Cancer: American Society of Clinical Oncology Clinical Practice Guideline.  J Clin 
Oncol 30(13): 1553-1561, 2012. 
 

 
Alliance A091401 
Version Date: 05/22/2019 
49 
Update #12 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.0. However, CTCAE v5.0 must be used for serious AE reporting through 
CTEP-AERS 
as 
of 
April 
1, 
2018. 
The 
CTCAE 
is 
available 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Attribution to protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms, using the codes provided. 
9.1 
Routine adverse event reporting (solicited) 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, “Adverse Events: Baseline”, 
“Adverse Events: Solicited” and “Adverse Events: Other” are used for routine AE reporting in 
Rave. 
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence should be solicited, and severity graded, at baseline and for each cycle of 
treatment. 
CTCAE v4.0 Term 
CTCAE v4.0 System Organ Class (SOC) 
Hypothyroidism 
Endocrine disorders 
Abdominal Pain 
Gastrointestinal disorders 
Diarrhea 
Gastrointestinal disorders 
Nausea 
Gastrointestinal disorders 
Fatigue 
General 
disorders 
and 
administration 
site 
conditions 
Blood bilirubin increased 
Investigations 
Anorexia 
Metabolism and nutrition disorders 
Arthralgia 
Musculoskeletal and connective tissue disorders 
Cough 
Respiratory, thoracic, and mediastinal disorders 
Dyspnea 
Respiratory, thoracic and mediastinal disorders 
9.2 
Routine adverse event reporting (not solicited) 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to 
the Alliance Statistics and Data Center. Questions about routine reporting should be directed 
to the Data Manager. 
*Combinations of CTCAE Grade & Attribution Required for Routine AE Data 
Submission on Case Report Forms (CRFs) 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
50 
Update #12 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
a 
a 
a, b 
a, b 
a, b 
Probable 
a 
a 
a, b 
a, b 
a, b 
Definite 
a 
a 
a, b 
a, b 
a, b 
a) Adverse Events: Other CRF - Applies to AEs occurring between registration and 
within 30 days of the patient’s last treatment date, or as part of the Clinical Follow-Up 
Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
9.3 
Expedited Adverse event reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Investigational Drug Branch 
(IDB), the Alliance Central Protocol Operations Program, the Study Chair, and their Institutional 
Review Board if a patient has a reportable serious adverse event. The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 will be utilized for AE reporting beginning April 1, 2018. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
reactions 
determined to be “reportable” in an expedited manner must be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS). 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause should be provided. 
9.3.1 Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE ≤ 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  

 
Alliance A091401 
Version Date: 05/22/2019 
51 
Update #12 
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
• 
Grade 1 
Timeframes 
• 
Grade 2 
Timeframes 
• 
Grade 3 
Timeframes 
• 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs  
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.  
Footnote “1” above applies after this reporting period. 
• 
Expedited AE reporting timelines defined: 
➢ “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-AERS 
≤ 24 hours of learning of the event followed by a complete CTEP-AERS report ≤ 5 calendar 
days of the initial 24-hour report. 
➢ “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted ≤ 10 
calendar days of the investigator learning of the event.  
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions (see below). 

 
Alliance A091401 
Version Date: 05/22/2019 
52 
Update #12 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via CTEP-AERS if the event occurs following treatment with 
an agent under a CTEP IND. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or non-CTEP IND: 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
• 
Alliance A091401 uses a drug under a CTEP IND. The reporting requirements for investigational 
agents under a CTEP IND should be followed for all agents (any arm) in this trial. 
• 
All new malignancies must be reported through CTEP-AERS whether or not they are thought to 
be related to either previous or current treatment. All new malignancies should be reported, i.e. 
solid tumors (including non-melanoma skin malignancies), hematologic malignancies, 
myelodysplasic syndrome/acute myelogenous leukemia, and in situ tumors. In CTCAE v5.0, 
secondary malignancies may be reported as one of the following three options: 1) Leukemia 
secondary to oncology chemotherapy, 2) Myelodysplastic syndrome, or 3) Treatment-related 
secondary malignancy. Whenever possible, the CTEP-AERS reports for new malignancies 
should include tumor pathology, history or prior tumors, prior treatment/current treatment 
including duration, any associated risk factors or evidence regarding how long the new 
malignancy may have been present, when and how the new malignancy was detected, molecular 
characterization or cytogenetics of the original tumor (if available) and of any new tumor, and 
new malignancy treatment and outcome, if available. 
• 
Treatment expected adverse events include those listed in Section 10.0 and in the package insert. 
• 
CTEP-AERS reports should be submitted electronically. 
• 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, 
the Pregnancy Information Form should be completed and submitted, along with any additional 
medical information (form is available on the CTEP website at http://ctep.cancer.gov/). The 
potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS report. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease Progression” under the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted. 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours. 
• 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, probably, 
or definitely related to the investigational agent/intervention. 
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any Pregnancy loss should be reported 
expeditiously, as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and perinatal 
conditions SOC. A Pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-AERS recognizes this 
event as a patient death. 
• 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 

 
Alliance A091401 
Version Date: 05/22/2019 
53 
Update #12 
9.4 
CAEPRs  
9.4.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) for BMS-936558 
(Nivolumab, MDX-1106, NSC 748726, IND #126336) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single 
list of reported and/or potential adverse events (AE) associated with an agent using a 
uniform presentation of events by body system. In addition to the comprehensive list, a 
subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs (SPEER) 
is a list of events that are protocol specific exceptions to expedited reporting to NCI (except 
as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pd
f for further clarification. Frequency is provided based on 2069 patients. Below is the 
CAEPR for BMS-936558 (Nivolumab, MDX-1106). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower of 
the grades to determine if expedited reporting is required. 
Version 2.3, June 18, 20181 
 
 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
  
 
 
Myocarditis 
  
 
 
Pericardial tamponade2 
  
 
 
Pericarditis 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency3 
 
  
 
Hypophysitis3 
 
  
 
Hyperthyroidism3 
 
  
 
Hypothyroidism3 
 
  
EYE DISORDERS 
  
 
 
Blurred vision  
  
 
 
Dry eye 
  
 
 
Eye disorders - Other (diplopia)3 
  
 
 
Eye disorders - Other (Graves 
ophthalmopathy)3 
  
 
 
Eye disorders - Other (optic neuritis 
retrobulbar)3 
  
 
Uveitis 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Colitis3 
 
  
 
 
Colonic perforation3 
  

 
Alliance A091401 
Version Date: 05/22/2019 
54 
Update #12 
 
 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
 
Gastritis 
  
 
 
 Mucositis oral 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis4 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Injection site reaction 
 
 Injection site reaction (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction3 
  
 
 
Autoimmune disorder3 
  
 
 
Cytokine release syndrome5 
  
 
 
Immune system disorders - Other 
(GVHD in the setting of 
allotransplant)3,6  
  
 
 
Immune system disorders - Other 
(sarcoid granuloma)3  
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction7 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased3 
 
 Alanine aminotransferase increased3 
(Gr 3)  
 
Aspartate aminotransferase 
increased3 
 
 Aspartate aminotransferase 
increased3 (Gr 3)  
 
Blood bilirubin increased3 
 
 Blood bilirubin increased3 (Gr 2)  
 
Creatinine increased 
 
  
 
Lipase increased 
 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 2) 
  
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
Serum amylase increased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
 
Hyperglycemia 
 Hyperglycemia (Gr 2) 
 
 
Metabolism and nutrition disorders - 
Other (diabetes mellitus with 
ketoacidosis)3 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
 
Musculoskeletal and connective 
tissue disorder - Other (polymyositis) 
  
 
 
Myositis 
  
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Encephalopathy3 
  
 
 
Facial nerve disorder3 
  

 
Alliance A091401 
Version Date: 05/22/2019 
55 
Update #12 
 
 Adverse Events with Possible  
 Relationship to BMS-936558 (Nivolumab, MDX-1106) 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Guillain-Barre syndrome3 
  
 
 
Myasthenia gravis3 
  
 
 
Nervous system disorders - Other 
(demyelination myasthenic 
syndrome) 
  
 
 
Nervous system disorders - Other 
(encephalitis)3 
  
 
 
Nervous system disorders - Other 
(meningoencephalitis) 
  
 
 
Nervous system disorders - Other 
(meningoradiculitis)3 
  
 
 
Nervous system disorders - Other 
(myasthenic syndrome) 
  
 
 
Peripheral motor neuropathy 
  
 
 
Peripheral sensory neuropathy 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome3 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury3 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pleural effusion3 
 
  
 
Pneumonitis3 
 
  
 
 
Respiratory, thoracic and mediastinal 
disorders - Other (bronchiolitis 
obliterans with organizing 
pneumonia)3 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme3 
  
 
Pruritus3 
 
 Pruritus3 (Gr 2)  
 
Rash maculo-papular3 
 
 Rash maculo-papular3 (Gr 2)  
 
 
Skin and subcutaneous disorders -
Other (bullous pemphigoid)  
  
 
Skin and subcutaneous 
disorders - Other (Sweet’s 
Syndrome)3 
 
  
 
Skin hypopigmentation3 
 
  
 
 
 Stevens-Johnson syndrome 
  
 
 
 Toxic epidermal necrolysis 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
 
3BMS-936558 (Nivolumab, MDX-1106) being a member of class of agents involved in the inhibition of “immune 
checkpoints”, may result in severe and possibly fatal immune-mediated adverse events probably due to T-cell 
activation and proliferation.  This may result in autoimmune disorders that can include (but are not limited to) 
autoimmune hemolytic anemia, acquired anti-factor VIII immune response, autoimmune aseptic meningitis, 

 
Alliance A091401 
Version Date: 05/22/2019 
56 
Update #12 
autoimmune hepatitis, autoimmune nephritis, autoimmune neuropathy, autoimmune thyroiditis, bullous pemphigoid, 
exacerbation of Churg-Strauss Syndrome, drug rash with eosinophilia systemic symptoms [DRESS] syndrome, 
facial nerve disorder (facial nerve paralysis), limbic encephalitis, hepatic failure, pure red cell aplasia, pancreatitis, 
ulcerative and hemorrhagic colitis, endocrine disorders (e.g., autoimmune thyroiditis, hyperthyroidism, 
hypothyroidism, autoimmune hypophysitis/hypopituitarism, thyrotoxicosis, and adrenal insufficiency), sarcoid 
granuloma, myasthenia gravis, polymyositis, and Guillain-Barre syndrome. 
 
4Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
 
5Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with accompanying fever and 
pancytopenia. 
 
6Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have occurred in patients 
receiving allo stem cell transplant (SCT) after receiving BMS-936558 (Nivolumab, MDX-1106).  These 
complications may occur despite intervening therapy between receiving BMS-936558 (Nivolumab, MDX-1106) and 
allo-SCT. 
 
7Infusion reactions, including high-grade hypersensitivity reactions which have been observed following 
administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, hypertension or hypotension, or 
difficulty breathing during and immediately after administration of nivolumab. 
 
