Conditions: Melanoma
Keywords: Ipilimumab Nivolumab Stage III-IV Melanoma Progressed or Relapsed on PD-1 Inhibitor Therapy 16-043
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
The purpose of this research study is to learn whether patients whose disease grows after being treated with nivolumab or pembrolizumab respond to ipilimumab (Yervoy®) alone or in combination with nivolumab (Opdivo®).

Detailed description:

Arms:
arm 1: For patients in the combination arm, nivolumab will first be administered intravenously at a dose of 1 mg/kg of body weight over a period of 60 minutes, once every 3 weeks for four doses. Thirty minutes after the completion of each nivolumab infusion, patients will receive 3 mg/kg of ipilimumab over a period of 30 minutes. arm 2: In the ipilimumab monotherapy group, patients will receive 3 mg/kg of ipilimumab over a period of 30 minutes once every 3 weeks for four doses.

Interventions: intervention 1: ipilimumab intervention 2: nivolumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
 
 
 
Clinical Study Protocol 
 
Protocol Number: PICI0001 
 
Protocol Title: A Randomized, Phase 2 Study of Ipilimumab Vs Ipilimumab plus 
Nivolumab in Patients with Stage III-IV Melanoma Who Have Progressed or 
Relapsed on PD-1 Inhibitor Therapy 
 
 
 
NCT Number: 
NCT02731729 
 
Sponsor: 
Parker Institute for Cancer Immunotherapy (PICI) 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
Tel: 
415-985-7311 
Fax: 
415-872-5305 
 
 
Protocol Version 
3.0 
 
 
Date Final 
06 MAR 2018 
 
 
 
 
 


1 
FINAL CLINICAL STUDY PROTOCOL 
Protocol Number:  PICI0001 
Protocol Title:  A Randomized, Phase 2 Study of Ipilimumab vs Ipilimumab 
plus Nivolumab in Patients with Stage III-IV Melanoma Who Have 
Progressed or Relapsed on PD-1 Inhibitor Therapy 
IND Number: 
Not Applicable 
Name of Product: 
Ipilimumab and Nivolumab 
Phase of Development: 
2 
Indication: 
Stage III-IV Melanoma 
Sponsor: 
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive, Suite D3500 
San Francisco, CA 94129 
Tel: 
 415-985-7311 
Fax:  (415) 872-5305 
Protocol Version: 
3.0 
Protocol Date: 
06 March 2018 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Parker 
Institute for Cancer Immunotherapy.  Any unauthorized copying or use of this 
document is prohibited.  


Parker Institute for Cancer Immunotherapy 
 
 
 
 
             PICI0001 
Ipilimumab/Nivolumab 
 
 
 
  
      Final Protocol 
 
2 
 
Document History 
Document 
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Changes To The Protocol 
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Original Protocol  
23 Aug 2016 
NA 
NA 
NA 
 
 
 
 
Final Protocol 28 Sept 
2016 (Location in Protocol 
Version 1.0, dated 19 Sept 
2016) 
 
 
 
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information on title 
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Investigator protocol 
agreement page 
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Required text and Principal Investigator’s details were added 
 
Section 1, Synopsis 
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protocol body text 
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protocol 
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template under various headings and subheadings  
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Section 7.5, Follow-Up for 
Drug 
Discontinuation/Participant 
Withdrawal from Study 
Addition of text 
If a participant discontinues study treatment and is withdrawn from the study 
for any reason, the study site must immediately notify the medical monitor.  
The date and the reason for study discontinuation must be recorded on the 
electronic case report form (eCRF).  Participants who withdraw prematurely 
are to attend an Early Termination Visit, if possible, and complete all 
assessments. 
In the event that a participant discontinues prematurely from the study due to 
a treatment-emergent adverse events (TEAE) or serious TEAE, the TEAE or 
serious TEAE will be followed until it resolves (returns to normal or baseline 
values) or stabilizes, or until it is judged by the Investigator to be no longer 
clinically significant.   
Once a participant is withdrawn from the study, the participant may not re-
enter the study. 
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Section 8.6, Treatment 
Accountability and 
Compliance 
Addition of text 
Administration of study drugs will be supervised by study personnel or 
assigned infusion room nursing staff, who will monitor compliance.  Study 
drugs accountability will be maintained in the Pharmacy Source documents 
i.e. accountability logs or in the study master file, as required.   
Text included in the 
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based on required 
section heading in 
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Section 9.2.4, Unscheduled 
Visits 
Addition of text 
The Investigator may at his/her discretion arrange for a participant to have an 
unscheduled assessment, especially in the case of AEs that require follow-up 
or an AE considered by the Investigator to be possibly related to the use of 
study drug.  The unscheduled visit page in the eCRF must be completed.   
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based on required 
section heading in 
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11.5.3, Pregnancy 
Addition of text 
Female participants of child-bearing potential must have a negative pregnancy 
test at Screening.  Following administration of study drug, any known cases 
of pregnancy in female participants will be reported until the participant 
completes or withdraws from the study.  The pregnancy will be reported 
immediately by phone and by faxing/emailing a completed Pregnancy Report 
to the Sponsor (or designee) within 24 hours of knowledge of the event.  The 
Investigator will follow the participant until completion of the pregnancy and 
must assess the outcome in the shortest possible time but not more than 
30 days after completion of the pregnancy.  The Investigator should notify the 
Sponsor (or designee) of the pregnancy outcome by submitting a follow-up 
Pregnancy Report on a Pregnancy Surveillance Form.  If the outcome of the 
pregnancy meets the criteria for immediate classification of an SAE (e.g., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an 
aborted fetus is to be documented], stillbirth, neonatal death, or congenital 
anomaly), the Investigator will report the event by phone and by faxing a 
completed SAE form to the Sponsor (or designee) within 24 hours of 
knowledge of the event. 
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updated protocol 
based on required 
section heading in 
new protocol template 
Section 11.5.4, Overdose 
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The Investigator must immediately notify the Sponsor of any occurrence of 
overdose with study drug. 
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updated protocol 
based on required 
section heading in 
new protocol template 
Section 12, Statistical 
analysis 
Addition of text 
A Statistical Analysis Plan (SAP) will be prepared after the protocol is 
approved.  This document will provide further details regarding the definition 
of analysis variables and analysis methodology to address all study objectives.  
Text included in the 
updated protocol 
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Parker Institute for Cancer Immunotherapy 
 
 
 
 
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Ipilimumab/Nivolumab 
 
 
 
  
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The SAP will serve as a compliment to the protocol and supersedes it in case 
of differences. 
The statistical evaluation will be performed using the Statistical Analysis 
Software (SAS®) Version 8.1 or higher (SAS Institute, Cary, NC).  All data 
will be listed, and summary tables will be provided.  Summary statistics will 
be presented by dose group.  For continuous variables, data will be 
summarized with the number of participants (N), mean, standard deviation, 
median, minimum, and maximum by treatment group.  For categorical 
variables, data will be tabulated with the number and proportion of participants 
for each category by treatment group. 
section heading in 
new protocol template 
Section 12.5, Interim 
Analysis 
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Section 12.5: 
Interim Analysis 
Section heading was 
created based on 
information available 
in previous protocol 
under “Design” 
section 
Section 12.6, Data 
Monitoring Committee 
Addition of text 
An independent Data Monitoring Committee (DMC) will be established by 
the Sponsor to review accumulating safety data at regular intervals throughout 
the study and monitor overall study conduct.  The DMC will also evaluate 
results of a formal interim efficacy analysis.  The DMC can recommend in 
writing to the Sponsor whether to continue, modify, or stop the clinical study 
on the basis of efficacy and safety considerations.  The DMC’s specific duties 
as well as statistical monitoring guidelines and procedures will be fully 
described in a DMC Charter. 
Text included in the 
updated protocol 
based on required 
section heading in 
new protocol template 
Section 13.1.1, Regulatory 
Guidelines 
 
 
Addition of text 
This study will be conducted in accordance with the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in 
Parts 50, 56, 312, Subpart D, of Title 21 of the Code of Federal Regulations 
(CFR), and in compliance with good clinical practice (GCP) guidelines. 
Text included in the 
updated protocol 
based on required 
section heading in 
new protocol template 
Section 13.1.2, Institutional 
Review Board/Independent 
Ethics Committee 
Addition of text 
Conduct of the study must be approved by an appropriately constituted 
Independent Ethics Committee (IEC)/IRB.  Approval is required for the study 
protocol, investigational drug brochure, protocol amendments, informed 
consent forms (ICFs), and participant information sheets.   
Text included in the 
updated protocol 
based on required 
section heading in 
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Parker Institute for Cancer Immunotherapy 
 
 
 
 
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Ipilimumab/Nivolumab 
 
 
 