 
Adverse events reported on BMS-936558 (Nivolumab, MDX-1106) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that BMS-936558 (Nivolumab, MDX-1106) caused 
the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; Ventricular 
arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; Gastrointestinal disorders - 
Other (mouth sores); Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Malaise; 
Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis  
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other (autoimmune thrombotic 
microangiopathy); Immune system disorders - Other (limbic encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Investigations - Other (protein total 
decreased); Lymphocyte count increased; Weight loss  
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; Hypoalbuminemia; 
Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Musculoskeletal and 
connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal and connective tissue disorder - Other 
(polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other (tubulointerstitial 
nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; Cough; Dyspnea; 
Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Pain of skin; 
Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other (rosacea) 

 
Alliance A091401 
Version Date: 05/22/2019 
57 
Update #12 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
 
Note: BMS-936558 (Nivolumab, MDX-1106) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
9.4.2 Comprehensive Adverse Events and Potential Risks list (CAEPR) for Ipilimumab 
(MDX-010, NSCs 732442, IND #126336) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform presentation 
of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol 
Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with 
bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific 
exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for 
further clarification. Frequency is provided based on 2678 patients. Below is the CAEPR for 
Ipilimumab (MDX-010). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 
 
Version 2.10, March 29, 20191 
 
Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Blood and lymphatic system 
disorders - Other (acquired 
hemophilia) 
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
  
 
 
Myocarditis2 
  
 
 
Pericardial effusion 
  
EAR AND LABYRINTH DISORDERS 
  
 
Hearing impaired 
 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypophysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  
 
Testosterone deficiency2 
 
  
EYE DISORDERS 
  
 
Eye disorders - Other (episcleritis)2  
  
 
Uveitis2 
 
  
GASTROINTESTINAL DISORDERS 
  

 
Alliance A091401 
Version Date: 05/22/2019 
58 
Update #12 
 
Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Abdominal pain 
 
  
 
Colitis2 
 
 Colitis2 (Gr 3) 
 
 
Colonic perforation3 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Enterocolitis 
 
  
 
Esophagitis 
 
  
 
 
Ileus 
  
Nausea 
 
 
 Nausea (Gr 3) 
 
Pancreatitis2 
 
  
 
Vomiting 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
 
General disorders and 
administration site conditions - 
Other (Systemic inflammatory 
response syndrome [SIRS]) 
  
 
 
Multi-organ failure 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(hepatitis)2 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Autoimmune disorder2 
 
  
 
 
Immune system disorders - 
Other (GVHD in the setting of 
allotransplant)4 
  
INFECTIONS AND INFESTATIONS 
  
 
 
 Infections and infestations - 
Other (aseptic meningitis)2 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
  
 
Aspartate aminotransferase 
increased 
 
  
 
 
Lymphocyte count decreased 
  
 
Neutrophil count decreased 
 
  
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Dehydration 
 
  
 
Hyperglycemia 
 
  

 
Alliance A091401 
Version Date: 05/22/2019 
59 
Update #12 
 
Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Metabolism and nutrition 
disorders - Other (exacerbation 
of pre-existing diabetes mellitus) 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Arthritis 
 
  
 
 
Generalized muscle weakness 
  
 
Musculoskeletal and connective 
tissue disorder - Other 
(polymyositis)2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Ataxia 
  
 
Facial nerve disorder2 
 
  
 
Guillain-Barre syndrome2 
 
  
 
Headache 
 
  
 
Myasthenia gravis2 
 
  
 
 
Nervous system disorders - 
Other (immune-mediated 
encephalitis)2 
  
 
 
Peripheral motor neuropathy 
  
 
 
Peripheral sensory neuropathy 
  
 
Trigeminal nerve disorder 
 
  
PSYCHIATRIC DISORDERS 
  
 
 
Psychiatric disorders - Other 
(mental status changes) 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Renal and urinary disorders - Other 
(granulomatous tubulointerstitial 
nephritis) 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis 
 
  
 
 
Respiratory failure 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(bronchiolitis obliterans with 
organizing pneumonia) 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(lung infiltration) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme 
  
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 

 
Alliance A091401 
Version Date: 05/22/2019 
60 
Update #12 
 
Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol Exceptions to 
Expedited Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Skin and subcutaneous tissue 
disorders - Other (Sweet's 
Syndrome) 
 
  
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
Urticaria 
 
  
VASCULAR DISORDERS 
  
 
Hypotension 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included 
in the e-mail. 
2Ipilimumab can result in severe and fatal immune-mediated adverse events probably due to T-cell activation and 
proliferation.  These can include (but are not limited to) autoimmune hemolytic anemia, acquired anti-factor VIII 
immune response, autoimmune aseptic meningitis, autoimmune hepatitis, autoimmune thyroiditis, hepatic failure, 
pure red cell aplasia, pancreatitis, ulcerative and hemorrhagic colitis, endocrine disorders (e.g., autoimmune 
thyroiditis, hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, and adrenal insufficiency), 
ocular manifestations (e.g., uveitis, iritis, conjunctivitis, blepharitis, and episcleritis), sarcoid granuloma, myasthenia 
gravis, polymyositis, and Guillain-Barre syndrome.  The majority of these reactions manifested early during 
treatment; however, a minority occurred weeks to months after discontinuation of ipilimumab especially with the 
initiation of additional treatments. 
3Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in association with 
subsequent IL-2 therapy. 
4Complications including hyperacute graft-versus-host disease (GVHD), may occur in patients receving allo stem 
cell transplant (SCT) after receiving Ipilimumab (MDX-010).  These complications may occur despite intervening 
therapy between receiving Ipilimumab (MDX-010) and allo-SCT. 
5In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia gravis). 
6Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper 
gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on Ipilimumab (MDX-010) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Ipilimumab (MDX-010) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system disorders - Other 
(pure red cell aplasia)2; Febrile neutropenia 
CARDIAC DISORDERS - Conduction disorder; Restrictive cardiomyopathy 
EYE DISORDERS - Extraocular muscle paresis5; Eye disorders - Other (retinal pigment changes) 
GASTROINTESTINAL DISORDERS - Colonic ulcer; Dyspepsia; Dysphagia; Gastrointestinal disorders - Other 
(gastroenteritis); Gastrointestinal hemorrhage6; Proctitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Non-cardiac 
chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure2 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infection7 

 
Alliance A091401 
Version Date: 05/22/2019 
61 
Update #12 
INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase increased; Platelet 
count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Joint range of motion 
decreased; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia cerebrovascular; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Cough; Dyspnea; 
Laryngospasm 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Skin 
hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal arteritis) 
 
Note: Ipilimumab (BMS-734016; MDX-010 Transfectoma-derived) in combination with other agents could cause 
an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result 
in events never previously associated with either agent. 
 

10.0 DRUG INFORMATION 
10.1 
General Considerations 
• 
The total administered dose of chemotherapy may be rounded up or down within a range of 
5% of the actual calculated dose.  
• 
It is not necessary to change the doses of all study agents due to changes in weight unless 
the calculated dose changes by ≥ 10% 
10.2 
Nivolumab (BMS-936558, MDX-1106, ONO-4538 NSC #748726, IND #126336, IND 
holder: CTEP) 
Procurement 
Nivolumab is supplied by Bristol-Myers Squibb and distributed by the Pharmaceutical 
Management Branch, CTEP/DCTD/NCI as 100 mg vials (10 mg/mL) with a 0.7mL overfill.  It 
is supplied in 10 mL type I flint glass vials, with fluoropolymer film-laminated rubber stoppers 
and aluminum seals. 
Drug Ordering 
NCI -supplied agents may be requested by eligible participating investigators (or their 
authorized designee) at each participating institution.  Pharmaceutical Management Branch 
(PMB) policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior approval 
from PMB is obtained).  The CTEP-assigned protocol number must be used for ordering all 
CTEP-supplied investigational agents.  The eligible participating investigators at each 
participating institution must be registered with CTEP, DCTD through an annual submission of 
FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment Form, and 
Financial Disclosure Form (FDF).  If there are several participating investigators at one 
institution, CTEP-supplied investigational agents for the study should be ordered under the name 
of one lead participating investigator at that institution. 
No starter supplies will be provided. Study agents must be ordered after the patient is 
enrolled on the assigned treatment arm. If expedited shipment is required, sites should 
provide an express courier account through the Online Agent Order Processing (OAOP) 
application. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active 
person registration status.  For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time.  Refer to the PMB’s website for specific policies and guidelines 
related to agent management. 
Agent Inventory Records - The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final disposition of all 
agents received from the PMB using the appropriate NCI Investigational Agent (Drug) 
Accountability Record (DARF) available on the CTEP forms page.  Store and maintain separate 
NCI Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 

 
Alliance A091401 
Version Date: 05/22/2019 
63 
Update #12 
CTEP IAM account and the maintenance of an “active” account status, and a “current” password 
and active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
• 
PMB 
Online 
Agent 
Order 
Processing 
(OAOP) 
application: 
https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx   
• 
CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/   
• 
CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov   
• 
IB Coordinator:  IBCoordinator@mail.nih.gov   
• 
PMB email:  PMBAfterHours@mail.nih.gov  
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
 
Formulation 
Nivolumab Injection is a clear to opalescent, colorless to pale yellow liquid; light (few) 
particulates may be present. The drug product is a sterile, nonpyrogenic, single-use, isotonic 
aqueous solution formulated in sodium citrate dihydrate, sodium chloride, mannitol, 
diethylenetriaminepentacetic acid (pentetic acid), polysorbate 80 (Tween® 80), and water for 
injection.  Dilute solutions of hydrochloric acid and/or sodium hydroxide may be used for pH 
adjustment (pH 5.5-6.5). 
Storage and Stability 
Vials of Nivolumab injection must be stored at 2°- 8°C (36°- 46°F) and protected from light and 
freezing. The unopened vials can be stored at room temperature (up to 25°C, 77°F) and room 
light for up to 48 hours. 
If a storage temperature excursion is identified, promptly return Nivolumab to 2°C-8°C and 
quarantine the supplies.  Provide a detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for 
determination of suitability. 
Shelf-life surveillance of the intact vials is ongoing.  The administration of undiluted and diluted 
solutions of nivolumab must be completed within 24 hours of preparation.  If not used 
immediately, the infusion solution may be stored up to 24 hours in a refrigerator at 2º to 8ºC 
(36º to 46ºF) and a maximum of 8 hours of the total 24 hours can be at room temperature (20º 
to 25ºC, 68º to 77ºF) and room light.  The maximum 8-hour period under room temperature and 
room light conditions includes the product administration period.  Caution:  The single-use 
dosage form contains no antibacterial preservative or bacteriostatic agent.  Therefore, it is 
advised that the product be discarded 8 hours after initial entry. 
Preparation 
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose.  When the dose is based on patient weight (i.e., mg/kg), 
nivolumab injection can be infused undiluted or diluted to protein concentrations as low as 0.35 
mg/mL. When the dose is fixed (eg, 240 mg, 360 mg, or 480 mg flat dose), nivolumab injection 
can be infused undiluted or diluted so as not to exceed a total infusion volume of 160 mL. For 
patients weighing less than 40 kilograms (kg), the total volume of infusion must not exceed 4 

 
Alliance A091401 
Version Date: 05/22/2019 
64 
Update #12 
mL per kg of patient weight. During drug product preparation and handling, vigorous mixing or 
shaking is to be avoided. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles. 
Administration 
Administer via intravenous infusion over 30 +/- 10 minutes through an intravenous line 
containing a 0.2-micron to 1.2-micron pore size, low-protein-binding polyethersulfone 
membrane in-line filter. It is not to be administered as an IV push or bolus injection. Flush the 
intravenous line with 0.9% NaCl after each dose.  Do not mix nivolumab with, or administer as 
an infusion with other medicinal products. 
Drug Interactions 
The indirect drug-drug interaction potential of nivolumab was assessed using systemic cytokine 
modulation data for cytokines known to modulate CYP enzymes.  There were no meaningful 
changes in cytokines known to have indirect effects on CYP enzymes across all dose levels of 
nivolumab. This lack of cytokine modulation suggests that nivolumab has no or low potential 
for modulating CYP enzymes, thereby indicating a low risk of therapeutic protein-drug 
interaction.. 
Pharmacokinetics 
Single dose nivolumab pharmacokinetics 
 
Distribution: The mean volume of distribution varied between 83 mL/kg and 113  mL/kg 
across doses. 
 
Half-life elimination: The mean terminal half-life of a single dose of nivolumab ranged 
between 17 and 25 days across the dose range of 0.3 mg/kg to 10 mg/kg.  The mean total 
clearance varied from 0.13 mL/h/kg to 0.19 mL/h/kg 
Multiple dose nivolumab pharmacokinetics 
Distribution:  Multiple-dose PK of nivolumab following Q2W dosing was linear with dose-
proportional increase in Cmax and AUC(TAU) in the studied range of 0.1 mg/kg to 10 
mg/kg. Nivolumab accumulation with Q2W dosing frequency was in the range of 2.9 
 to 3.3 based on AUC(TAU), 2.0 to 2.4 based on Cmax, and 3.1 to 4.8 based on Cmin. 
Half-life elimination: The mean of terminal half-life was 25.6 days and the typical 
clearance was 8.8 mL/h. 
Adverse Events 
Refer to CAEPR in Section 9.4.1. 
Nursing Guidelines 
• 
Nivolumab side effects vary greatly from those of traditional chemotherapy and can vary 
in severity from mild to life threatening. Instruct patients to report any side effects to the 
study team immediately. Side effects may be immediate or delayed up to months after 
discontinuation of therapy. Most side effects are reversible with prompt intervention of 
corticosteroids. Additionally combination therapy (with ipilimumab) tends to have a 
higher rate of immune mediated side effects. 
• 
Diarrhea can be common and can be very severe, leading to colonic perforation. Instruct 
patients to report ANY increase in the number of stools and/or change in baseline, blood 
in the stool, abdominal pain to the study team immediately.  
• 
Rash/pruirits/dermatitis is seen. Patients should report any rash to the study team. Treat 
per section 8.0 and monitor for effectiveness.  

 
Alliance A091401 
Version Date: 05/22/2019 
65 
Update #12 
• 
Monitor LFT’s closely as elevations in these levels could indicate early onset 
autoimmune hepatitis. Patients should also be instructed to report any jaundice, or right 
upper quadrant pain to the study team immediately. 
• 
Pneumonitis can be seen and may be mild (only seen on imaging) to severe. Patients 
should be instructed to report any SOB, dyspnea, cough, chest pain, etc. to the study team 
immediately. Patients reporting these symptoms should have a pulse ox checked and 
consider immediate imaging per the treating MD. 
• 
Endocrinopathies (including hypopituitarism, hypothyroidism, hypophysistis, and 
adrenal insufficiency) are seen with this agent. Patients may present only with the vague 
sense of fatigue and “not feeling well” .Additional symptoms may be that of nausea, 
sweating and decreased activity tolerance. Instruct patients to report these signs or 
symptoms immediately and obtain appropriate labs as ordered by MD.  
• 
Pancreatitis is possible with nivolumab. Instruct patients to report abdominal pain, 
nausea and vomiting to the study team. 
• 
Patients who are started on steroid therapy for any side effects of nivolumab toxicity 
should be instructed to take the steroids as ordered, and not to discontinue abruptly as 
symptoms may return and be severe. Patients may be on steroid therapy for weeks. 
Instruct patients to report any increase or change in side effects with any dosage decrease 
as patients may need a slower taper 
10.3 
Ipilimumab (BMS-734016, MDX-010, NSC#s 732442 and 720801, IND #126336, IND 
holder: CTEP) 
Procurement 
Ipilimumab is an investigational agent supplied by the National Cancer Institute (NCI).  Bristol-
Myers-Squibb (BMS) will supply ipilimumab to the DCTD/NCI and will be distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI.    
Drug Ordering: NCI -supplied agents may be requested by eligible participating investigators 
(or their authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where the patient 
is to be treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered under the 
name of one lead participating investigator at that institution. 
No starter supplies will be provided. Study agents must be ordered after the patient is enrolled 
on the assigned treatment arm. If expedited shipment is required, sites should provide an express 
courier account through the Online Agent Order Processing (OAOP) application. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, a “current” password, and active 
person registration status.  For questions about drug orders, transfers, returns, or accountability, 
call or email PMB any time.  Refer to the PMB’s website for specific policies and guidelines 
related to agent management. 
Agent Inventory Records - The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final disposition of all 

 
Alliance A091401 
Version Date: 05/22/2019 
66 
Update #12 
agents received from the PMB using the appropriate NCI Investigational Agent (Drug) 
Accountability Record (DARF) available on the CTEP forms page.  Store and maintain separate 
NCI Investigational Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol. 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, and a “current” password 
and active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
• 
PMB 
Online 
Agent 
Order 
Processing 
(OAOP) 
application: 
https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx   
• 
CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/   
• 
CTEP Associate Registration and IAM account help:  ctepreghelp@ctep.nci.nih.gov   
• 
IB Coordinator:  IBCoordinator@mail.nih.gov   
• 
PMB email:  PMBAfterHours@mail.nih.gov  
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
 
Formulation 
Ipilimumab injection, 200 mg/40 mL (5 mg/mL), is formulated as a clear to slightly opalescent, 
colorless to pale yellow, sterile, non-pyrogenic, single-use, isotonic aqueous solution that may 
contain particles.  Ipilimumab Injection, 200 mg/40 mL, is supplied in 10-cc or 50-cc Type I 
flint glass vials, respectively, stoppered with gray butyl stoppers and sealed with aluminum 
seals.  The drug product is formulated at a concentration of 5 mg/mL at a pH of 7.0.   
 
Component 
50 mg/vial 
200 mg/vial 
Ipilimumab 
53.5 mg 
213.0 mg 
Sodium chloride 
62.6 mg 
249.0 mg 
TRIS hydrochloride 
33.7 mg 
134.3 mg 
Pentacetic acid 
0.42 mg 
1.67 mg 
Mannitol 
107 mg 
426 mg 
Polysorbate 80 
1.18 mg 
4.69 mg 
Sodium hydroxide 
QS to pH 7.0 
Hydrochloric acid 
QS to pH 7.0 
Water for Injection 
QS to 10.7 mL 
QS to 42.6 mL 

 
Alliance A091401 
Version Date: 05/22/2019 
67 
Update #12 
Nitrogen 
Processing agent 
Storage and Stability 
Ipilimumab Injection, 200 mg/40 mL (5 mg/mL), must be stored refrigerated (2ºC to 8ºC) and 
protected from light.  Ipilimumab injection must not be frozen.  Partially used vials or empty 
vials of ipilimumab injection should be discarded at the site according to appropriate drug 
disposal procedures.   
Ipilimumab injection may be stored undiluted 5 mg/mL or following dilution in 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose in PVC, non-PVC/non-DEPH or glass containers for 
up to 24 hours at (2ºC to 8ºC).   
Preparation 
Allow the vials to stand at room temperature for approximately 5 minutes prior to preparation 
of the infusion.  Withdraw the required volume of ipilimumab and transfer into an intravenous 
bag.  Ipilimumab injection (5 mg/mL) may be diluted in 0.9% Sodium Chloride Injection, USP 
or 5% Dextrose Injection, USP to concentrations between 1 mg/mL and 2 mg/mL.  Mix the 
diluted solution by gentle inversion.  Store the diluted solution for no more than 24 hours under 
refrigeration (2ºC to 8ºC, 36ºF to 46ºF) or at room temperature (20ºC to 25ºC, 69ºF to 77ºF). 
Administration 
Do not mix ipilimumab with, or administer as an infusion with, other products.  Administer the 
diluted solution over 90 +/- 10 minutes through an intravenous line containing a sterile, non-
pyrogenic, low-protein binding in-line filter.  Ipilimumab must not be administered as an IV 
push or bolus injection.  Flush the intravenous line with 0.9% Sodium Chloride Injection, USP 
or 5% Dextrose Injection, USP after each dose.   
Drug Interactions 
No formal pharmacokinetic drug interaction studies have been conducted with ipilimumab. 
Pharmacokinetics 
Distribution:  Vss: 7.21L 
Half-life elimination:  Terminal: 14.7 days 
Renal impairment:  The effect of renal impairment on the clearance of ipilimumab was 
evaluated in subjects with mild (GFR < 90 and >= 60 mL/min/1.73m2; n=349), moderate (GFR 
< 60 and >= 30 mL/min/1.73m2; n=82), or severe (GFR < 30 and > 15 mL/min/1.73m2; n=4) 
compared to subjects with normal renal function (GFR >= 90 mL/min/1.73m2; n=350) in 
population PK analyses.  No clinically important differences in the clearance of ipilimumab 
were found between subjects with mild to moderate renal impairment and subjects with normal 
renal function.  No specific dose adjustment is necessary in subjects with mild to moderate renal 
impairment.   
Hepatic impairment:  The effect of hepatic impairment on the clearance of ipilimumab was 
evaluated in 76 subjects with mild hepatic impairment (total bilirubin 1 to 1.5 x ULN or AST < 
ULN) compared to 708 subjects with normal hepatic function (total bilirubin and AST <= ULN).  
No clinically important differences in the clearance of ipilimumab were found between subjects 
with mild hepatic impairment and normal hepatic function.  Ipilimumab has not been studied in 
patients with moderate (total bilirubin > 1.5 to 3 x ULN and any AST) or severe hepatic 
impairment (total bilirubin > 3 x ULN and any AST).   
Adverse Events 
Refer to CAEPR in Section 9.4.2. 
Nursing Guidelines 

 
Alliance A091401 
Version Date: 05/22/2019 
68 
Update #12 
• 
Ipilimumab side effects vary greatly from those of traditional chemotherapy and can vary 
in severity from mild to life threatening. Instruct patients to report any side effects to the 
study team immediately. Side effects may be immediate or delayed up to months after 
discontinuation of therapy. Most side effects are reversible with prompt intervention of 
corticosteroids. 
• 
Diarrhea can be common and can be very severe, leading to colonic perforation. Instruct 
patients to report ANY increase in the number of stools and/or change in baseline, blood 
in the stool, abdominal pain to the study team immediately.  
• 
Rash/pruirits/dermatitis is seen. Patients should report any rash to the study team. Mild 
rash may be able to be managed topically. Rarely TENS can be seen. Instruct patients 
with any rash (especially a blistering/peeling rash) and fever and/or lesions in the mouth 
to seek immediate medical attention. 
• 
Monitor LFT’s closely as elevations in these levels could indicate early onset 
autoimmune hepatitis. Patients should also be instructed to report any jaundice, or right 
upper quadrant pain to the study team immediately. 
• 
Pneumonitis can be seen and may be mild (only seen on imaging) to severe. Patients 
should be instructed to report any SOB, dyspnea, cough, chest pain, etc. to the study team 
immediately. Patients reporting these symptoms should have a pulse ox checked and 
consider immediate imaging per the treating MD. 
• 
Endocrinopathies (including hypopituitarism, hypothyroidism, hypophysitis, and adrenal 
insufficiency) are seen with this agent. Patients may present only with the vague sense 
of  fatigue and “not feeling well” . Additional symptoms may be that of nausea, sweating 
and decreased activity tolerance. Instruct patients to report these signs or symptoms 
immediately and obtain appropriate labs as ordered by MD.  
• 
Patients who are started on steroid therapy for any side effects of Ipilimumab toxicity 
should be instructed to take the steroids as ordered, and not to discontinue abruptly as 
symptoms may return and be severe. Patients may be on steroid therapy for weeks. 
Instruct patients to report any increase or change in side effects with any dosage decrease 
as patients may need a slower taper. 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
69 
Update #12 
11.0 MEASUREMENT OF EFFECT 
Response and progression as primary endpoints will be evaluated in this study using the new 
international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guidelines (version 1.1).[47]  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the short axis measurements in the case of lymph nodes are 
used in the RECIST guideline. 
11.1 
Schedule of Evaluations: 
Initial Treatment (Assigned at Registration/Randomization): For the purposes of this study, 
patients should be evaluated every 6 weeks for 12 weeks, and then every 8 weeks thereafter. In 
addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. See Section 7.0 for further details. Additionally, see 
Section 7.1 for instructions for how to treat, rescan, and use the proper disease assessment (e.g. 
baseline, reset baseline, or crossover baseline) for comparison in patients who demonstrate 
progressive disease within the first 12 weeks of study participation. For patients receiving initial 
treatment beyond 2 years from randomization date; scans may be performed every 3 months for 
year 3, every 4 months for year 4, every 6 months for year 5 and then yearly thereafter.   One 
confirmatory scan continues to be required if patient achieves a response for the first time and 
during this period.   Thereafter, returning to the assessment schedule. 
Crossover Treatment: Patients having crossed over to dual agent therapy following 
progression of disease while receiving single agent nivolumab (per section 3.4) should be 
evaluated every 6 weeks for 12 weeks, and then every 8 weeks thereafter. As per section 5.0, 
patients must have imaging performed within 28 days of re-registration to dual agent therapy. 
This scan will be the baseline scan for patients to determine response to dual agent therapy. For 
patients receiving crossover treatment beyond 2 years from date of crossover, scans may be 
performed every 3 months for year 3, every 4 months for year 4, every 6 months for year 5 and 
then yearly thereafter. One confirmatory scan continues to be required if patient achieves a 
response for the first time and during this period. One confirmatory scan continues to be required 
if patient achieves a response for the first time and during this period. Thereafter, returning to 
the assessment schedule. 
See Section 7.0 for further details. Additionally, see Section 7.1 for instructions for how to treat, 
rescan, and use the proper disease assessment for comparison for patients who demonstrate 
progressive disease within the first 12 weeks of study participation. 
In all cases, supporting documentation of response and progression should be submitted, per 
Section 6.1.1.  
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.2.1 Measurable Disease 
A non-nodal lesion is considered measurable if its longest diameter can be accurately 
measured as 2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, CT component of a 
PET/CT, or MRI.  
A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in diameter 
as assessed using calipers (e.g. skin nodules) or imaging.  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
A malignant lymph node is considered measurable if its short axis is >1.5 cm when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 5 mm).   