  
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Section 13.1.3, Informed 
Consent 
Change of text 
Section heading “Informed Consent Procedures” was changed to “Informed 
Consent” 
To match with the 
current template 
heading 
Section 13.3, Data Handling 
Addition of text 
Any data to be recorded directly on the eCRFs (to be considered as source 
data) will be identified at the start of the study.  Data reported on the eCRF 
that are derived from source documents should be consistent with the source 
documents, or the discrepancies must be explained. 
Clinical data will be entered on eCRFs for transmission to the Sponsor.  Data 
on eCRFs transmitted via the web-based data system must correspond to and 
be supported by source documentation maintained at the study site, unless the 
study site makes direct data entry to the databases for which no other original 
or source documentation is maintained.  In such cases, the study site should 
document which eCRFs are subject to direct data entry and should have in 
place procedures to obtain and retain copies of the information submitted by 
direct data entry.  All study forms and records transmitted to the Sponsor must 
carry only coded identifiers such that personally identifying information is not 
transmitted.  The primary method of data transmittal is via the secure, internet-
based electronic data capture (EDC) system maintained by inVentiv Health 
Clinical.  Access to the EDC system is available to authorized users via the 
study’s Internet web site, where an assigned username and password are 
required for access. 
Any changes made to data after collection will be made through the use of 
Data Clarification Forms.  eCRFs will be considered complete when all 
missing and/or incorrect data have been resolved. 
Text included in the 
updated protocol 
based on required 
section heading in 
new protocol template 
Section 13.4, Source 
Documents 
Addition of text 
Source documents are considered to be all information in original records and 
certified copies of original records of clinical findings, observations, data or 
other activities in a clinical study necessary for the reconstruction and 
evaluation of the study. 
Text included in the 
updated protocol 
based on required 
section heading in 
new protocol template 


Parker Institute for Cancer Immunotherapy 
 
 
 
 
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Ipilimumab/Nivolumab 
 
 
 
  
      Final Protocol 
 
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Section 13.5, Record 
Retention 
Addition of text 
Study records and source documents must be preserved for at least 15 years 
after the completion or discontinuation of/withdrawal from the study or 2 
years after the last approval of a marketing application in an International 
Conference on Harmonization region, whichever is the longer time period. 
The Investigator agrees to comply with all applicable federal, state, and local 
laws and regulations relating to the privacy of participant health information, 
including, but not limited to, the Standards for Individually Identifiable Health 
Information, 45 CFR, Parts 160 and 164 (the Health Insurance Portability 
Accountability Act of 1996 [HIPAA] Privacy Regulation).  The Investigator 
shall ensure that study participants authorize the use and disclosure of 
protected health information in accordance with HIPAA Privacy Regulation 
and in a form satisfactory to the Sponsor. 
Text included in the 
updated protocol 
based on required 
section heading in 
new protocol template 
Section 13.8.1, Protocol 
Amendment 
Addition of text 
Amendments to the protocol that entail corrections of typographical errors, 
clarifications of confusing wording, changes in study personnel, and minor 
modifications that have no impact on the safety of participants or the conduct 
of the study will be classed as administrative amendments and will be 
submitted to the IRB/IEC for information only.  The Sponsor will ensure that 
acknowledgement is received and filed.  Amendments that are classed as 
substantial amendments must be submitted to the appropriate Regulatory 
Authorities and the IRBs/IECs for approval.   
Text included in the 
updated protocol 
based on required 
section heading in 
new protocol template 
Section 13.8.2, Protocol 
Deviations 
Addition of text 
Should a protocol deviation occur, the Sponsor must be informed as soon as 
possible.  Protocol deviations and/or violations and the reasons they occurred 
will be included in the clinical study report.  Reporting of protocol deviations 
to the IRB/IEC and in accordance with applicable Regulatory Authority 
mandates is an Investigator responsibility. 
Text included in the 
updated protocol 
based on required 
section heading in 
new protocol template 
Section 13.9, Ethical 
Considerations 
Addition of text 
This study will be conducted in accordance with the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in 
Parts 50, 56, 312, Subpart D, of Title 21 of the CFR, and in compliance with 
GCP guidelines. 
IRBs/IECs will review and approve this protocol and the ICF.  All participants 
are required to give written informed consent prior to participation in the 
study.   
Text included in the 
updated protocol 
based on required 
section heading in 
new protocol template 
Section 13.10, Financing 
and Insurance 
Addition of text 
Prior to the study commencing, the Sponsor (or its designee) and the 
Investigator (or the institution, as applicable) will agree on costs necessary to 
perform the study.  This agreement will be documented in a financial 
Text included in the 
updated protocol 
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Parker Institute for Cancer Immunotherapy 
 
 
 
 
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agreement that will be signed by the Investigator (or the institution 
signatory) and the Sponsor (or its designee).  
The Investigator is required to have adequate current insurance to cover claims 
for its negligence and/or malpractice.  The Sponsor, or the manufacturer of the 
study drug, will provide insurance coverage for the clinical study as required 
by national regulations. 
section heading in 
new protocol template 
Section 13.11, Publication 
Policy / Disclosure of Data 
Addition of text 
Both the use of data and the publication policy are detailed within the clinical 
study agreement.  Intellectual property rights (and related matters) generated 
by the Investigator and others performing the clinical study will be subject to 
the terms of a clinical study agreement that will be agreed between the 
Institution and the Sponsor or their designee.   
Text included in the 
updated protocol 
based on required 
section heading in 
new protocol template 
 
 
 
 
Final Protocol 05 Dec 2016 
((Location 
in 
Protocol 
Version 28 Sept 2016) 
 
 
 
Synopsis 
Change of text 
Number of Investigator/Study sites increased to more than 1 site 
 
 
Main Inclusion Criteria 
Change of text 
#3 Changed text from “by MSKCC” to “the enrolling site” 
#5 Changed text from who have “PD” to “primary progressive disease” 
#9e,f from “MSKCC” to “institution’s” upper limit of normal 
#9g changed from Serum creatinine > 1.5x to Serum creatinine < 1.5x  
 
 
Main Exclusion Criteria 
Change of text 
#1 Text changed from “Consult the study MSKCC Principal Investigator” to 
“Consult the study Medical Monitor” 
 
 
Section 5.2.3, Exploratory 
Endpoints and Section 
12.3.3, Analysis of 
Exploratory Efficacy 
Endpoints 
Change of text 
Changed text to will be analyzed at “a Parker Institute for Cancer 
Immunotherapy selected testing center” from “Memorial Sloan Kettering 
Cancer Center” 
 
Section 7, Selection and 
Withdrawal of Participants 
Change of text, 
added text 
Changed text from “on the clinicaltrials.gov website and on the Memorial 
Sloan Kettering Cancer Center website” to “the institution’s website” 
 
Added the following text: “Participants must meet the inclusion and exclusion 
criteria; no exceptions will be made for enrollment” 
 


Parker Institute for Cancer Immunotherapy 
 
 
 
 
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Section 9.2.1.1/9.2.2 
Change of text 
Changed text from “by a MSKCC pathologist” and per “MSKCC guidelines” 
to “the institution’s” pathologist and “the institution’s” guidelines 
 
Section 10.1.2, Target 
Lesions 
Added section 
Section 10.1.2.3, Lymph Nodes  
To be consistent with 
RECIST v1.1 
Section 10.1.5, Best 
Response 
Deleted 
and 
added text 
Deleted “Unequivocal progression of existing non-target lesions, other than 
pleural effusions without cytological proof of neoplastic origin, in the opinion 
of the treating physician within 8 weeks of study entry is also considered 
increasing disease (in this circumstance an explanation must be provided).”   
Added “In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.” 
To be consistent with 
RECIST v1.1 
Section 11.1.2, Serious 
Adverse Events 
Deleted, added 
text 
Deleted text referring to Clinical Research Database (CRD) and added text 
indicating inVentiv Health Clinical will manage SAEs using ARGUS. Also 
added text “Disease Progression is considered a non-reportable event”. 
Other sites do not 
have access to 
MSKCC CRD 
Section 11.1.4, Overdose 
Added text 
Added “Overdose is defined as any dose higher than the dose specified to be 
administered in accordance with the protocol.  All overdoses should be 
reported to inVentiv as SAEs (see Section 11.1.2).  Details of signs and 
symptoms, clinical management, and outcome should be reported, if available.  
Overdoses should also be captured as protocol deviations.” 
 
Section 11.2, Unexpected 
Problems/Non-Compliance 
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Section 11.2:  Unexpected Problems/Non-Compliance 
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include text on 
unexpected problems, 
non-compliance issues 
Section 12.6, Data 
Monitoring Committee 
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added text 
Data Monitoring Committee (DMC) section deleted. Replaced with Data 
Monitoring section 
Now using Data 
Review Team (DRT); 
see Section 12.6.1 
Section 12.6.1, Date 
Review Team 
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Added text describing Data Review Team 
 
Section 13.2, Research 
Participant Registration 
Change of text 
Interactive Voice Response vendor changed to Almac 
 
Section 13.6, Monitoring 
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added text 
Deleted old text and added new text describing monitoring procedures 
 
Section 13.8.2, Protocol 
Deviations 
Deleted text 
Deleted “as soon as possible” from the sentence “Should a protocol deviation 
occur, the Sponsor must be informed as soon as possible”. 
 
Section 15.3, Tumor tissue 
specimens 
Change of text 
Text updated to include 3 core biopsies snap frozen and 1 biopsy formalin 
fixed and preserved in paraffin embedded blocks 
 


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Section 15.3, RNA and 
DNA 
Preparation/Exploratory 
Serum and Plasma 
Biomarkers 
Change of text 
Changed text from “PAXgene tube” to “lavender top tube” 
 
 
Table 3: Schedule of 
Assessments 
Deleted text 
“Additional Follow-Up Visits” column updated to include only AEs and 
Survival Data   
 
Appendix 3 
Addition of text 
Added text describing shipping and testing of samples 
 
Final Protocol 23 Jan 2017 
 
 
 
Title Page, Synopsis, 
Document Header 
Change of text 
Protocol number changed from 16-043 A to PICI0001 
To clarify transition 
from Investigator 
Initiated Trial to 
Sponsor Trial 
Investigator Protocol 
Agreement Page 
Deleted text 
Deleted investigator name “Jedd Wolchok” 
Cell should be blank 
to allow each 
investigator to print 
their name 
Section 3, List of 
Abbreviations 
Deleted text / 
Addition of text 
Deleted “RSA / Research Study Assistant” and added “SC / Study 
Coordinator.” Added “IVR / Interactive Voice Recognition.” 
 
Section 6.1.2, 
Randomization 
Change of text 
Added text indicating that an IVR system will be used to manage 
randomization 
 
Section 11.2, Unanticipated 
Events / Non-Compliance 
Change of text 
In section title, first subsection title, and first subsection text, changed 
instances of “Events” or “event” to “Problems” or “problem.”   This section 
was revised to clarify the investigator’s responsibility for reporting. 
 
Section 13.3, Data Handling 
Change of text 
Changed “Research Study Assistant / RSA” to “Study Coordinator / SC.” 
 
Section 13.8.1, Protocol 
Amendment 
Change of text 
This section was revised to indicate that any change to the protocol, whether 
substantial or minor, will require a formal amendment. 
 
Section 13.8.2, Protocol 
Deviations 
Change of text 
This section was revised to clarify the investigator’s responsibility to report 
protocol deviations and where they are to be reported, and to indicate that 
prospective deviation requests will not be allowed. 
 
Final Protocol 06 Mar 
2018 (Location in Protocol 
Version 05 Dec 2016) 
 
 
 
Synopsis 
Changed text 
Revised the synopsis to be consistent with changes to the body of the protocol 
(described below).   
 


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Section 6.1, Description of 
Overall Study Design and 
Plan, Section 6.2, 
Discussion of Study Design, 
and Section 12.1, 
Determination of Sample 
Size 
Changed text 
Revised the text to reflect the change in total sample size from 70 participants 
(35 per arm) to 24 participants (12 per arm). 
Sponsor decision to 
lower overall accrual 
goal due to challenges 
with enrollment, 
competing trials, and 
available participant 
population.  
Section 7.1, Inclusion 
Criteria 
Changed text 
Criterion #4: Removed language that defined “primary progression 
participants” and “participants with relapsed disease”. Added language to 
indicate that any participant who had refractory or relapsed disease is eligible 
for study enrollment. 
Broadening of 
eligibility criteria to 
make clinical trials 
more representative.  
Section 7.2, Exclusion 
Criteria 
Changed text 
Criterion #1: Clarified the eligibility of participants with concurrent 
malignancies. 
Broadening of 
eligibility criteria to 
make clinical trials 
more representative.  
Section 8.3, Treatment of 
Nivolumab or Ipilimumab 
Related Infusion Reactions 
Removed text 
Removed the use of “mild”, “moderate”, and “severe” language. 
Clarity 
Section 8.4.1, Dosage and 
Administration and Section 
15.1, Appendix 1, Product 
Information and Pharmacy 
Manual 
Added text 
Added text to indicate that infusion times are approximate.  
Clarity 
Section 8.4.2, Monitoring 
and Dose Delay Criteria 
Added text 
Added text to indicate that participants should follow timed assessments and 
that continuation on study is at the principal investigator’s discretion. 
Clarity 
Section 9, Study Procedures 
(Table 3 – Schedule of 
Assessments) 
Added text 
Added a separate column for “Early Termination Visit” to clearly define the 
end of treatment visit and the assessments that need to be collected as part of 
the Early Termination Visit. 
Clarity 
Added text 
Added a footnote to clarify survival for participants who progress (ie, after 
disease progression participants are not required to have scans every 12 weeks 
but instead, survival could be assessed via calls every 3 months ± 7 days). 
Clarity 
Added text 
Added a footnote to clarify CT scan assessment intervals and the minimum 
scan requirements. 
Clarity 
Section 11.1.2, Serious 
Adverse Event 
Changed text 
Revised text to clarify that hospital admission for elective pre-planned 
surgeries is not considered an SAE. 
Clarity 


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SAE Reporting to BMS and 
inVentiv 
Added text 
Added text to indicate that all AEs are to be followed until resolution, until a 
stable clinical endpoint is reached, or for 100 days after the last dose of study 
treatment, unless other anticancer therapy is initiated. 
Clarity 
Section 11.1.3, Pregnancy 
Added text 
Revised text to clarify pregnancy-related information.  
Clarity 
Section 11.1.5, Disease-
Related Events and/or 
Disease-Related Outcomes 
Not Qualifying as Adverse 
Events or Serious Adverse 
Events 
Added new 
section 
Added this section to specify that progression of cancer under study, as judged 
by the Investigator, is not considered a reportable adverse event. 
Clarity 
Section 12.4, Safety 
Analysis 
Changed text 
Removed reference to interim analysis. 
Section removed as 
interim analysis is no 
longer required. 
Section 13.11, Study and 
Site Closure 
Added new 
section 
Added this section to specify the procedure for study and site closure. 
 
Section 15.1, Appendix 1, 
Product Information and 
Pharmacy Manuals 
Changed text 
Updated the text regarding dose calculations based on body weight to indicate 
that dose adjustments are only required for participants who have a 10% 
change compared with their initial weight on Cycle 1, Day 1. 
Clarity 
Section 15.3, Appendix 3, 
Laboratory Procedures 
Changed text 
Gene expression profiling: Removed reference to the specific method and 
instead indicate that gene expression profiling will be run using different 
methodologies. 
RNA and DNA preparation: Revised text to indicate that DNA or RNA will 
be extracted from any core biopsy (not just fresh snap frozen core biopsies). 
Exploratory serum and plasma biomarkers: Removed the language that 
required 4 CPT tubes and 1 lavender top tube to be collected. 
Clarity 
Section 15.4, Appendix 4, 
Contraceptive Guidance and 
Collection of Pregnancy 
Information 
Added new 
appendix 
Added this appendix to provide pregnancy-related information and specific 
guidance for contraception. 
 
 
 




Parker Institute for Cancer Immunotherapy 
PICI0001 
Ipilimumab/Nivolumab 
Final Protocol 
 
13 
 
INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with this protocol, any future amendments, and 
with any other study conduct procedures provided by Parker Institute for Cancer 
Immunotherapy. 
• 
Not to implement any changes to the protocol without written agreement from Parker 
Institute for Cancer Immunotherapy and prior review and written approval from the 
Independent Ethics Committee (IEC) except where necessary to eliminate an 
immediate hazard to participants. 
• 
That I am thoroughly familiar with the appropriate use of the study drug, as described 
in this protocol and any other information provided by Parker Institute for Cancer 
Immunotherapy including, but not limited to, the current Investigator’s Brochure 
(IB).  
• 
That I am aware of, and will comply with, good clinical practices (GCP) and all 
applicable regulatory requirements. 
• 
To ensure that all persons assisting me with the study are adequately informed about 
the Parker Institute for Cancer Immunotherapy study drug and of their study-related 
duties and functions as described in the protocol. 
 
 
Signature: 
 
 
Date: 
 
 
Name 
(print): 
 
  
 
Site 
Number: 
Principal Investigator 
 
___________ 
  
 


Parker Institute for Cancer Immunotherapy 
PICI0001 
Ipilimumab/Nivolumab 
Final Protocol 
 
14 
 
1 
SYNOPSIS 
Title of Study: 
A Randomized, Phase 2 Study of Ipilimumab vs Ipilimumab plus 
Nivolumab in Participants with Stage III-IV Melanoma Who Have 
Progressed or Relapsed on PD-1 Inhibitor Therapy 
Protocol Number: 
PICI0001 
Investigators/Study Sites: 
This study will be conducted at multiple sites in the United States.   
Phase of Development: 
2 
Objectives: 
Primary Objectives:   
To assess response rates of combination ipilimumab/nivolumab and 
ipilimumab alone in participants previously treated with a programmed 
death receptor (PD-1) inhibitor by Week 18 of therapy.  
Secondary Objectives:   
• 
To assess clinical benefit of combination ipilimumab/nivolumab and 
ipilimumab alone 
• 
To evaluate time to treatment failure and overall survival (OS) for 
each arm 
• 
To assess safety and tolerability of ipilimumab alone and in 
combination with nivolumab in previously treated participants 
Exploratory Objectives:   
• 
To evaluate peripheral lymphocyte phenotype changes throughout 
treatment 
• 
To evaluate changes in quantities of myeloid derived suppressor cells 
(MDSCs), defined as CD14+HLA-DRlow cells, and Treg cells, defined 
as CD4+FOX3P+ cells, throughout treatment 
• 
To evaluate nCounter immune profiling of the tumor before treatment  
• 
To explore tumor neoepitopes and mutational burden via whole gene 
and exome sequencing on pre-treatment tumor biopsy and correlation 
with clinical response 
• 
To stratify clinical response rate by PD-L1 expression on 
pre-treatment biopsies 
• 
To evaluate the tumor immune microenvironment on pre- and 
on-treatment tumor biopsies 
Study Design: 
This is a multi-center, randomized Phase 2 study of ipilimumab vs 
ipilimumab plus nivolumab in participants previously treated with a PD-1 
inhibitor by Week 18 of therapy.  There will be 2 arms in the study.   
Arm A: Participants will receive combination checkpoint blockade with 
ipilimumab and nivolumab.   
Arm B: Participants in this arm will receive ipilimumab alone.   
A Simon 2-stage design will be implemented in each arm, allowing for 
early stopping for futility.  Participants who are eligible will be required to 
have a pre-treatment biopsy and then will be randomized to either 
ipilimumab alone or ipilimumab in combination with nivolumab.  
Participants will be required to have an on-treatment biopsy within 
14±5 days of their first dose of treatment.  Participants will receive up to 
4 cycles of treatment followed by observation phase.   
Participants will be assessed for the primary endpoint at 18 weeks and then 
be followed for time to treatment failure (TTF) and OS for up to 2 years.   