 
Alliance A091401 
Version Date: 05/22/2019 
70 
Update #12 
Tumor lesions in a previously irradiated area are considered measurable disease under the 
following conditions: they have been demonstrated to grow by at least 0.5 cm from 
measurement prior to radiation. 
11.2.2 Non-Measurable Disease 
All other lesions (or sites of disease) are considered non-measurable disease, including 
pathological nodes (those with a short axis ≥ 1.0 to < 1.5 cm).  Bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-
measurable as well. 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. However, 
if non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions.  In addition, lymph nodes that have a short axis < 1.0 cm are considered non-
pathological (i.e., normal) and should not be recorded or followed. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.3.1 Measurement Methods:   
• 
All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to characterize 
each identified and reported lesion at baseline and during follow-up. For patients having 
only lesions measuring at least 1 cm to less than 2 cm must use CT imaging for both 
pre- and post-treatment tumor assessments.   
• 
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used at the same evaluation to assess the antitumor effect of a 
treatment.  
11.3.2 Acceptable Modalities for Measurable Disease: 
• 
Conventional CT and MRI:  This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. 
As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  
The lesions should be measured on the same pulse sequence.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
• 
PET-CT:  If the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.   
• 
Chest X-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung.  However, CT scans are preferable. 
• 
Physical Examination:  For superficial non-nodal lesions, physical examination is 
acceptable, but imaging is preferable, if both can be done. In the case of skin lesions, 

 
Alliance A091401 
Version Date: 05/22/2019 
71 
Update #12 
documentation by color photography, including a ruler to estimate the size of the lesion, 
is recommended. 
• 
FDG-PET:  FDG-PET scanning is allowed to complement CT scanning in assessment 
of progressive disease [PD] and particularly possible 'new' disease.  A ‘positive’ FDG-
PET scanned lesion is defined as one which is FDG avid with an update greater than 
twice that of the surrounding tissue on the attenuation corrected image; otherwise, an 
FDG-PET scanned lesion is considered ‘negative.’  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:   
1) If the positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.   
2) If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT at the same evaluation, additional follow-up CT scans (i.e., additional 
follow-up scans at least 4 weeks later) are needed to determine if there is truly 
progression occurring at that site. In this situation, the date of PD will be the 
date of the initial abnormal PDG-PET scan.   
3) 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, it is 
not classified as PD. 
11.3.3 Measurement at Follow-up Evaluation:  
Important: Refer to Section 11.1 for a full description of the correct baseline scan to use 
due to the retreatment after PD during treatment in the 1st 12 weeks, as well as baseline 
scan to be used for crossover treatment. 
• 
A subsequent scan must be obtained at least 4 weeks following initial documentation of 
an objective status of either complete response (CR) or partial response (PR). This is 
applicable to both response during initial treatment assignment and to response to 
crossover to dual agent therapy. 
• 
In the case of stable disease (SD), follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 6 weeks (see Section 
11.4.4). 
• 
If a scan shows progressive disease during the first 12 weeks of therapy and patient and 
treating physician elect to remain on treatment, imaging should be repeated within 4 
weeks. If that imaging confirms progression, then that patient has progressive disease 
and therapy should be discontinued. See Section 7.1 for further details. 
• 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
• 
Cytologic and histologic techniques can be used to differentiate between PR and CR in 
rare cases (e.g., residual lesions in tumor types such as germ cell tumors, where known 
residual benign tumors can remain.) 
11.4 
Measurement of Treatment/Intervention Effect 
11.4.1 Target Lesions & Target Lymph Nodes 

 
Alliance A091401 
Version Date: 05/22/2019 
72 
Update #12 
• 
Measurable lesions (as defined in Section 11.2.1) up to a maximum of 5 lesions, 
representative of all involved organs, should be identified as “Target Lesions” and 
recorded and measured at baseline.  These lesions can be non-nodal or nodal (as defined 
in 11.2.1), where no more than 2 lesions are from the same organ and no more than 2 
malignant nodal lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there often 
will be), there is no reason to perform additional studies beyond those specified in the 
protocol to discover new lesions.   
• 
Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on occasion, 
the largest lesion (or malignant lymph node) does not lend itself to reproducible 
measurements in which circumstance the next largest lesion (or malignant lymph node) 
which can be measured reproducibly should be selected.   
• 
Baseline Sum of Dimensions (BSD):  A sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes will be calculated 
and reported as the baseline sum of dimensions (BSD).  The BSD will be used as 
reference to further characterize any objective tumor response in the measurable 
dimension of the disease. Important: Refer to Section 11.1 for a full description of 
the correct baseline scan to use due to the retreatment after PD during treatment 
in the 1st 12 weeks, as well as baseline scan to be used for crossover treatment. 
• 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the post-baseline sum of dimensions (PBSD).  If the 
radiologist is able to provide an actual measure for the target lesion (or target lymph 
node), that should be recorded, even if it is below 0.5 cm.  If the target lesion (or target 
lymph node) is believed to be present and is faintly seen but too small to measure, a 
default value of 0.5 cm should be assigned.  If it is the opinion of the radiologist that the 
target lesion or target lymph node has likely disappeared, the measurement should be 
recorded as 0 cm. Important: Refer to Section 11.1 for a full description of the 
correct baseline scan to use due to the retreatment after PD during treatment in 
the 1st 12 weeks, as well as baseline scan to be used for crossover treatment. 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the 
PBSD. 
11.4.2 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.2.2) are classified as non- target lesions or non-
target lymph nodes and should also be recorded at baseline.  These lesions and lymph nodes 
should be followed in accord with 11.4.3.3. 
Important: Refer to section 11.1 for a full description of the correct baseline scan to 
use due to the retreatment after PD during treatment in the 1st 12 weeks, as well as 
baseline scan to be used for crossover treatment. 
11.4.3 Response Criteria 
11.4.3.1 All target lesions and target lymph nodes followed by CT/MRI/PET-CT/Chest X-
ray/physical examination must be measured on re-evaluation at evaluation times 
specified in Section 11.1.  Specifically, a change in objective status to either a PR or 
CR cannot be done without re-measuring target lesions and target lymph nodes.  

 
Alliance A091401 
Version Date: 05/22/2019 
73 
Update #12 
Note: Non-target lesions and non-target lymph nodes should be evaluated at each 
assessment, especially in the case of first response or confirmation of response.  In 
selected circumstances, certain non-target organs may be evaluated less frequently.  
For example, bone scans may need to be repeated only when complete response is 
identified in target disease or when progression in bone is suspected. 
11.4.3.2 Evaluation of Target Lesions 
Important: Refer to Section 11.1 for a full description of the correct baseline scan 
to use due to the retreatment after PD during treatment in the 1st 12 weeks, as 
well as baseline scan to be used for crossover treatment. 
• 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all target lesions. 
b. Each target lymph node must have reduction in short axis to < 1.0 cm. 
• 
Partial Response (PR): At least a 30% decrease in PBSD (sum of the longest 
diameter for all target lesions plus the sum of the short axis of all the target lymph 
nodes at current evaluation) taking as reference the BSD (see Section 11.4.1). 
• 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any lymph node that 
was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 cm short 
axis during follow-up.  
b. At least a 20% increase in PBSD (sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes at current 
evaluation) taking as reference the MSD (Section 11.4.1).  In addition, the 
PBSD must also demonstrate an absolute increase of at least 0.5 cm from the 
MSD.  
c. See Section 11.3.2 for details in regards to the requirements for PD via FDG-
PET imaging. 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient 
increase to qualify for PD taking as reference the MSD. 
11.4.3.3 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
Important: Refer to Section 11.1 for a full description of the correct baseline scan 
to use due to the retreatment after PD during treatment in the 1st 12 weeks, as 
well as baseline scan to be used for crossover treatment. 
• 
Complete Response (CR): 
All of the following must be true: 
a. Disappearance of all non-target lesions.  
b. Each non-target lymph node must have a reduction in short axis to <1.0 cm. 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesions or non-target 
lymph nodes. 
• 
Progression (PD): At least one of the following must be true: 
a. At least one new malignant lesion, which also includes any lymph node that 
was normal at baseline (< 1.0 cm short axis) and increased to ≥ 1.0 cm short 
axis during follow-up.   
b. Unequivocal progression of existing non-target lesions and non-target lymph 
nodes.  (NOTE:  Unequivocal progression should not normally trump target 

 
Alliance A091401 
Version Date: 05/22/2019 
74 
Update #12 
lesion and target lymph node status.  It must be representative of overall 
disease status change.)  
c. See Section 11.3.2 for details in regards to the requirements for PD via FDG-
PET imaging. 
11.4.4 Overall Objective Status 
Important: Refer to Section 11.1 for a full description of the correct baseline scan to 
use due to the retreatment after PD during treatment in the 1st 12 weeks, as well as 
baseline scan to be used for crossover treatment. 
The overall objective status for an evaluation is determined by combining the patient’s status 
on target lesions, target lymph nodes, non-target lesions, non-target lymph nodes, and new 
disease as defined in the following table:  
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
* 
See Section 11.4.3.1 
11.4.5 Symptomatic Deterioration: Patients with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time, 
and not either related to study treatment or other medical conditions, should be reported as 
PD due to “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment due to symptomatic 
deterioration. 
11.5 
Definitions of analysis variables 
Formal definitions of variables used in analyses can be found in the Statistical Considerations 
section of the protocol. 

 
Alliance A091401 
Version Date: 05/22/2019 
75 
Update #12 
12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Treatment 
12.1.1 CR, PR, or SD: Patients who are in CR, PR or SD will continue on therapy for a total of 
108 weeks. After treatment is discontinued, patients will be followed per the study calendar 
in section 5.0. 
12.1.2 Disease Progression:  
Any patient with disease progression must be removed from protocol therapy, with the 
exception of management as per Section 7.1. In the 1st 12 weeks of therapy, patients are 
allowed to continue therapy in the face of progression, as long as they meet all required 
bullets as per Section 7.1. Note that this is applicable to both the initial treatment assignment 
and to treatment once patients have crossed over to dual agent therapy. 
After disease progression, patients should be followed for survival per the study calendar 
(Section 5.0). 
12.1.3 Discontinuation of study agent: If the patient discontinues study agent for reasons other 
than withdrawal of consent, he or she should be followed for survival per the study calendar 
(Section 5.0). 
12.2 
Crossover 
Any patient that is originally randomized to the Nivolumab alone arm (Arm 1) will have the 
option to cross over to the nivolumab + ipilimumab combination therapy ONLY IF they were 
removed due to disease progression. Eligibility must be evaluated as per Section 3.4 and patients 
must be re-registered to the crossover portion of the study per Section 4.6.  
Once patients re-register and cross-over to the nivolumab + ipilimumab dual therapy, all cross 
over patients must have a scan ≤ 28 days of starting their new treatment as per Section 5.0. 
Crossover patients previously removed from Arm 1 for progression who were being followed 
for survival will no longer be followed by the survival schedule nor survival case report form 
but will proceed to the crossover treatment schedule, crossover test schedule, and crossover case 
report forms. Cycles/data collection will resume from the last treatment cycle patient received. 
Contact the data manager for assistance with RAVE data entry. 
 
12.3 
Managing ineligible patients and registered patients who never receive protocol 
intervention  
Definition of ineligible patients: A study participant who is registered to the trial but does not 
meet all of the eligibility criteria is deemed to be ineligible. Patients who are deemed ineligible 
may continue protocol treatment, provided the treating physician, study chair, and executive 
officer agree there are no safety concerns if the patient continues protocol treatment. All scans, 
tests, and data submission are to continue as if the patient were eligible. Notification of the local 
IRB may be necessary per local IRB policies. 
Study participants who are registered to the trial but never receive study intervention (for a 
reason other than because they were deemed ineligible) are replaceable for efficacy endpoints. 
They must still complete follow-up requirements as specified below: 
Baseline, on-study and off-treatment notice data submission required. 

 
Alliance A091401 
Version Date: 05/22/2019 
76 
Update #12 
12.4 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 

 
Alliance A091401 
Version Date: 05/22/2019 
77 
Update #12 
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Overview 
Our study is designed to evaluate both single agent nivolumab as well as dual agent 
nivolumab+ipilmumab.  Confirmed response rate over the first 6 months of treatment is our 
primary endpoint. Patients experiencing response within 4 weeks of reaching 6 months beyond 
their randomization date, will be included if their repeat 4 week scan confirms response. Patients 
will be randomized to receive either monotherapy or dual therapy, not for direct comparisons 
across treatments, but to conduct two independent single arm phase II studies simultaneously.  
The sample size of the design has been selected to 1) maximize the possibility of performing 
subset analysis (within specific histologically defined cohorts), and 2) improve precision of 
secondary and correlative endpoints. Stratification factors will not be used for randomization as 
there will be no direct comparison between the arms. All treatment decisions and the evaluation 
of the primary endpoint will be based on RECIST v1.1. 
In early October 2015, the study was suspended to pre-registration after an unprecedented rate 
of pre-registrations and greater than anticipated interest in the trial.  The study design was 
modified to best serve this population, of which effective treatments are lacking, and in 
consideration of the known safety profile of the agents.  The use of a single stage design was 
supported by CTEP/NCI, the Alliance Experimental Therapeutics Committee Co-Chair (G. 
Schwartz), and the A091401 study team. 
With Update #04, the study was approved to include a crossover to the dual agent therapy for 
patients having experienced PD during treatment with single agent Nivolumab.   Of note: 
• 
Patients are allowed to crossover to the dual agent therapy and within a specific time 
period, despite progression occurring months before the implementation of the Protocol 
Update.    
• 
Analyses will be exploratory in this patient group and careful consideration will be given 
to the data, as described within the Statistical Considerations.  
With Update #06, the study was amended to evaluate treatment arms within patient groups 
defined as having tumors of one of the following histologic subtypes:   
• 
LPS 
• 
UPS/MFH 
• 
GIST 
In essence, this study is now a total of 8 independent phase II trials.  Patient enrollment and 
accrual will not include those patients already enrolled to the initial cohort.  Randomization will 
continue to be used, similar to the application within the initial cohort of patients.   Here, patients 
having tumors of a one histologic subtype will be randomly assigned to one of the two treatment 
arms, only to reduce physician/patient selection bias.  Randomizing membership will be the only 
stratification factor.  The evaluation of all study endpoints will be repeated within these 
histologically defined subgroups and in the same manner as the initial study cohort was 
designed.  However, the study designs will differ, by cohort, and as described within section 
13.1. 
13.2 
Primary Endpoint 
To evaluate the confirmed response rate of single agent nivolumab, as well as dual agent 
nivolumab + ipilimumab, within patients having locally advanced/unresectable or metastatic 
soft tissue sarcoma. 