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Selection of Participants: 
Main Inclusion Criteria:   
1. AJCC (2009) Stage IV cutaneous melanoma or Stage III cutaneous, 
acral or mucosal melanoma that is judged inoperable.  Participants 
with a history of uveal melanoma are not eligible.   
2. Measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm with conventional techniques or as >10 mm 
with computerized tomography (CT) scan.  Participants must have at 
least one measurable lesion by Response Evaluation Criteria in Solid 
Tumors (RECIST) and a separate lesion amenable to biopsy.   
3. Histologic proof of melanoma reviewed and confirmed by the 
enrolling site.  
4. Previous treatment with a PD-1 or PD-L1 inhibitor with documented 
progression of disease on most recent CT scan.  Progression of 
disease is defined as 1) the appearance of a new measurable lesion 
(>10 mm) on cross-sectional imaging or physical examination OR 2) 
enlargement of previously detected lesions on two consecutive 
imaging studies OR 3) enlargement of a previously detected lesion 
with correlative symptomatology on one cross-sectional imaging 
study.  Participants remain eligible if they had a previous response to 
a PD-1 inhibitor, including participants who had a complete response, 
partial response or stable disease (SD).  Any participant who had 
refractory or relapsed disease is eligible for study enrollment. 
Treatment populations are defined in Section 12. 
5. Participants who received adjuvant PD-1 therapy who then develop 
measurable disease are eligible.  However, they must have received 
their last dose of PD-1/PD-L1 blockade within two months of 
enrollment in this study.  They will be stratified with participants who 
have primary progressive disease.  
6. Life expectancy of greater than 3 months. 
7. Age ≥ 18 years old. 
8. Eastern Cooperative Oncology Group performance status = 0 or 1 or 
Karnofsky Performance Status equivalent.   
9. Participants must have adequate organ and marrow function as 
defined below: 
a. 
White blood cells >2, 000/mcL 
b. Absolute neutrophil count >1,500/mcL 
c. 
Platelets >100,000/mcL 
d. Hemoglobin > 9.0 g/dL  
e. 
Total bilirubin ≤ 1.5 X institution’s upper limit of normal 
f. 
Aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase)/alanine aminotransferase (serum glutamic pyruvic 
transaminase) ≤ 2.5 X institution’s upper limit of normal for 
participants with no concurrent liver metastases, OR ≤ 5 X 
institution’s upper limit of normal for participants with 
concurrent liver metastases 
g. Serum creatinine < 1.5x OR creatinine clearance of at least 40 
10. Women of childbearing potential must have a negative serum 
pregnancy test within 24 hours prior to the start of study drug.  A 
woman of childbearing potential is defined as any female who has 
experienced menarche and who has not undergone surgical 
sterilization (hysterectomy or bilateral oophorectomy) or is not 
postmenopausal.  Menopause is defined clinically as 12 months of 
amenorrhea in a woman over age 50 in the absence of other biologic 
or physiologic causes.  


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11. Women with child bearing potential and men with reproductive 
potential must be willing to practice acceptable methods of 
contraception. 
12. Ability to understand and the willingness to sign a written informed 
consent document.  
13. Willingness to undergo biopsy of metastatic site or site of 
unresectable disease prior to randomization.  
 
Main Exclusion Criteria: 
1. Concurrent malignancies: 
a. Participants with a previously treated malignancy are eligible to 
participate if all treatment of that malignancy was completed at 
least 2 years before registration and the participant has no 
evidence of disease. 
b. Participants who have a concurrent malignancy that is clinically 
stable and does not require tumor-directed treatment are eligible 
to participate if the risk of the prior malignancy interfering with 
either safety or efficacy endpoints is very low (with agreement 
from the sponsor and principal investigator). 
c. Other malignancies may be permitted if the risk of the prior 
malignancy interfering with either safety or efficacy endpoints is 
very low (with agreement from the sponsor and principal 
investigator). 
2. Any major surgical procedures or external beam radiotherapy within 
14 days prior to study drug administration.  
3. Use of other investigational drugs within 28 days prior to study drug 
administration.   
4. Symptomatic or untreated leptomeningeal or brain metastases or 
spinal cord compression. Treated brain metastases must have been 
stable for at least 1 month and require treatment with less than 
10mg/day prednisone equivalent for at least 2 weeks prior to study 
drug administration.   
5. Prior exposure to either ipilimumab or combined checkpoint 
blockade.  
6. Any diagnosis of autoimmune disease.  Participants with Type I 
diabetes 
mellitus, 
hypothyroidism 
only 
requiring 
hormone 
replacement, adrenal insufficiency on replacement dose steroids, skin 
disorders (such as vitiligo, psoriasis or alopecia) not requiring 
systemic treatment, or conditions not expected to recur in the absence 
of an external trigger are permitted to enroll.   
7. Pregnant women and lactating women.  
8. History of uveal melanoma.  
9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus 
(HBV), or Hepatitis C Virus (HCV) infection (with the exception of 
chronic or cleared HBV or HCV infection, which will be allowed). 
Once-documented negative result for HIV, HBV, and HCV is 
sufficient.   
10. Uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection and psychiatric illness/social situations 
that would limit compliance with study requirements.   
11. Participants with a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalent) or other 
immunosuppressive medications within 14 days of study drug 
administration.  Inhaled or topical steroids and adrenal replacement 
steroid doses > 10 mg daily prednisone equivalent are permitted.  


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12. Participants with history of any grade 4 toxicity during previous anti 
PD-1 treatment or history of Grade 3 or higher pneumonitis.  
13. Participants with a history of Grade ≥2 neuropathy.  
14. Prisoners or participants who are involuntarily incarcerated.  
15. Children under the age of 18.   
16. Participants who require hemodialysis.  
17. Participants with a history of allergy to study drug components or 
history of a severe hypersensitivity reaction to any monoclonal 
antibody.   
Planned Sample Size: 
Twelve participants will be enrolled in each arm for a total of 
24 participants.   
Investigational Therapy: 
Not Applicable 
Reference Therapy: 
Arm A: Nivolumab (1 mg/kg of body weight) in combination with 
ipilimumab (3 mg/kg), both once every 3 weeks for 4 doses administrated 
intravenously.   
Or  
Arm B: ipilimumab (3 mg/kg) alone, once every 3 weeks for 4 doses 
administrated intravenously.   
Treatment Duration: 
Participants on both arms will receive treatment for up to 4 cycles (each 
cycle is of 21 days±4 days) and then be observed for up to 2 years in the 
follow up period.   
Participants will undergo screening and, if eligible, will undergo 
intervention in the selected arm of the study up to 4 cycles.   
Criteria for Evaluation: 
Efficacy:  Therapeutic response and outcome assessment will be done in 
this study using the international criteria proposed by the RECIST 
version 1.1 Committee.  Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the 
RECIST criteria.  Lesions are either measurable or non-measurable.  
“Target” and “Non-Target” lesions will be identified and recorded at 
baseline.  Responses will be assessed as follows: 
• 
Complete Response (CR): Disappearance of all target and non-target 
lesions and no evidence of new lesions documented by 2 disease 
assessments at least 4 weeks apart.   
• 
Partial Response (PR):  At least a 30% decrease in the in the longest 
dimension (LD) of all target lesions, taking as reference the baseline 
sum LD.  There can be no unequivocal progression of non-target 
lesions and no new lesions.  Documentation by 2 disease assessments 
at least 4 weeks apart is required.  Progressive Disease (PD):  At least 
a 20% increase in the sum of LD of target lesions, taking as reference 
the smallest sum LD or the appearance of new lesions within 8 weeks 
of study entry. In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.   
• 
Stable Disease (SD):  Any condition not meeting the above criteria.   
• 
Inevaluable for response is defined as having no repeat tumor 
assessments following initiation of study therapy for reasons 
unrelated to symptoms or signs of disease.  
Outcome will be assessed as follows: 
• 
Objective Response Rate (ORR):  The proportion of participants with 
either (1) CR or (2) PR by RECIST 1.1 criteria.   
• 
Survival:  The observed length of life from first dose of study drug to 
death or the date of last contact.   
• 
Time to treatment failure:  Is defined as the time from first study drug 
treatment until the participant is started on another line of systemic 
therapy or participant death, whichever occurs first.  Participants who 