 
Alliance A091401 
Version Date: 05/22/2019 
78 
Update #12 
With Update #06 - the study objectives will be evaluated within the initial cohort of patients 
enrolled, as well as within 3 cohorts of patients defined by the following histologic subtypes:  
LPS, UPS/MFH, and GIST. 
13.3 
Study Design   
Primary Endpoint: Confirmed response over the first 6 months of treatment is our primary 
endpoint. Patients experiencing response within 4 weeks of reaching 6 months beyond 
randomization date, will be included if their repeat 4 week scan confirms response. (For 
example, a patient achieves response 10 days prior to having been enrolled for 6 months.  The 
confirmation scan is to occur within 28 days (+/- 7 days), which is beyond 6 months. If 
confirmed as CR or PR, the patient will be classified in the analysis as having a confirmed 
response). All patients meeting the eligibility criteria who have signed a consent form and have 
begun treatment will be considered evaluable for the primary endpoint. Patients will be included 
in the analyses according to the treatment they were randomized to. In addition, patients having 
experienced PD within the initial 12 weeks of treatment which fails to satisfy the criteria for PD 
at the subsequent confirmatory repeat scan will be considered as evaluable and subsequent 
cycles will be included in determining a patient’s tumor response status for the primary endpoint. 
However, neither treatment nor disease assessment data beyond the date of crossover will be 
included in the evaluation of the primary endpoint and for those patients crossing to dual agent 
treatment from single agent treatment. Patients will additionally be censored at their most recent 
disease assessment prior to receiving any anti-cancer therapy after ending study treatment. The 
confirmed response rate will be estimated as the number of patients having a best objective 
tumor status of CR or PR lasting at least 4 weeks during the first 6 months of treatment, divided 
by the number of evaluable patients. 
13.3.1:  Initial Study Cohort (Prior to Update #06): 
Two independent phase II studies will be conducted concurrently and patients will be 
randomized to receive one of the two treatments. 
Hypotheses: We will evaluate the confirmed response of both single agent nivolumab and 
dual agent nivolumab + ipilimumab. We are testing the hypothesis of a confirmed response 
rate being at most 5% (clinically inactive) versus a confirmed response rate of at least 20% 
(clinically active).  
Design Characteristics (each treatment arm): Enroll a total of 38 evaluable patients to each 
arm.   An arm demonstrating at least 5 confirmed responses will be considered as having 
sufficient evidence of promising activity in this population and may be proposed for larger 
studies in this population. 
This design yields 90% power to detect a true confirmed response rate of at least 20%, with 
a 0.05 significance level (1-sided test) if the true confirmed response rate is 5%. 
13.3.2:  LPS and UPS/MFH Cohorts (Added in Update #06): 
Four (4) independent phase II studies will be conducted concurrently and patients will be 
randomized to receive one of the two treatments. Patients will be included in the analyses 
according to the treatment they were randomized to. We are looking for an early signal of 
efficacy, based on scientific data described in Section 1.9 and available in June 2016 and 
indicating activity in these new cohorts. 
Hypotheses: We will evaluate the confirmed response of both single agent nivolumab and 
dual agent nivolumab + ipilimumab. We are testing the hypothesis of a confirmed response 
rate being at most 5% (clinically inactive) versus a confirmed response rate of at least 25% 
(clinically active).  

 
Alliance A091401 
Version Date: 05/22/2019 
79 
Update #12 
Study Design (for both treatment arms): Patient enrollment and accrual will not include 
those patients already enrolled to the initial cohort.  We will enroll a total of 12 evaluable 
patients to each arm. An arm demonstrating at least 2 confirmed responses during the first 
6 months of treatment will be considered as having sufficient evidence of promising activity 
in this population and may be proposed for larger studies in this population. 
Design Characteristics (each treatment arm): This design yields 85% power to detect a true 
confirmed response rate of at least 25%, with a 0.15 significance level (1-sided test) if the 
true confirmed response rate is 5%.  
13.3.3:  GIST Cohorts (Added in Update #06): 
Two (2) independent phase II studies will be conducted concurrently and patients will be 
randomized to receive one of the two treatments. Patients will be included in the analyses 
according to the treatment they were randomized to. 
Hypotheses: We will evaluate the confirmed response of both single agent nivolumab and 
dual agent nivolumab + ipilimumab. We are testing the hypothesis of a confirmed response 
rate being at most 5% (clinically inactive) versus a confirmed response rate of at least 20% 
(clinically active).  
Study Design (for both treatment arms): Patient enrollment and accrual will not include 
those patients already enrolled to the initial cohort. We will enroll a total of 24 evaluable 
patients to each arm. At the time we have 9 evaluable patients, we will perform a planned 
interim analysis.  Any demonstration of confirmed response in these 9 patients during the 
first 6 months of treatment allows accrual to continue. An arm demonstrating at least 3 
confirmed responses during the first 6 months of treatment in 24 evaluable patients will be 
considered as having sufficient evidence of promising activity in this population and may 
be proposed for larger studies in this population. 
The study will not be suspended at the time of the planned interim analysis due unless there 
is an unexpectedly high enrollment rate or excessive toxicity.  Excessive toxicity would be 
3 or more patients a month in this population. 
Design Characteristics (each treatment arm):  This design yields 80% power to detect a true 
confirmed response rate of at least 20%, with a 0.10 significance level (1-sided test) if the 
true confirmed response rate is 5%. There is a 64% chance of stopping early, if the true 
confirmed response rate is at moat 5%.  
13.4 
Secondary Endpoints   
• 
Evaluating adverse event rates (NCI CTCAE v4.0), within each study treatment arm.  
Categorical data analysis will be used to summarize adverse event rates and as a 
maximum severity during treatment for each patient and AE classification. 
• 
Evaluating duration of response, clinical benefit rate (CBR), progression-free survival 
(PFS), and overall survival (OS), within each study treatment arm. Patients having PD 
within the first 12 weeks of starting treatment which is not a PD at their 4 week 
confirmation assessment will not be classified has having PD for time to event analyses.  
That is, estimates for response, CBR, and PD endpoints will not be censored at the first 
PD in such cases. Patients who are unable to continue treatment for a 4-week 
confirmation of PD occurring within the 1st 12 weeks of treatment will be counted as 
having PD at their first date of PD during the treatment period (eg, initial, crossover). 
In addition, disease assessment data beyond the date of crossover will not be included 
in the evaluation of the primary endpoint and for those patients crossing to dual agent 
treatment from single agent treatment.  Such patients will be censored for estimating 

 
Alliance A091401 
Version Date: 05/22/2019 
80 
Update #12 
duration of response, CBR, and PFS.  Patients will be additionally censored at their most 
recent disease assessment prior to receiving any anti-cancer therapy after ending study 
treatment. 
Kaplan-Meier methodology will be used to evaluate time to event endpoints: duration 
of response (time from first response to disease progression), PFS (time from 
randomization to the earliest of either disease progression or death from any cause), and 
OS (time from randomization to death from any cause). The CBR will be evaluated by 
counting up the number of patients with a response or stable disease (PR, CR, SD) and 
dividing by the total number of evaluable patients. Cumulative Incidence Function 
methodology may be used, as appropriate. 
13.5 
Exploratory and Correlative Endpoints 
• 
The study is not powered to detect specific hypotheses, rather this data and analysis will 
help better identify patients that have the potential to benefit from this therapy and aid 
in designing larger Phase III studies. No direct comparisons will be made between the 
single and dual agent regimens. We will address the issue of multiple comparisons at 
the time of the analyses, which will be dependent on the number of hypotheses 
investigated. 
• 
To assess the potential association between PD-L1 expression (by IHC) and clinical 
outcome, within each study treatment arm.  Categorical data analysis and logistic 
regression will be used to evaluate the associations between PD-L1 expression (by IHC) 
and clinical outcome (eg, response, clinical benefit, progression-free survival, and 
survival). Kaplan-Meier methodology and Cox Proportional Hazards models will be 
used to evaluate time to event endpoints.      
• 
To evaluate the associations between selected biomarker measured in serial peripheral 
blood and with clinical efficacy, within each study component.  Summary statistics will 
be used to for describing changes across time.  In addition, the time course of biomarker 
outcomes will be investigated graphically, by summary plots or individual patient plots.  
Categorical data analysis and logistic regression will be used to evaluate the associations 
between PD-L1 expression (by IHC) and clinical outcome (eg, response, clinical 
benefit, time to progression, progression-free survival, and survival).  If there is 
suggestion of meaningful trend, methods such as linear mixed models may be used to 
characterize the pattern of change over time.  Kaplan-Meier methodology and Cox 
Proportional Hazards models will be used to evaluate time to event endpoints.    
• 
To evaluate the association between selected biomarker measured in tumor tissue with 
clinical efficacy, within each study component.  Categorical data analysis and logistic 
regression will be used to correlated biomarkers with and clinical outcome (eg, 
response, clinical benefit, time to progression, progression free survival, and survival) 
within each study component.  Kaplan-Meier methodology and Cox Proportional 
Hazards models will be used to evaluate time to event endpoints. 
• 
Confirmed response and secondary endpoints will be evaluated in patients who 
crossover from single agent nivolumab to dual agent treatment following progression.  
The date used for the calculations of duration of response, TTP, PFS, and OS will be 
the date the patient initiated crossover treatment with dual agent therapy. 
13.6 
Total Sample Size, Accrual Duration, and Anticipated time to study completion   
Although, we observed an unprecedented accrual rate for the initial portion of this study and 
pre-registered over 80 cases within 9-10 weeks (August-October 2015) and 15-17 cases within 

 
Alliance A091401 
Version Date: 05/22/2019 
81 
Update #12 
5 hours (March 2016) and there is continued interest in this trial, we conservatively estimate that 
we can enroll a maximum of 2 patients per month within each of the histologic cohorts.    
• 
If both GIST arms terminate at the interim analysis, we will need a maximum of 76 
patients across 6 arms and will enroll these cases in 13 months. 
• 
If at both GIST arms complete full enrollment, we will need a maximum of 110 
patients.  These cases will be enrolled in 24 months, without a suspension. 
Therefore, we plan to enroll a minimum of 76 patients to a maximum of 110 patients across all 
6 cohorts and arms (per Update #06), which includes 10% over accrual for non-evaluable 
patients.  We will pre-register a maximum of 82 and 120 cases to obtain these enrollment figures 
and based on current screen failure rates at the time of central pathology review. The number of 
pre-registrations and registrations/randomizations to each group are summarized below: 
 
 
 
New Pre-registration & Enrollment, by Group (Per Update #06) 
(Two (2) Arms in 1 Group) 
Group 
Step 1a 
Step 2a 
Group Total 
LPS 
28 (30)b 
N/A 
28 (30) 
UPS/MFH 
28 (30) 
N/A 
28 (30) 
GIST 
20 (22) 
34 (38) 
54 (60) 
Step Total 
76 (82) 
34 (38) 
110 (120) 
a) Total for both arms. 
b) Registered (Pre-registered) 
Assuming that patients were allowed to remain in treatment for a maximum of 2 years and that 
we would need 6 months for quality assurance for the interim and final analyses, we estimate 
the maximum duration of the study to be an additional 36 months (3 years) from activation of 
Update #06. 
Inclusive of those patients pre-registered and enrolled prior to Update #06 and for administrative 
purposes, this trial is targeting a maximum of 216 (i.e., 96 + 120) patients to be pre-registered 
and a maximum of 195 (i.e., 85 + 110) patients to complete final registration/randomization onto 
the study. 
13.7 
AE Stopping Rule   
The stopping rule specified below is based on the knowledge available at study development. 
We note that the Adverse Event Stopping Rule may be adjusted in the event of either (1) the 
study re-opening to accrual after any temporary suspension or (2) at any time during the conduct 
of the trial and in consideration of newly acquired information regarding the adverse event 
profile of the treatment(s) under investigation. The study team may also choose to suspend 
accrual because of unexpected adverse event profiles that have not crossed the specified rule 
below. 
Accrual will be temporarily suspended to this study if at any time we observe events considered 
at least possibly related to study treatment (i.e., an adverse event with attribute specified as 

 
Alliance A091401 
Version Date: 05/22/2019 
82 
Update #12 
"possible", "probable", or "definite") that satisfy any of the following criteria for each arm 
separately and applies to the treatment patients were initially randomized to: 
• 
If at any time, 4 of the initial 10 treated patients or 40% or more of all patients (i.e. when 
accrual is greater than 10 patients) have experienced a ≥ grade 3 adverse event.  
• 
If at any time, 2 patients have experienced a grade 5 adverse event (non -progressive 
disease). 
• 
In addition, each grade 5 event will be reviewed on a case by case basis in a real time fashion 
to determine whether study accrual should be suspended.  We may suspend accrual after 
just 1 grade 5 AE, if needed. 
• 
In addition, for patients who are assigned to single agent nivolumab and cross over to dual 
agent therapy, the same 3 conditions would trigger a temporarily suspension and would not 
allow further patients to re-register and receive dual agent therapy.  
 
13.8  Accrual Monitoring Stopping Rule 
At study activation, the expected accrual rate was 7 patients per month, and would take around 
12 months to fully accrue. This study far surpassed the accrual stopping rule, as of mid-October 
2015 after pre-registering 81 patients in 9-10 weeks and 15-17 patients in 5 hours in March 
2016. Conservatively, we anticipate enrolling 6 patients per month (2 per cohort). 
13.9 
Primary Endpoint Completion Time Estimation (For clinicaltrails.gov reporting) 
The primary endpoint is confirmed response, as discussed in detail in section 13.2 and 13.3. The 
final analyses for the primary endpoint within all study cohorts are expected to be completed 
approximately 6.5 years after the study begins (section 13.6) and adjusted for activation of 
enrollment to the expansion cohorts associated with Update #6, so we expect that the primary 
endpoint completion time to be around 6.5years after initial study activation. 
13.10 Descriptive Factors  
• 
Histologic Subtype 
- 
Leiomyosarcoma 
- 
Liposarcoma 
- 
Malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma 
- 
Bone sarcomas  
- 
Vascular sarcomas  
- 
Ewing/Primitive neuroectodermal tumors 
- 
Synovial sarcoma 
- 
GIST 
- 
Other (specify) 
• 
Disease Status:  locally advanced vs metastatic vs both. 
13.11 Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of race, gender, or ethnic origin.  
There is no information currently available regarding differential effects of this regimen in 
subsets defined by race, gender, or ethnicity, and there is no reason to expect such differences 
to exist.  Based on prior studies involving similar disease sites, we expect about 20% of patients 
will be classified as minorities by race and about 50% of patients to be women.  Expected sizes 
of racial by gender subsets are shown in the following table, based on enrollment prior to 
protocol Update #6 and for maximum enrollment to the trial: 

 
Alliance A091401 
Version Date: 05/22/2019 
83 
Update #12 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
4 
4 
0 
0 
8 
Asian 
3 
0 
0 
0 
3 
Native Hawaiian or 
Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
6 
5 
2 
2 
15 
White 
74 
81 
8 
6 
169 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
87 
90 
10 
8 
195 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
14.0 CORRELATIVE AND COMPANION STUDIES 
As of Update #06, PD-L1 testing on FFPE tissue and on tumor infiltration lymphocytes (TILs); and 
characterization of TILs will be mandatory for all patient to participate. These mandatory assays will 
be done on FFPE tumor tissue required for all patients to submit (see section 6.2 .4). If patients opted 
into “Fresh tumor biopsy”, these tests will also be performed on the fresh biopsy samples (see section 
6.2.4). The rest of tests described below in section 14 are only applicable for patients who consent 
and registered to A091401-ST1. 
For patients who enrolled to A091401 prior to protocol Update #06, FFPE tissue collected from 
patients who consented to future research question (question #2 SAMPLES FOR FUTURE 
RESEARCH STUDIES) will be used for testing PD-L1 expression on FFPE tissue and on tumor 
infiltration lymphocytes (TILs); and characterization of TILs. 
There will be one substudy within Alliance A091401. This correlative science study must be offered 
to all patients enrolled on Alliance A091401 (although patients may opt to not participate). This 
substudy does not require separate IRB approval. The substudy included within Alliance A091401 
is:  

 
Alliance A091401 
Version Date: 05/22/2019 
84 
Update #12 
14.1 
Mandatory studies and optional Correlative Science (Alliance A091401-ST1) 
14.1.1 Background 
PDL-1 Expression in Sarcoma Cell Lines 
In vitro models using sarcoma cell lines have documented very high PDL1 expression at 
baseline by Western blot (Figure 1) and by flow cytometry (Figure 1) that is also induced 
by interferon.  Expression is noted in nearly 65% of the cell lines including synovial 
sarcoma, Ewing sarcoma, rhabdomyosarcoma, liposarcoma, malignant peripheral nerve 
sheath tumors, desmoplastic small round cell, osteosarcoma and chondrosarcoma. 
PDL-1 Expression in Sarcoma Tumor Specimens 
PDL-1 expression was evaluated in 50 sarcoma tumor specimens of various subtypes using 
immunohistochemistry with the use of a rabbit monoclonal antihuman PD-L1 antibody 
(clone 28-8) and an automated assay developed by Dako. Greater than 1% PDL-1 expression 
was identified in 6/50 (12%) of samples (Table 1) There was evidence of macrophage and 
lymphocyte infiltration in the tumor, outside of the tumor, and both.    
Median age 46 years (range, 22 - 76), 66% male.  Disease status: 70% primary 
disease/locally recurrent, 26% metastatic and 4% unknown. Tumor, lymphocyte and 
macrophage PD-L1 expression was noted in 12%, 30% and 58%, respectively.  Lymphocyte 
and macrophage infiltration was present in 98% and 90%, respectively. (Table 1) 
Table 1: PD-L1 expression 
Histology  
n  
% Tumor 
PD-L1  +   
% Lymphocyte 
PD-L1 +  
% Macrophage 
PD- L1 +  
Angiosarcoma  
3  
 0  
100  
100  
GIST  
14  
27  
100  
100  
Leiomyosarcoma  
4  
0  
0  
25  
Liposarcoma  
5  
0  
20  
60  
Synovial Sarcoma  
3  
0  
33  
0  
Radiation associated pleomorphic 
sarcoma  
1  
100  
100  
100  
Other  
20  
5  
10  
70  
Overall  
50  
12  
30  
58  
PD-L1 expression is not an established biomarker predictive of response  
The significance of PD-L1 expression as a biomarker of response to checkpoint blockade 
with PD-1 inhibitors remains a controversial topic. PD-L1 expression remains a dynamic 
marker, that can change over time and under different conditions in the microenvironment.  
Tumor heterogeneity can also contribute to varied PD-L1 expression.(30)    Based on the 
initial phase I clinical data of the combination of ipilimumab and nivolumab in melanoma 
patients, patients with PD-L1 expression may be more likely to respond, however, lack of 
expression did not exclude responses. (29)   These data suggest that either PD-L1 expression 
may change as a result of therapy with checkpoint blockade such as ipilimumab or 
nivolumab.    
Tumor production of neoantigens may underlie response to immune checkpoint 
inhibition 
Recently, a report by van Rooij et al associated a response to ipilimumab in a patient with 
melanoma with T cell recognition of a tumor-specific mutant protein, termed a ‘neoantigen.’ 
(31) To do this, they performed whole exome sequencing of the melanoma tumor tissue and 
tumor infiltrating lymphocytes (TILs) and identified >1000 tumor-specific mutations. They 
then utilized NetMHC, an online predictor of Class I major histocompatibility complex 

 
Alliance A091401 
Version Date: 05/22/2019 
85 
Update #12 
(MHC)-specific affinities for specific sequences of 9-11 amino acids (32), to narrow the 
mutant sequences to 448 peptides predicted to bind with medium to high affinity to the 
patient’s CD8+ T cells. These peptides were screened for binding with patient TILs, and 
they identified 3.3% of all patient CD8+ T cells reacted with a specific mutated epitope in 
the ataxia-telangiectasia and Rad3-related protein (ATR) pathway, suggesting this resulted 
in the clinical benefit seen in this patient. 
Further support for neoantigen-specific immune surveillance has come from in vivo models 
of sarcoma. In a murine model of chemically-induced sarcomas arising in immune-deficient 
Rag2-/- mice, Matsushita et al reported that implantation into an immunocompetent murine 
host resulted in “immune editing” of the tumor, and tumors with a greater neoantigen load 
were frequently rejected by the new host. (33) Similar results were seen in a conditional 
Kras-p53 knockout mouse model. (34) Whereas the work of van Rooij et al and Matsushita 
et al suggests that certain key mutations predict response, DuPage et al and other authors 
(35) imply that a higher overall mutational load and resulting neoantigen burden may lead 
to efficacy.  By associating mutational burden and additional analyses with clinical 
response, our data has the potential to determine which effect plays a greater role in the 
context of sarcoma.  
The Chan lab at MSKCC has presented data at ASCO 2014 supporting the association 
between this patient-specific neoantigen analysis in melanoma with individual clinical 
benefit from ipilimumab [48].  Using whole exome sequencing of tumors and peripheral 
blood mononuclear cells, a neoantigen signature incorporating both mutational load and 
patient-specific neoantigens separated patients with prolonged clinical benefit from patients 
with progressive disease.  Putative neoantigens were validated in vitro using patients’ 
peripheral blood mononuclear cells and tumor infiltrating lymphocytes. These data are 
pending publication. 
Peripheral Blood Lymphocyte Subsets Are Altered by Immune Therapy 
Recent investigations in patients with melanoma, lung cancer, and/or bladder cancer treated 
with nivolumab with or without ipilimumab have identified dynamic changes in the 
proportion of circulating CD8+ or CD4+ T effector (FoxP3-) or CD4+ T regulatory 
(FoxP3+) cells that express the proliferation marker Ki67 with therapy. The highest 
magnitude of change is seen about 1 week after the first doses of ipilimumab and nivolumab.  
14.1.2 Objectives 
14.1.2.1 Objective 1: Neoantigen Analysis To identify overall mutational burden and 
number of putative tumor ‘neoantigens’ in sarcoma specimens 
• 
To explore the association between mutational and predicted ‘neoantigen’ 
burden in sarcoma samples with degree of clinical benefit in patients treated 
with nivolumab with or without ipilimumab 
14.1.2.2 Objective 2: Characterization of Tumor Markers, Gene Expression, Infiltrating 
Lymphocytes and Circulating Lymphocytes  
• 
To investigate immune infiltrates in sarcoma tumors at baseline and following 
one cycle of therapy with nivolumab with or without ipilimumab 
• 
To investigate subsets of circulating lymphocytes at baseline and at various 
timepoints during therapy with nivolumab with or without ipilimumab 
• 
To analyze changes in gene expression in tumor samples at baseline and 
following one cycle of therapy with nivolumab with or without ipilimumab 

 
Alliance A091401 
Version Date: 05/22/2019 
86 
Update #12 
• 
To explore associations between changes in tumor immune infiltrates, tumor 
gene expression, and circulating lymphocytes with degree of clinical benefit 
• 
To evaluate PD-L1 expression in tumor and TILs and correlate with degree 
of clinical benefit 
14.1.2.3 Objective 3: Serum/Plasma Cytokines  
To explore the composition of circulating factors, such as chemokines, cytokines, and 
other immune mediators in the blood at baseline and how they change with therapy 
with nivolumab with or without ipilimumab. 
14.1.3 Methods 
14.1.3.1 Objective 1: Neoantigen Analysis 
Tumor (and matched normal) whole exome and transcriptome sequencing for 
evaluation of mutational burden (MSKCC Genomics Core): 
Tumor DNA, matched normal DNA, and tumor RNA will be extracted for whole 
exome and transcriptome analysis. Once DNA has been obtained and extracted, we 
will perform massively parallel sequencing of the whole exome of the tumor tissue 
and the available normal tissue. Genomic DNA will be captured via solution-based 
hybrid selection and sequenced on the Illumina HiSeq platform by the Genomics Core 
at MSKCC. Matched normal DNA will also be collected from whole blood and 
sequenced in conjunction with somatic tumor DNA. This is necessary to make variant 
calls in next-generation sequencing assays. It is not the intent of this analysis to utilize 
these samples to identify germline susceptibility mutations. However, in the course of 
investigating somatic sequence variations, germline susceptibility variants may be 
suggested by comparative germline sequencing. In addition, some somatic mutations 
are themselves directly suggestive of a germline predisposition (e.g. BRCA1). 
Germline BAM files will not be separately analyzed in the future without additional 
informed consent, anonymization, and/or human subjects review.  
The somatic sequencing data will be analyzed for base mutations, insertions, fusions, 
deletions, copy number alterations and in all target genes. Exon capture will be 
performed using the SureSelect Human All Exon 50MB kit (Agilent). Enriched exome 
libraries will be sequenced on the HiSeq 2000 platform (Illumina) to >100X coverage. 
Raw sequencing data will be mapped to the human reference genome. All filtered 
candidates will be annotated and manually reviewed (36) using the Integrated 
Genomic Viewer (IGV) (37). Mutations will be annotated using SnpEffect (38). In 
order to improve quality of calls in these FFPE samples, mutations will be analyzed 
using four callers: Somatic Sniper (39), VarScan (40),  Strelka (41) and MuTect  (42) 
then filtered by allelic frequency of  each alteration in tumor (>10%) and normal 
(<3%), depth of coverage (≥7X) and call quality.  All calls made by only one caller 
will be manually reviewed using IGV (37). 
Whole transcriptome tumor mRNA will be sequenced using next-generation 
sequencing. Briefly, after quantification and quality control, poly(A)RNA will be 
isolated  and then fragmentated and purified. The Fragmented Samples quality and 
yield are evaluated and will undergo Whole transcriptome Library preparation. 
Samples will be prepared using the ion one touch system II and Ion PI™Template 