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are alive and do not start another therapy will be censored at the time 
of last follow-up.   
Safety:  Safety assessments (vital signs, physical examinations, 
performance status, height/weight, electrocardiogram (ECG) recording, 
adverse events (AEs), clinical laboratory results (routine hematology and 
biochemistry, and CT and magnetic resonance imaging [MRI] scans) are 
to be performed at protocol-specified visits. 
Study Endpoints: 
Primary endpoints:  
• 
The response to combination ipilimumab/nivolumab and ipilimumab 
alone at Week 18 defined as having achieved a complete response or 
PR as measured by RECIST 1.1 criteria or a PR/complete response 
at any time prior to Week 18.   
Secondary endpoints:  
• 
Disease control rate (DCR) by RECIST v1.1 criteria of overall tumor 
burden at Week 12 and Week 18.  DCR is defined as participants who 
achieve SD, PR or complete response. 
• 
TTF and OS up to 2 years.  
• 
Safety and tolerability measured via metrics such as laboratory tests, 
vital signs, physical examinations as well as toxicity as graded by 
Common Terminology Criteria for Adverse Events v4.0.  
Exploratory endpoints:  
• 
All research samples for exploratory endpoints will be analyzed at a 
Parker Institute for Cancer Immunotherapy selected testing center.   
• 
Peripheral lymphocyte phenotype changes throughout treatment, 
including Treg cells, defined as CD4+FOX3P+ cells, will be expressed 
using descriptive statistics at pre and post treatment time points. 
These will be assessed via flow cytometry of peripheral blood 
mononuclear cells. 
• 
Changes in quantities of MDSCs, defined as CD14+HLA-DRlow 
cells, throughout treatment will be expressed using descriptive 
statistics at pre and post treatment time points.  
• 
nCounter immune profiling of the tumor before treatment will be 
expressed using descriptive statistics at pre and post treatment time 
points and will be correlated with clinical response also using logistic 
regression models. 
• 
Tumor neoepitopes and mutational burden will be correlated with 
clinical response also using logistic regression models. 
• 
Summary statistics will be generated and differences between 
mutation burden or neo-antigen score as they relate to PD-L1 
expression 
• 
Immunohistochemistry (IHC) will be used to assess PD-L1 
expression on both immune cells and tumor cells.  PDL-1 expression 
will be assessed pretreatment and on-treatment.  A participant will be 
PD-L1 + if >1% of cells express PD-L1. If response data permit, the 
tumor positivity of PD-L1 expression will be compared in the pre- 
and post-treatment biopsies using a Wilcoxon signed rank test. 
• 
Pre- and on- treatment PD-L1 expression and will be correlated with 
clinical response also using logistic regression models.  
• 
IHC will be used to quantify cytotoxic and regulatory T-cells, 
including stains for CD3, CD4, CD8, FOXP3, inducible 
co-stimulatory and Lag3.  Associations from pre to post treatment 
will be assessed using the Wilcoxon signed rank test for paired 


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comparisons (e.g., the continuous measure, density of cells per 
high powered field). 
Statistical Methods and 
Planned Analyses: 
This is a multi-center, randomized, Phase 2 study of ipilimumab and 
combined checkpoint blockade with ipilimumab and nivolumab.  
Randomization will be performed via a central process.  In each arm, an 
optimal Simon 2-stage design will be implemented.  A response rate of 
10% or less would not be considered promising (null hypothesis) as the 
ipilimumab response rate in untreated participants is 10.9%.  A response 
rate of at least 30% is promising (alternative hypothesis).  Point estimates 
and 95% confidence intervals for the response rates will be reported. Alpha 
(probability of Type I error) for hypothesis tests will be 0.1.  If 4 or more 
of 12 participants in an arm respond (response rate of 33% or greater), the 
treatment will be considered promising for further investigation. 
Efficacy evaluable population:  All participants who receive at least 
1 dose of study drug(s) will be evaluated for the primary endpoint.  
Participants who develop rapid symptomatic disease progression or drop 
out early due to death will be treated as non-responders.  Participants who 
develop early toxicities that require treatment delay or discontinuation will 
continue to be evaluable on study.  Participants may be replaced in either 
arm if they complete randomization but do not complete any cycles of 
therapy.   
The toxicity evaluable population:  Participants who have completed at 
least 1 treatment cycle on either arm will be considered evaluable for 
toxicity. 
Preferable treatment arm will be decided as follows:   
• 
If both arms have comparable response rates, the investigators will 
perform a comprehensive review of both the response data and 
toxicity data to decide which study arm is the preferable treatment 
moving forward.   
 


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2 
TABLE OF CONTENTS 
1 
SYNOPSIS ................................................................................................................ 14 
2 
TABLE OF CONTENTS ......................................................................................... 20 
IN-TEXT TABLES ........................................................................................... 24 
IN-TEXT FIGURES .......................................................................................... 25 
3 
LIST OF ABBREVIATIONS .................................................................................. 26 
4 
INTRODUCTION .................................................................................................... 28 
4.1 
Background on Melanoma .............................................................................. 28 
4.2 
Clinical Studies ............................................................................................... 30 
4.3 
Rationale......................................................................................................... 34 
5 
STUDY OBJECTIVES AND ENDPOINTS ............................................................ 35 
5.1 
Study Objectives ............................................................................................. 35 
5.1.1 
Primary Objective ............................................................................. 35 
5.1.2 
Secondary Objectives ....................................................................... 35 
5.1.3 
Exploratory Objectives ..................................................................... 36 
5.2 
Study Endpoints .............................................................................................. 36 
5.2.1 
Primary Endpoint ............................................................................. 36 
5.2.2 
Secondary Endpoints ........................................................................ 36 
5.2.3 
Exploratory Endpoints ...................................................................... 36 
6 
INVESTIGATIONAL PLAN ................................................................................... 37 
6.1 
Description of Overall Study Design and Plan ................................................. 37 
6.1.1 
Study duration .................................................................................. 38 
6.1.2 
Randomization ................................................................................. 38 
6.2 
Discussion of Study Design ............................................................................ 38 
7 
SELECTION AND WITHDRAWAL OF PARTICIPANTS.................................. 39 
7.1 
Inclusion Criteria ............................................................................................ 39 
7.2 
Exclusion Criteria ........................................................................................... 40 
7.3 
Withdrawal, Removal, and Replacement of Participants.................................. 41 
7.4 
Follow-Up for Drug Discontinuation/Participant Withdrawal from Study ....... 42 
8 
TREATMENTS ........................................................................................................ 42 
8.1 
Details of Study Treatments/Intervention ........................................................ 44 
8.1.1 
Ipilimumab ....................................................................................... 44 


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8.1.2 
Nivolumab ........................................................................................ 45 
8.2 
Toxicities / Side Effects .................................................................................. 46 
8.2.1 
Ipilimumab ....................................................................................... 46 
8.2.2 
Ipilimumab and Nivolumab .............................................................. 46 
8.3 
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions ............... 46 
8.4 
Intervention..................................................................................................... 48 
8.4.1 
Dosage and administration ................................................................ 48 
8.4.2 
Monitoring and Dose Delay Criteria ................................................. 48 
8.4.3 
Management Algorithms for Immune-related Adverse Events .......... 48 
8.4.4 
Dose Modifications .......................................................................... 48 
8.4.5 
Criteria to Resume Treatment ........................................................... 49 
8.5 
Blinding .......................................................................................................... 49 
8.6 
Treatment Accountability and Compliance ...................................................... 49 
9 
STUDY PROCEDURES .......................................................................................... 49 
9.1 
Participant Informed Consent .......................................................................... 52 
9.2 
Procedures by Study Visit or Period ................................................................ 52 
9.2.1 
Pretreatment Evaluation .................................................................... 52 
9.2.1.1 At any time prior to the start of the study drug .................... 52 
9.2.1.2 Within 4 weeks prior to the start of the study drug .............. 52 
9.2.2 
Within 2 Weeks Prior to the Start of the Study .................................. 52 
9.2.3 
Unscheduled Visits ........................................................................... 52 
10 
EFFICACY ASSESSMENTS .................................................................................. 53 
10.1 
Response in Solid Tumor Criteria 1.1 .............................................................. 53 
10.1.1 
Definitions of Measurable Disease .................................................... 53 
10.1.2 
Target” and “Non-Target” lesions ..................................................... 53 
10.1.2.1 Target Lesions .................................................................. 53 
10.1.2.2 Non-Target Lesions .......................................................... 53 
10.1.2.3 Lymph Nodes ................................................................... 53 
10.1.3 
Baseline Evaluation .......................................................................... 53 
10.1.4 
Repeat Evaluations ........................................................................... 53 
10.1.5 
Best Response .................................................................................. 54 
10.2 
Quantifying Clinical Correlates of Response ................................................... 54 
11 
SAFETY ASSESSMENTS ....................................................................................... 54 
11.1 
Adverse Events ............................................................................................... 54 