 
Alliance A091401 
Version Date: 05/22/2019 
87 
Update #12 
OT2 200kit v2 Kit (Life Technologies). Enriched particles will be sequenced on a 
Proton sequencing system . 
Bioinformatic Analysis - identification of candidate neoantigens (Chan, Wolchok, and 
Callahan Labs, MSKCC): 
Bioinformatic techniques are being developed to use whole exome sequencing to 
identify candidate neoantigens. Neoantigens are modeled in silico by examining the 
components of antigen presentation on MHC (antigenicity) (43) and recognition by 
T-cells (immunogenicity). First, expressed somatic missense mutations are translated 
into pairs of short peptide strings: one including the mutation and one corresponding 
to the wild-type sequence. Next, in silico analysis is performed using NetMHC 
(http://www.cbs.dtu.dk/services/ NetMHC-3.2/  (32, 44))  to predict the binding 
affinity of a given peptide for patient-specific MHC I. IEDB (http://www.iedb.org 
(33)) is also used to predict the induction of a T-cell response to a given amino acid 
peptide sequences. Candidate neoantigens will be identified by having high predicted 
MHC binding affinity (<50nM), significantly greater affinity than their WT 
counterpart, and having the capacity to induce a T-cell response. 
The binding affinity of a given candidate neoantigen is dependent in part on the 
specific MHC I and II alleles that are presenting the antigen. Although initial studies 
restricted analysis to the predicted binding affinity to HLA-A*02:01 (45), the most 
common allele in Caucasians, NetMHC 3.2 is now able to predict the nanomolar 
peptide binding affinity of nearly any human HLA allele (46). Exome sequencing 
done above may not provide sufficient coverage to accurately determine the patient-
specific HLA allele, so HLA typing will be performed separately using normal DNA.  
Due the rapid improvement of bioinformatics tools, the details of the analytical plan 
described above is subject to change. 
14.1.3.2 Study 2: Characterization of Tumor Markers, Gene Expression, Infiltrating 
Lymphocytes and Circulating Lymphocytes (Wolchok Laboratory, MSKCC) 
PBMCs will be obtained at various time points coinciding with patient visits for 
clinical assessments (Arm 1: baseline, Weeks 1, 3, 5, 9, 11, 13; End of Treatment; 
progression, withdrawal or removal from study) (Arm 2: baseline, Weeks 1, 4,  7, 10, 
14, 16; End of Treatment; progression, withdrawal or removal from study). Tumor 
samples from baseline (archived specimen or fresh biopsy) and Week 6 (fresh biopsy) 
will be obtained. 
PBMC Processing will be performed by the Alliance Biorepository at Ohio State 
University. 
Recommended PBMC preparation protocol: 
PBMC processing will be performed by Alliance Biorepository at Ohio State 
University. Centrifuge for 20 minutes at 1700 x g. If after centrifugation the upper 
phase above the gel is not clear of RBCs, the tube should be centrifuged for an 
additional 15 minutes. After centrifugation, the PBMCs will be found in a diffuse, 
whitish layer above the gel or on the sides of the tube. Without disturbing the cell 
layer, use a transfer pipette to remove approximately half the upper clear plasma layer 
(~3 mL). With a clean transfer pipette, gently pipette the remaining plasma and cells 
up and down to dislodge any cells that may be resting on the gel layer, or the sides of 
the tube. Transfer the cell suspension to a 15 mL conical tube. Add room temperature 

 
Alliance A091401 
Version Date: 05/22/2019 
88 
Update #12 
RPMI-10 to the conical tube to a final volume of 13 mL, cap the tube tightly, and mix 
by gentle inversion. Centrifuge at 250 × g for 15 min at room temperature. The 
supernatant may be cloudy. These are platelets above the cell pellet. Decant or aspirate 
the supernatant without disturbing the cell pellet.  Flick the tube to resuspend cells. 
Repeat washing steps (RPMI-10, suspension, centrifuge, decant supernatant) 1-2 
more times. While waiting for the 2nd (or 3rd) wash, fill an insulated ice pan with ice. 
After the 2nd (or 3rd) wash is complete, remove a small aliquot to record the cell 
count and viability, then place tube on ice. For each timepoint, collect the following 
parameters: 
i. 
Cell viability (%) before freezing 
ii. 
Total yield of PBMCs (x 106 cells/mL/vial) isolated prior to freezing 
Prepare a freezing container (e.g. Nalgene cat #5100-0001 or equivalent) Remove the 
high-density polyethylene vial holder and foam insert from the Nalgene  Freezing 
Container. Do not discard the foam insert. Container must be at room temperature 
prior to use. Do not pre-chill. Add approximately 250 mL of 100% isopropyl alcohol 
to the fill line on the Freezing Container. Do not overfill. Carefully replace the foam 
insert and vial holder in the Freezing Container. 
To freeze the PBMCs: Important to Note: PBMC Freezing media contains DMSO, 
which is toxic to the cells if they are not frozen immediately after suspension in 
freezing media. Flick 15mL centrifuge tube containing the PBMC pellet to resuspend 
cells. Using a transfer pipette, quickly resuspend the pellet in 1 mL of COLD Freezing 
Medium. 
i. 
NOTE:  Prepare media per the instructions contained inside the media kit box.   
ii. 
Mix the cells up-and-down a few times until well mixed (no visible clumps). 
iii. 
Immediately dispense the entire volume into the pre-labeled cryovial. Cap the 
vial tightly. Keep samples on ice until transferred to the Freezing Container. 
Aliquot PBMCs into provided labeled cryovials. A minimum of seven (7) 
cryovials should be obtained. 
iv. 
NOTE: Each cryovial should contain a minimum of 5x106 cells/mL/vial and 
a maximum of 15x106 cells/mL/vial.  For each cryovial prepared, please 
record the total # of PBMCs in the cryovial.  
v. 
If there are less than 35 million cells, as many cryovials with 5 million cells 
should be made as possible. 
vi. 
Place sample vials in Freezing Container vial holder. Place the lid on the 
Freezing Container and place in a -70 C/-80°C freezer immediately. For 
each cryovial prepared, please record the date and time placed into the freezer. 
vii. 
NOTE: Leave undisturbed overnight or for a minimum of 12 hrs and a 
maximum of 24 hrs. 
Transfer samples to liquid nitrogen storage freezer. Record the time, date, and location 
that the samples were placed in liquid nitrogen storage.  For each cryovial prepared, 
please record the date and time placed into liquid nitrogen storage.  
Immunohistochemistry for PD-L1: Immunohistochemical staining for PD-L1 
(DAKO, Carpinteria, CA) will be performed on 5 µm thick sections obtained from 

 
Alliance A091401 
Version Date: 05/22/2019 
89 
Update #12 
formalin-fixed paraffin embedded tissue of the selected cases. PD-L1 positivity was 
defined as >1% of tumor cells (minimum of 100 evaluable cells) demonstrating 
plasma membrane staining. Macrophage and lymphocyte PD-L1 status will be 
determined qualitatively. Positive macrophage or lymphocyte PD-L1 expression 
inside and/or outside of the tumor expression will be defined.  
Immunohistochemical 
staining 
for 
PD1 
(mouse 
clone 
NAT 
antibody, 
LOT#GR81330-2 Abcam Cambridge, MA or equivalent 
Gene Expression: 
Fresh tumor biopsy will be examined for RNA gene expression by Affymetrix gene 
array technology and/or qRT-PCR to detect expression of immune related genes.  
Genes of interest include, but are not limited to PD-1, PD-L1, IDO2, Il-6, CTLA-4, 
KIR/KIR-ligand mismatch. 
Flow Cytometry: 
Markers including, but not limited to, activated (HLA-DR+) and memory (CD45RA-
) T cells; CD4/CD25/FoxP3, CD4/CD8/CD45RA/CCR7, CD4/CD8/LAG3/PD-1/PD-
L1, CD4/CD8/CD137 will be assessed utilizing MSKCC immune core facilities. The 
functional status of effector T cells will be assessed using assays such as interferon-
gamma and granzyme B. 
14.1.3.3  
Study 3: Serum/Plasma Cytokines 
Whole blood will be obtained at various time points coinciding with patient visits for 
clinical assessments (Arm 1: baseline, Weeks 1, 3, 5, 9, 11, 13; End of Treatment; 
progression, withdrawal or removal from protocol therapy) (Arm 2: baseline, Weeks 
1, 4, 7, 10, 14, 16; End of Treatment; progression, withdrawal or removal from 
protocol therapy). Serum will be extracted by the Alliance Biorepository at Ohio State. 
Plasma isolated during PMBC preparation can substitute for serum when necessary. 
Multiplex ELISA assays for factors which may include but are not limited to IL-2, -
4, -5, -6, -8, -10, -12, -17; CXCL9, CXCK10, and VEGF will be assessed at baseline 
and at various time points. Associations will be explored between these changes and 
degree of clinical benefit. 
Considering the rapid improvement of biotechnology, more updated analytical tools 
and platforms may be used 
15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
There are no credentialing requirements for A091401. 

 
Alliance A091401 
Version Date: 05/22/2019 
90 
Update #12 
16.0 REFERENCES 
1. 
Brennan MF, S.S., Maki RG, O'Sullivan B, editors, Cancer: Principles and Practice of Oncology. 
8 ed2008: Lippincott, Williams and Wilkins. 
2. 
Lindberg, R.D., et al., Conservative surgery and postoperative radiotherapy in 300 adults with 
soft-tissue sarcomas. Cancer, 1981. 47(10): p. 2391-7. 
3. 
Weitz, J., C.R. Antonescu, and M.F. Brennan, Localized extremity soft tissue sarcoma: improved 
knowledge with unchanged survival over time. J Clin Oncol, 2003. 21(14): p. 2719-25. 
4. 
Billingsley, K.G., et al., Pulmonary metastases from soft tissue sarcoma: analysis of patterns of 
diseases and postmetastasis survival. Ann Surg, 1999. 229(5): p. 602-10; discussion 610-2. 
5. 
Van Glabbeke, M., et al., Prognostic factors for the outcome of chemotherapy in advanced soft 
tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line 
regimens--a European Organization for Research and Treatment of Cancer Soft Tissue and Bone 
Sarcoma Group Study. J Clin Oncol, 1999. 17(1): p. 150-7. 
6. 
Brennan MF, A.C., Maki RG, Management of Soft Tissue Sarcoma2012, New York: Springer  
7. 
Van Glabbeke, M., et al., Progression-free rate as the principal end-point for phase II trials in 
soft-tissue sarcomas. Eur J Cancer, 2002. 38(4): p. 543-9. 
8. 
T, C., Historical Perspectives and Current Trends in Cancer Immunotherapy, in Cancer 
Immunotherapy: Paradigms, Practice and Promise, C. T, Editor 2012, Springer. 
9. 
Coley, W.B., II. Contribution to the Knowledge of Sarcoma. Ann Surg, 1891. 14(3): p. 199-220. 
10. 
Gatti, R.A. and R.A. Good, Occurrence of malignancy in immunodeficiency diseases. A literature 
review. Cancer, 1971. 28(1): p. 89-98. 
11. 
Mesri, E.A., E. Cesarman, and C. Boshoff, Kaposi's sarcoma and its associated herpesvirus. Nat 
Rev Cancer, 2010. 10(10): p. 707-19. 
12. 
Sorbye, S.W., et al., Prognostic impact of lymphocytes in soft tissue sarcomas. PLoS One, 2011. 
6(1): p. e14611. 
13. 
Peggs, K.S., et al., Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. 
Curr Opin Immunol, 2006. 18(2): p. 206-13. 
14. 
Robert, C. and F. Ghiringhelli, What is the role of cytotoxic T lymphocyte-associated antigen 4 
blockade in patients with metastatic melanoma? Oncologist, 2009. 14(8): p. 848-61. 
15. 
Freeman, G.J., et al., Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family 
member leads to negative regulation of lymphocyte activation. J Exp Med, 2000. 192(7): p. 1027-
34. 
16. 
Nishimura, H. and T. Honjo, PD-1: an inhibitory immunoreceptor involved in peripheral 
tolerance. Trends Immunol, 2001. 22(5): p. 265-8. 
17. 
Carter, L., et al., PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is 
overcome by IL-2. Eur J Immunol, 2002. 32(3): p. 634-43. 
18. 
Latchman, Y., et al., PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat 
Immunol, 2001. 2(3): p. 261-8. 

 
Alliance A091401 
Version Date: 05/22/2019 
91 
Update #12 
19. 
Robert, C., et al., Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N 
Engl J Med, 2011. 364(26): p. 2517-26. 
20. 
Hodi, F.S., et al., Improved survival with ipilimumab in patients with metastatic melanoma. N 
Engl J Med, 2010. 363(8): p. 711-23. 
21. 
Wolchok, J.D., et al., Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: 
Immune-Related Response Criteria. Clinical Cancer Research, 2009. 15(23): p. 7412-7420. 
22. 
Maki, R.G., et al., A Pilot Study of Anti-CTLA4 Antibody Ipilimumab in Patients with Synovial 
Sarcoma. Sarcoma, 2013. 2013: p. 168145. 
23. 
Woo, S.R., et al., Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell 
function to promote tumoral immune escape. Cancer Res, 2012. 72(4): p. 917-27. 
24. 
Taube, J.M., et al., Colocalization of inflammatory response with B7-h1 expression in human 
melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl 
Med, 2012. 4(127): p. 127ra37. 
25. 
Thompson, R.H., et al., Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor 
aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A, 2004. 101(49): p. 
17174-9. 
26. 
Thompson, R.H., et al., Costimulatory molecule B7-H1 in primary and metastatic clear cell renal 
cell carcinoma. Cancer, 2005. 104(10): p. 2084-91. 
27. 
Thompson, R.H., et al., Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma 
patients with long-term follow-up. Cancer Res, 2006. 66(7): p. 3381-5. 
28. 
Ohigashi, Y., et al., Clinical significance of programmed death-1 ligand-1 and programmed 
death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res, 2005. 11(8): p. 2947-
53. 
29. 
Wu, C., et al., Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in 
gastric carcinoma and its clinical significance. Acta Histochem, 2006. 108(1): p. 19-24. 
30. 
Dong, H. and L. Chen, B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med 
(Berl), 2003. 81(5): p. 281-7. 
31. 
Nomi, T., et al., Clinical significance and therapeutic potential of the programmed death-1 
ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res, 2007. 13(7): 
p. 2151-7. 
32. 
Zitvogel, L., A. Tesniere, and G. Kroemer, Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol, 2006. 6(10): p. 715-27. 
33. 
Sznol, M., et al., Survival and long-term follow-up of safety and response in patients (pts) with 
advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-
4538). J Clin Oncol, 2013. 31(Suppl). 
34. 
Brahmer, J., et al., Survival and long-term follow-up of the phase I trial of nivolumab (Anti-PD-1; 
BMS-936558; ONO-4538) in patients (pts) with previously treated advanced non-small cell lung 
cancer (NSCLC). J Clin Oncol, 2013. 31(suppl): p. abstract 8030. 
35. 
Drake, C., et al., Survival, safety, and response duration results of nivolumab (Anti-PD-1; BMS-
936558; ONO-4538) in a phase I trial in patients with previously treated metastatic renal cell 
carcinoma (mRCC): long-term patient follow-up. J Clin Oncol, 2013. 31(suppl): p. abstract 4514. 

 
Alliance A091401 
Version Date: 05/22/2019 
92 
Update #12 
36. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N 
Engl J Med, 2012. 366(26): p. 2443-54. 
37. 
Konishi, J., et al., B7-H1 expression on non-small cell lung cancer cells and its relationship with 
tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res, 2004. 10(15): p. 
5094-100. 
38. 
Thompson, R.H., et al., B7-H1 glycoprotein blockade: a novel strategy to enhance 
immunotherapy in patients with renal cell carcinoma. Urology, 2005. 66(5 Suppl): p. 10-4. 
39. 
Tsushima, F., et al., Predominant expression of B7-H1 and its immunoregulatory roles in oral 
squamous cell carcinoma. Oral Oncol, 2006. 42(3): p. 268-74. 
40. 
Rizvi, N., et al., A phase I study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus 
platinum-based doublet chemotherapy (PT-doublet) in chemotherapy-naive non-small cell lung 
cancer (NSCLC) patients (pts). J Clin Oncol, 2013. 31: p. abstract 8072. 
41. 
Wolchok, J.D., et al., Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med, 2013. 
369(2): p. 122-33. 
42. 
Curran, M.A., et al., PD-1 and CTLA-4 combination blockade expands infiltrating T cells and 
reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A, 
2010. 107(9): p. 4275-80. 
43. 
Hammers, H.J., et al. Phase I study of nivolumab in combination with ipilimumab in metastatic 
renal cell carcinoma (mRCC). in ASCO Annual Meeting Proceedings. 2014. 
44. 
Tan, A.D., P.J. Novotny, and e. al., A patient-level meta-analytic investigation of the prognostic 
significance of baseline quality of life (QOL) for overall survival (OS) among 3,704 patients 
participating in 24 North Central Cancer Treatment Group (NCCTG) and Mayo Clinic Cancer 
Center (MC) oncology clinical trials. J Clin Oncol, 2008. 26 (20 suppl): p. 9515. 
45. 
Takei, S., et al., Immunohistochemical demonstration of increased prostaglandin F(2)alpha levels 
in the rat hippocampus following kainic acid-induced seizures. Neuroscience, 2012. 218: p. 295-
304. 
46. 
Thompson, R.H. and E.D. Kwon, Significance of B7-H1 overexpression in kidney cancer. Clin 
Genitourin Cancer, 2006. 5(3): p. 206-11. 
47. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
48. 
Snyder, A., et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J 
Med, 2014. 371(23): p. 2189-99. 
49. 
Hammers H, P.E., Infante JR, Ernstoff M, Rini BI, McDermott DF, Razak A, Pal SK, Voss M, 
Sharma P, Kollmannsberger CK, Heng D, Shen Y, Kurland J, Spratlin J, Gagnier P and Amin A, 
Phase I Study of Nivolumab in combination with Ipilimumab in metastatic Renal Cell Carcinoma. 
Annals of Oncology, 2014. 25(4). 
50. 
Postow, M.A., et al., Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N 
Engl J Med, 2015. 372(21): p. 2006-17. 
51. 
Rizvi NA, G.S., Goldman JW, et al, Safety and efficacy of first-line nivolumab and ipilimumab in 
non-small cell lung cancer. 2015. 16th World Conference on Lung Cancer. 
52. 
Wolchok, J.D., et al., Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med, 2013. 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
93 
Update #12 
 
APPENDIX I 
REGISTRATION FATIGUE/UNISCALE ASSESSMENTS 
 
 
Registration Fatigue/Uniscale Assessments 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, 
and entered into Medidata Rave at the time of registration. 
 
If needed, this appendix can be adapted to use as a source document.  A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
 
 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Fatigue 
 
 
 
 
 
 
 
 
 
Fatigue 
as bad  
as it can be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
it can be 
 
 
 
 
 
 
 
 
 
As good as 
it can be 
 

Version Date: 05/22/2019 
93 
Update #12 
APPENDIX II CRADA 
Collaborative Agreements Language 
 
Protocols that involve agent(s) covered by a collaborative agreement with a biotech/pharma 
company(ies) must incorporate the NCI/ DCTD Collaborative Agreement Language shown below. 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1.   Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study.  Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the 
investigators. The protocol documents for studies utilizing Agents contain confidential information 
and should not be shared or distributed without the permission of the NCI.  If a copy of this protocol 
is requested by a patient or patient’s family member participating on the study, the individual should 
sign a confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2.   For a clinical protocol where there is an investigational Agent used in combination with (an)other 
Agent(s), each the subject of different Collaborative Agreements, the access to and use of data by 
each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be 
referred to as "Multi-Party Data”): 
 
a.   NCI will provide all Collaborators with prior written notice regarding the existence and nature of 
any agreements governing their collaboration with NCI, the design of the proposed combination 
protocol, and the existence of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 
b.   Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any 
other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain 
regulatory approval or commercialize its own Agent. 
 
c.   Any Collaborator having the right to use the Multi-Party Data from these trials must agree in 
writing prior to the commencement of the trials that it will use the Multi-Party Data solely for 
development, regulatory approval, and commercialization of its own Agent. 
 
3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional 
disclosure is required by law or court order as described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all Clinical 

 
Alliance A091401 
Version Date: 05/22/2019 
95 
Update #12 
Data and Results and Raw Data will be collected, used and disclosed consistent with all applicable 
federal statutes and regulations for the protection of human subjects, including, if applicable, the 
Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4.   When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI 
for other studies) of Collaborator's wish to contact them. 
 
5.   Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines 
and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical 
trial. 
 
6.   Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the Group 
office for Cooperative Group studies or by the principal investigator for non-Cooperative Group 
studies for immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an additional 30 days 
in order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at 
least three (3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must also be forwarded 
to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ media presentation 
should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
96 
Update #12 
APPENDIX III TOXICITY ALGORITHMS 
 
 
 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
97 
Update #12 
 
 
 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
98 
Update #12 
 
 
 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
99 
Update #12 
 
 
 
 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
100 
Update #12 
 
 
 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
101 
Update #12 
 
 
 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
102 
Update #12 
 
 
 
 
 
 
 
 
 
 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
103 
Update #12 
APPENDIX IV DEFINITION OF ACTIVE AUTOIMMUNE DISEASE 
Patients with active autoimmune disease or history of autoimmune disease that might recur, which 
may affect vital organ function or require immune suppressive treatment including systemic 
corticosteroids, should be excluded.  These include but are not limited to patients with a history of 
immune related neurologic disease,  multiple sclerosis, autoimmune (demyelinating)  neuropathy, 
Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, 
polymyositis, rhabdomyolysis, scleroderma, inflammatory bowel disease (IBD), Crohn’s, ulcerative 
colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson 
syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or 
exacerbation of disease.  
Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement 
hormones including physiologic corticosteroids are eligible.   
Patients with rheumatoid arthritis and other arthropathies, Sjögren’s syndrome, vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone 
replacement, psoriasis not requiring systemic treatment, psoriasis controlled with topical medication, 
or conditions not expected to recur in the absence of an external trigger (precipitating event).and 
patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should 
be evaluated for the presence of target organ involvement and potential need for systemic treatment 
but should otherwise be eligible. 
 
 

 
Alliance A091401 
Version Date: 05/22/2019 
104 
Update #12 
APPENDIX V MANAGEMENT OF INFUSION REACTIONS 
All infusion reactions should be reported as an SAE if criteria are met.  Infusion reactions should be 
graded according to NCI CTCAE version 4.0 guidelines. 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as medically appropriate: 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated) 
Monitor subject continuously until recovery from symptoms.  Infusion rate may be slowed.  If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when symptoms 
resolve; if no further complications ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate.  Monitor patient closely. 
The 
following 
prophylactic 
pre-medications 
are 
recommended 
for 
future 
infusions:  
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 
30 minutes before additional nivolumab administrations, slowing infusion rate as above. 
For Grade 2 symptoms:  (Moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; close observation for recurrence and treatment  
medications may need to be continued for 24-48 hours).   
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen); 
continuously monitor patient until resolution of symptoms.  Corticosteroid or bronchodilator therapy 
may also be administered as appropriate.  If the infusion is interrupted, then restart the infusion at 
50% of the original infusion rate when symptoms resolve; if no further complications ensue after 30 
minutes, the rate may be increased to 100% of the original infusion rate.  Monitor patient closely.  If 
symptoms recur, then no further nivolumab will be administered at that visit.  Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the patient until resolution of 
symptoms.  The amount of study drug infused must be recorded on the electronic case report form 
(eCRF).  The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and (acetaminophen) (or paracetamol) 325 to 1000 mg 
should be administered at least 30 minutes before additional nivolumab administrations.  If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms:  
Grade 3 symptoms (Severe reaction): prolonged [i.e., not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion]; recurrence of symptoms following initial 
improvement; hospitalization indicated for other clinical sequelae [e.g., renal impairment, pulmonary 
infiltrates]). 
Grade 4 symptoms: (life threatening; pressor or ventilatory support indicated). 
Immediately discontinue infusion of nivolumab.  Begin an IV infusion of normal saline, and treat the 
subject as follows.  Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV 
administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or 
equivalent), as needed.  Patient should be monitored until the investigator is comfortable that the 
symptoms will not recur.  Nivolumab will be permanently discontinued.  Investigators should follow 
their institutional guidelines for the treatment of anaphylaxis.  Remain at bedside and monitor patient 
until recovery from symptoms.   
In the case of late-occurring hypersensitivity symptoms (e.g., fever, hypotension, appearance of a 
localized or generalized pruritus within 1 week after treatment), symptomatic treatment may be given 

 
Alliance A091401 
Version Date: 05/22/2019 
105 
Update #12 
(e.g., oral antihistamine, or corticosteroids). Note that late occurring events including isolated fever 
and fatigue may represent the presentation of systemic inflammation (e.g. hepatitis, hypophysitis, 
colitis) associated with treatment.  Please evaluate accordingly.