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11.1.1 
Definition of Non-serious Adverse Events ........................................ 54 
11.1.2 
Serious Adverse Events .................................................................... 55 
SAE Reporting to BMS and inVentiv .............................................................. 56 
11.1.3 
Pregnancy ......................................................................................... 57 
11.1.4 
Overdose .......................................................................................... 57 
11.1.5 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as Adverse Events or Serious Adverse Events ................. 57 
11.2 
Unanticipated Problems/Non-Compliance ....................................................... 58 
12 
STATISTICAL ANALYSIS .................................................................................... 59 
12.1 
Determination of Sample size ......................................................................... 59 
12.2 
Analysis Populations ....................................................................................... 59 
12.3 
Efficacy Analysis ............................................................................................ 60 
12.3.1 
Analysis of Primary Efficacy Endpoint ............................................. 60 
12.3.2 
Analysis of Secondary Efficacy Endpoints........................................ 60 
12.3.3 
Analysis of Exploratory Efficacy Endpoints ..................................... 60 
12.4 
Safety Analysis ............................................................................................... 61 
12.5 
Data Review Team .......................................................................................... 61 
13 
STUDY MANAGEMENT ........................................................................................ 61 
13.1 
Approval and Consent ..................................................................................... 61 
13.1.1 
Regulatory Guidelines ...................................................................... 61 
13.1.2 
Institutional Review Board/Independent Ethics Committee............... 61 
13.1.3 
Informed Consent ............................................................................. 61 
13.2 
Research Participant Registration .................................................................... 62 
13.3 
Data Handling ................................................................................................. 62 
13.4 
Source Documents .......................................................................................... 63 
13.5 
Record Retention ............................................................................................ 63 
13.6 
Monitoring ...................................................................................................... 63 
13.7 
Quality Control and Quality Assurance ........................................................... 64 
13.8 
Protocol Amendment and Protocol Deviation .................................................. 64 
13.8.1 
Protocol Amendment ........................................................................ 64 
13.8.2 
Protocol Deviations .......................................................................... 64 
13.9 
Ethical Considerations .................................................................................... 64 
13.10 Financing and Insurance.................................................................................. 64 


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13.11 Study and Site Closure .................................................................................... 65 
13.12 Publication Policy / Disclosure of Data ........................................................... 65 
14 
REFERENCES ......................................................................................................... 66 
15 
APPENDICES .......................................................................................................... 70 
15.1 
Appendix 1: Product Information and Pharmacy Manuals ............................... 70 
15.2 
Appendix 2:  Management Algorithms for Immuno-Oncology Agents ............ 74 
15.3 
Appendix 3: Laboratory Procedures ................................................................ 80 
15.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
 ....................................................................................................................... 83 
 


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IN-TEXT TABLES 
Table 1: Published Trials of Chemotherapy in Metastatic Melanoma ................................ 28 
Table 2: Details of Study Treatments/Intervention ............................................................ 44 
Table 3: Schedule of Assessments..................................................................................... 50 


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IN-TEXT FIGURES 
Figure 1: The Interaction between Antigen Presenting Cell and Cytotoxic T-cell via CTLA-4
 ........................................................................................................................... 30 
Figure 2: Kaplan-Meier Curves for Overall Survival and Progression Free Survival 
Demonstrating a Survival Benefit in Patients Treated with Ipilimumab vs gp100 
Vaccine Alone .................................................................................................... 31 
Figure 3: Primary Analysis of Pooled OS Data (3-year Survival Rate was 22%) ................ 32 
Figure 4: The Role of PD-1 in Early T-Cell Activation....................................................... 33 
Figure 5: Kaplan-Meier Curves for Overall Survival and Progression Free Survival 
Demonstrating a Survival Benefit in Patients Treated with Pembrolizumab Dosed 
Every Two or Three Weeks vs Ipilimumab ......................................................... 34 
Figure 6: Simplified randomization schema ....................................................................... 38 
 


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3 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration versus time curve 
BMS 
Bristol-Myers Squibb 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Peak concentration 
Cmin 
Trough concentration 
CMP 
Comprehensive metabolic panel 
CR 
Complete Response 
CRO 
Contract Research Organization 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease control rate 
DILI 
Drug induced liver injury 
DRT 
Data Review Team 
DSM 
Data and Safety Monitoring 
DTIC 
Dacarbazine 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EORTC 
European Organisation for Research and Treatment of Cancer 
FDA 
Food and Drug Administration 
FFPE 
Paraffin embedded blocks 
GCP 
Good Clinical Practice 
gp100 
Glycoprotein 100 
HBV 
Hepatitis B Virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C Virus 


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HIPAA 
Health Insurance Portability Accountability Act 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICOS 
Inducible co-stimulatory 
IDE 
Investigational Device Exemption  
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IV 
Intravenous 
IVR 
Interactive Voice Recognition 
LD 
Longest dimension 
LDH 
Lactate dehydrogenase 
MDSCs 
Myeloid derived suppressor cells 
MRI 
Magnetic resonance imaging 
MSKCC 
Memorial Sloan-Kettering Cancer Center 
NCI 
National Cancer Institute 
OR 
Objective response 
ORR 
Objective Response Rate 
OS 
Overall survival 
PBMCs 
Peripheral blood mononuclear cells 
PD 
Progressive Disease 
PD-1 
Programmed death receptor 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PPR 
Protocol Participant Registration 
PR 
Partial Response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SC 
Study Coordinator 
SD 
Stable Disease 
SEER 
Surveillance, Epidemiology, and End Results 
TEAE 
Treatment-emergent adverse events 
Tregs 
Regulatory T-cells 
TSH 
Thyroid-stimulating hormone 
TTF 
Time to treatment failure 
ULN 
Upper limit of normal 
WBC 
White blood cell 


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4 
INTRODUCTION 
4.1 
Background on Melanoma 
Epidemiology and Prognosis of Cutaneous Melanoma 
According to the Surveillance, Epidemiology, and End Results (SEER) database, there was an 
estimated 73,870 new cases of melanoma diagnosed in the United States in 2015.  There will 
be an estimated 9,940 deaths due to metastatic disease.  The incidence of melanoma continues 
to increase dramatically, at an overall rate of 33% for men and 23% for women from 2002 to 
2006.1  Approximately 9% of patients present with regional metastases (Stage III disease) and 
4% present with distant disease; however, patients with Stage III disease who have full surgical 
resection remain at an elevated risk of disease recurrence and death.  Data from our Center 
show that the 5-year relapse-free survival for Stage IIIC melanoma is 15%.2  Data from the 
SEER database demonstrates a 5-year overall survival (OS) rate of 16.6%.   
Chemotherapy in the treatment of metastatic melanoma 
Prior to the advent of immunotherapy, chemotherapy was the mainstay of treatment of 
metastatic melanoma.  Dacarbazine (DTIC) is the only single-agent chemotherapy approved 
by the Food and Drug Administration (FDA) for treating patients with metastatic melanoma, 
with an approximate 20% objective response rate, a median response duration of 5 to 6 months 
and complete response rates of 5%.3  Numerous agents were tried alone and in combination to 
treat metastatic melanoma as summarized in the chart below.  However, response rates were 
modest, ranging from 13.5% to 26%, and OS remained dismal, with median survival for the 
most part measured in months and the majority of patients surviving less than one year.  The 
lack of efficacy of traditional chemotherapy prompted research efforts to find alternative 
treatments.   
Table 1: Published Trials of Chemotherapy in Metastatic Melanoma 
Investigator 
Study Treatment 
Response Rate 
Overall 
Survival 
Progression-
Free Survival 
Wiernik et all,19934 
Paclitaxel 
16.4% 
NR 
NR 
Bajetta et al, 19945 
DTIC 
20% 
11 months 
NR 
Middleton et al, 20006 
DTIC, BCNU, Cisplatin 
and tamoxifen 
26.4% 
202 days 
NR 
Chapman et al, 19997 
DTIC, BCNU, Cisplatin 
and tamoxifen 
18.5% 
7 months 
NR 
Middleton et al, 20008 
Temozolomide 
13.5% 
7.7 months 
1.9 months 
Rao et al, 20069 
Carboplatin/paclitaxel 
26% 
7.8 months 
3 months 
Hersh et al, 201010 
Albumin-bound Paclitaxel  
2.7% in 
previously treated 
patients; 21.6% in 
chemo naïve 
patients 
12.1 months; 
9.6 months 
3.5 months; 
4.5 months 
Flaherty et al, 201311 
Carboplatin/paclitaxel/ 
Sorafenib 
20% 
11.3 months 
4.9 months 


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Early immunotherapy 
High dose interferon was the initial immunotherapy used in the adjuvant setting for patients 
with either Stage IIB or Stage III disease.  In the Eastern Cooperative Oncology Group (ECOG) 
1684 trial, 287 patients were randomly assigned to one year of high dose IFNa-2b or 
observation.  Treatment with high dose interferon resulted in a nine-month prolongation in 
relapse-free survival (RFS, median 1.7 versus 1.0 years) with an 11% absolute increase in RFS 
at five years (37% vs 26%).12  However, there was no difference in OS on later analysis.13 The 
RFS benefit of high dose interferon was confirmed in the intergroup E1690 trial which 
compared high dose IFNa to low dose IFNa vs observation, but again, no OS benefit was 
seen.14  In the EORTC 18991 trial, patients with Stage III melanoma were randomized to 
pegylated IFNa or observation.  The 7 year RFS was increased with IFNa compared with 
observation (39.1% vs 34.6%) but again there was no difference in OS.15  Interestingly, a recent 
meta-analysis of all patients treated with adjuvant IFNa did demonstrate an OS benefit.16 
In patients with metastatic disease, high dose IL2 demonstrated a clinical benefit.  In 
270 patients treated between 1985 and 1993, the objective response rate was 16%, including 
17 complete responses (CRs).17  Median duration of the CRs was greater than 59 months.18  
However, 6 patients (2%) died from adverse events (AEs), all related to sepsis.   
The tumor immune microenvironment 
There are a number of changes in the tumor immune microenvironment that are induced by 
both CTLA-4 and programmed death receptor (PD-1) blockade to inhibit adaptive immune 
resistance.  A clinical response to ipilimumab has been found to be associated with increased 
infiltration of tumor infiltrating lymphocytes 19 and of CD4 T cells expressing the inducible 
co-stimulatory (ICOS) molecule.19  CD8+ T cell expression at the invasive tumor margin has 
found to be predictive of response to PD-1 blockade21, as has a more clonal T-cell receptor 
repertoire.21  Interestingly, both classes of drugs are thought to decrease regulatory T-cells 
(Tregs) in the tumor microenvironment22,23 which may dampen a cytotoxic T cell response.   
Biomarkers for clinical response 
Expression of PD-L1 has been found to be an unreliable biomarker.24 The first Phase 1 trial 
with nivolumab demonstrated that only tumors that were PD-L1+ demonstrated an objective 
response rate (ORR)25; however, in another early phase trial of nivolumab, both PD-L1+ and 
PD-L1- patients responded, although PD-L1+ patients had a higher ORR, progression-free 
survival (PFS) and OS.26  In patients treated with MPDL3280A, a PD-L1 inhibitor, PD-L1 
expression on infiltrating immune cells but not tumor cells, was found to correlate with 
response.27   
Gene expression profiling 
There is growing interest in examining gene expression related to the immune response which 
may correlate with response to checkpoint blockade or provide new insights into mechanisms 
of immune escape.  Ribas and colleagues have found that two immune signatures analyzed 
using the NanoString nCounter were correlated with ORR and PFS.28  Tumors expressing 
PD-L1 also appear to have upregulation of pathways involved in CD8+ T-cell activation, 
antigen presentation and immunosuppression.29  Both studies underscore the importance of 
interferon-ɣ induced adaptive immune resistance as a mechanism of tumor escape.   


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4.2 
Clinical Studies 
Clinical development of CTLA-4 inhibitors 
Normally after T-cell activation, CTLA-4 is upregulated on the plasma membrane where it 
functions to downregulate T-cell function through a variety of mechanisms, including 
preventing co-stimulation by outcompeting CD28 for its ligand, B7 and also by inducing T-cell 
cycle arrest.   
Figure 1: The Interaction between Antigen Presenting Cell and Cytotoxic T-cell via 
CTLA-4  
 
Source:  Postow et al, JCO 2015 
On the basis of this preclinical rationale, an antibody targeting CTLA-4 now known as 
ipilimumab entered clinical development.  Early reports showed durable clinical responses in 
some patients.30-32  This was confirmed in two large Phase 2 trials.  In the first trial, ipilimumab 
was administered with or without a glycoprotein 100 (gp100) peptide vaccine vs. gp100 alone 
in patients with previously treated metastatic melanoma.  The median OS with ipilimumab 
alone was 10.1 months vs. 6.4 months among patients receiving gp100 alone (HR for death, 
0.68; p<.001).33  This represented a significant increase in median survival over chemotherapy 
alone, as discussed earlier. 


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Figure 2: Kaplan-Meier Curves for Overall Survival and Progression Free Survival 
Demonstrating a Survival Benefit in Patients Treated with Ipilimumab vs 
gp100 Vaccine Alone 
 
Source: Hodi et all, 2010 
In the second trial, patients with previously untreated metastatic melanoma were assigned to 
receive ipilimumab plus dacarbazine vs dacarbazine plus placebo.  Overall survival was 
significantly longer in the group receiving ipilimumab- dacarbazine vs dacarbazine plus 
placebo (11.2 months vs 9.1 months) with an associated OS advantage at three years (30.8% 
vs 12.2%).34 
The long-term survival advantage of ipilimumab has been confirmed in a pooled analysis of 
1,861 patients from 10 prospective and two retrospective studies.  Patients were both 
previously treated (n=1,257) or treatment naïve (n=604).  Overall median survival was 
11.4 months (95% confidence interval (CI), 10.7 to 12.1 months), which included 254 patients 
with at least three years of survival.  Three-year survival rates were 22%, 26%, and 20% for 


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all patients, treatment-naive patients, and previously treated patients, respectively.35  This long-
term survival rate demonstrated a marked improvement when compared to historical controls.  
Figure 3: Primary Analysis of Pooled OS Data (3-year Survival Rate was 22%) 
 
Source: Schadendorf et al, 2015 
 
Patients who have had progressive disease (PD) after initial treatment with ipilimumab have 
also been able to be successfully retreated with ipilimumab.36  The sum of this data led to its 
FDA approval for treatment of metastatic melanoma in March 2011. 
Clinical development of PD-1 inhibitors 
PD-1 is a negative regulator of T-cell activity that limits the activity of T cells at a variety of 
stages of the immune response when it interacts with its two ligands PD-L1 and PD-L2.37  PD-
1 is primarily believed to inhibit effector T-cell activity in the effector phase within tissues.  
This pathway is likely important in the tumor microenvironment where PD-L1 expressed by 
tumors interacts with PD-1 on T cells to suppress T-cell effector function by limiting T-cell 
receptor localization to the immunologic synapse at the site of target engagement.   


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Figure 4: The Role of PD-1 in Early T-Cell Activation 
 
Source: Postow et al, JCO 2015 
 
Anti-PD-1 antibodies have robust clinical activity, with a response rate of 17% in patients with 
metastatic melanoma in a Phase 1 multi-center study.40  This was confirmed in several larger 
studies.  In 107 patients with advanced melanoma who were treated with nivolumab, the ORR 
was 31% with a median OS of 16.8 months.  Among patients who had an objective response, 
the median response duration was two years.41  In another trial of patients who had previously 
received ipilimumab, patients who received pembrolizumab had a similar ORR of 26%.42 
Most recently, 834 patients were enrolled in a randomized Phase 3 study of ipilimumab vs 
pembrolizumab, dosed either every 2 or 3 weeks.  The ORR was 33.7% with pembrolizumab 
every 2 weeks, 33.9% every 3 weeks and 11.9% with ipilimumab (P<.001).  The 12-month OS 
rates were 74.1%, 68.4%, and 58.2%, respectively.43  The sum of these data lead to the FDA 
approval of both pembrolizumab and nivolumab for the treatment of metastatic melanoma.   


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Figure 5: Kaplan-Meier Curves for Overall Survival and Progression Free Survival 
Demonstrating a Survival Benefit in Patients Treated with Pembrolizumab 
Dosed Every Two or Three Weeks vs Ipilimumab 
 
Source: Robert et all, 2015 
Clinical development of combination checkpoint blockade 
Strong preclinical rationale for the combined evaluation of combined CTLA-4 and PD-1 
pathway blockade was provided by basic immunologic observations, which supported the 
notion that CTLA-4 and PD-1 are non-redundant pathways for regulation of T-cell responses.  
This hypothesis was first tested in a Phase 1 clinical trial of nivolumab plus ipilimumab in 
advanced melanoma.  The ORR in the concurrent treatment group was 40%, but 53% in the 
patients who were treated with the maximum doses with an acceptable level of adverse 
effects.44  This initial finding was confirmed in two Phase 3 trials in previously untreated 
patients.45,46 
4.3 
Rationale 
Checkpoint inhibitors enhance antitumor immunity by blocking negative regulators of T-cell 
function that exist both on immune cells and on tumor cells.  There are 2 classes of checkpoint 


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blockade currently FDA approved, CTLA-4 antibodies and PD-1 antibodies.  CTLA-4 and 
PD-1 are non-redundant pathways for the regulation of T-cell responses; CTLA-4 is believed 
to regulate immune responses early in T-cell activation, while PD-1 is believed to inhibit T-
cell effector function within the tissues.  Interestingly, both agents are thought to decrease 
regulatory T cells in the tumor microenvironment, which may dampen a cytotoxic T cell 
response.   
Ipilimumab blocks CTLA-4 and has a demonstrated survival benefit for patients with 
previously untreated advanced melanoma in two Phase 3 trials.33,34  Nivolumab is a PD-1 
antibody and has demonstrated a survival benefit both in patients with ipilimumab-refractory 
advanced melanoma 42,47 and in patients with previously untreated metastatic melanoma.41 
The two agents have demonstrated a synergistic effect, consistent with their various pathways, 
in a large clinical trial of combination checkpoint blockade with an overall response rate 
57.6%.47 
PD-1 inhibitors are increasingly being utilized in the first-line treatment setting for metastatic 
melanoma due to a more favorable response rate and side effect profile compared to 
ipilimumab.  However, as a result, there is no current standard of care for the 60% of patients 
who will have progressive or relapsed disease after single agent PD-1 blockade.  While the 
response rate of PD-1 inhibitors in patients previously treated with ipilimumab is well known, 
there is no data for the efficacy of ipilimumab as a second agent.  Moreover, combination 
checkpoint blockade has also never been tried in this population.   
We hypothesize that by administering a CTLA-4 antibody to this population of PD-1 inhibitor 
pre-treated patients, we will activate alterative T-cell activation pathways and deplete 
regulatory T cells in the tumor microenvironment, thus increasing immune activation and 
resulting in clinical efficacy.  We are interested in administering ipilimumab both as a single 
agent and in combination with nivolumab to explore whether dual checkpoint blockade 
synergy is as active in a pre-treated population as in a treatment-naïve population.  In addition, 
given the elevated toxicity rates associated with combination checkpoint blockade, it is 
important to assess toxicity profiles in both single and combined immunotherapy approaches 
in this pre-treated population.   
Thus, we propose this randomized, parallel single arm, 2-stage Phase 2 study to assess response 
rates to ipilimumab alone and in combination with nivolumab in participants who have 
progressed after anti-PD-1 therapy.   
5 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Study Objectives 
5.1.1 Primary Objective 
The primary objective is to assess response rates of combination ipilimumab/nivolumab and 
ipilimumab alone in participants previously treated with a PD-1 inhibitor by Week 18 of 
therapy. 
5.1.2 Secondary Objectives 
The Secondary Objectives are:  
• 
To assess clinical benefit of combination ipilimumab/nivolumab and ipilimumab alone 


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• 
To evaluate time to treatment failure and OS for each arm 
• 
To assess safety and tolerability of ipilimumab alone and in combination with 
nivolumab in previously treated participants. 
5.1.3 Exploratory Objectives 
• 
To evaluate peripheral lymphocyte phenotype changes throughout treatment  
• 
To evaluate changes in quantities of myeloid derived suppressor cells (MDSCs), 
defined as CD14+HLA-DRlow cells, and Treg cells, defined as CD4+FOX3P+ cells, 
throughout treatment  
• 
To evaluate nCounter immune profiling of the tumor before treatment  
• 
To explore tumor neoepitopes and mutational burden via whole gene and exome 
sequencing on pre-treatment tumor biopsy and correlation with clinical response 
• 
To stratify clinical response rate by PD-L1 expression on pre-treatment biopsies 
• 
To evaluate the tumor immune microenvironment on pre- and on-treatment tumor 
biopsies.  
5.2 
Study Endpoints 
5.2.1 Primary Endpoint  
The primary endpoint of this study is the response to combination ipilimumab/nivolumab and 
Ipilimumab alone at Week 18 defined as having achieved a complete response or partial 
response (PR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
criteria or a PR/complete response at any time prior to Week 18.   
5.2.2 Secondary Endpoints 
The secondary endpoints are as follows:   
• 
Disease control rate (DCR) by RECIST v1.1 criteria of overall tumor burden at 
Week 12 and Week 18.  DCR is defined as participants who achieve stable disease 
(SD), PR or complete response. 
• 
Time to treatment failure and OS up to two years 
• 
Safety and tolerability measured via metrics such as laboratory tests, vital signs, 
physical examinations as well as toxicity as graded by Common Terminology Criteria 
for AEs (CTCAE) v4.0.  
5.2.3 
Exploratory Endpoints 
The exploratory endpoints of this study are as follows:  
• 
All research samples for exploratory endpoints will be analyzed at a Parker Institute 
for Cancer Immunotherapy selected testing center.  Please see Appendix 3 for further 
information 
• 
Peripheral lymphocyte phenotype changes throughout treatment, including Treg cells, 
defined as CD4+FOX3P+ cells, will be expressed using descriptive statistics at pre 
and post treatment time points.  These will be assessed via flow cytometry of 
peripheral blood mononuclear cells (PBMCs). 
• 
Changes in quantities of MDSCs, defined as CD14+HLA-DRlow cells, throughout 
treatment will be expressed using descriptive statistics at pre and post treatment time 
points.  


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• 
nCounter immune profiling of the tumor before treatment will be expressed using 
descriptive statistics at pre and post treatment time points and will be correlated with 
clinical response also using logistic regression models. 
• 
Tumor neoepitopes and mutational burden will be correlated with clinical response 
also using logistic regression models. 
• 
Summary statistics will be generated and differences between mutation burden or neo-
antigen score as they relate to PD-L1 expression. 
• 
Immunohistochemistry (IHC) will be used to assess PD-L1 expression on both 
immune cells and tumor cells.  PDL-1 expression will be assessed pretreatment and 
on-treatment.  A participant will be PD-L1 + if >1% of cells express PD-L1.  If 
response data permit, the tumor positivity of PD-L1 expression will be compared in 
the pre- and post-treatment biopsies using a Wilcoxon signed rank test. 
• 
Pre- and on- treatment PD-L1 expression and will be correlated with clinical response 
also using logistic regression models.  
• 
IHC will be used to quantify cytotoxic and Tregs, including stains for CD3, CD4, CD8, 
FOXP3, ICOS and Lag3.  Associations from pre to post treatment will be assessed 
using the Wilcoxon signed rank test for paired comparisons (e.g., the continuous 
measure, density of cells per high powered field). 
6 
INVESTIGATIONAL PLAN 
6.1 
Description of Overall Study Design and Plan 
This is a multi-center, randomized, Phase 2 study of ipilimumab vs ipilimumab plus nivolumab 
in participants previously treated with a PD-1 inhibitor by Week 18 of therapy.   
There will be 2 treatment arms in this study.  
Arm A:  Participants will receive combination checkpoint blockade with ipilimumab and 
nivolumab.   
Arm B:  Participants in this arm will receive ipilimumab alone.  
A Simon 2-stage design will be implemented in each arm, allowing for early stopping for 
futility.  Participants who are eligible will be required to have a pre-treatment biopsy and then 
will be randomized to either ipilimumab alone or ipilimumab in combination with nivolumab.  
Participants will be required to have an on-treatment biopsy within 14±5 days of their first 
dose of treatment.  Participants will receive treatment for up to 4 cycles followed by 
observation phase.   
The primary objective is to determine the response rate of combination ipilimumab/nivolumab 
and ipilimumab alone in participants previously treated with a PD-1 inhibitor by Week 18 of 
therapy.  The total planned accrual is 12 participants in each arm.  Participants will be assessed 
for the primary endpoint at 18 weeks.  They will then be followed for TTF and OS for up to 
2 years.   
Secondary objectives include assessment of tolerability of ipilimumab and combination 
checkpoint blockade in previously treated participants as well as assessment of OS and time to 
treatment failure.   


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6.1.1 
Study duration 
Participants on both arms will receive treatment for up to 4 cycles and then be observed for up 
to 2 years.  After 2 years, all participants will go off study.   
6.1.2 
Randomization 
Randomization will be managed centrally using an interactive voice response (IVR) system.  
Participants will be randomized following their pre-treatment biopsy at Screening/Baseline 
Visit.  Participants will be stratified based on their previous response to PD-1 therapy (primary 
refractory vs progressive disease) and melanoma subtype.  The primary refractory and 
progressive disease cohorts are defined in Section 7.1 (inclusion criteria number 4).   
Figure 6 illustrates randomization schema:  
Figure 6: Simplified randomization schema 
 
Note: The on-treatment biopsy has a window of ±5 days.  
6.2 
Discussion of Study Design 
This is a multi-center, randomized, parallel single arm, 2-stage Phase 2 study of ipilimumab 
and combined checkpoint blockade with ipilimumab and nivolumab in participants with 
unresectable Stage III or Stage IV melanoma who have previously received monotherapy with 
a PD-1 inhibitor with progression of disease or relapsed disease.   
Checkpoint blockade has emerged as an effective therapeutic strategy for participants with 
advanced stage melanoma.  Checkpoint inhibitors enhance antitumor immunity by blocking 
negative regulators of T-cell function that exist both on immune cells and on tumor cells.  There 
are two classes of checkpoint blockade currently FDA approved, CTLA-4 antibodies and PD-1 
antibodies.  Ipilimumab blocks CTLA-4 and nivolumab is a PD-1 antibody.  In this study, 
participants will be administered ipilimumab both as a single agent and in combination with 
nivolumab to explore whether dual checkpoint blockade synergy is as active in a pre-treated 
population as in a treatment-naïve population.   


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A total of 24 participants will be enrolled in this study.  All participants will be followed up to 
2 years after receiving the last dose of study drug.   
7 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
Participants will be recruited by their medical, surgical, and radiation oncologist who 
encounter them in the clinical setting.  The clinical trial will be listed on the clinicaltrials.gov 
website and on the institution’s website.  Participants will be identified through internal 
referrals and external referrals by Medical and Surgical Oncologists nationally and 
internationally.  Participants will also be approached by the institution’s co-investigators.  
Every effort will be made to maximize recruitment of participants, including women and 
minorities.  The target population of participants include those who have previously received 
monotherapy with a PD-1 inhibitor with progression of disease or relapsed disease. Participants 
must meet the inclusion and exclusion criteria; no exceptions will be made for enrollment.  
7.1 
Inclusion Criteria 
All participants must meet all of the following criteria at screening and baseline to participate 
in the study:  
1. AJCC (2009) Stage IV cutaneous melanoma or Stage III cutaneous, acral or mucosal 
melanoma that is judged inoperable.  Participants with a history of uveal melanoma are 
not eligible.   
2. Measurable disease, defined as at least one lesion that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as >20 mm with conventional 
techniques or as >10 mm with computerized tomography (CT) scan.  Participants must 
have at least one measurable lesion by RECIST and a separate lesion amenable to biopsy.   
3. Histologic proof of melanoma reviewed and confirmed by the enrolling site.  
4. Previous treatment with a PD-1 or PD-L1 inhibitor with documented progression of 
disease on most recent CT scan.  Progression of disease is defined as 1) the appearance of 
a new measurable lesion (>10 mm) on cross-sectional imaging or physical examination 
OR 2) enlargement of previously detected lesions on two consecutive imaging studies OR 
3) enlargement of a previously detected lesion with correlative symptomatology on one 
cross-sectional imaging study.  Participants remain eligible if they had a previous response 
to a PD-1 inhibitor, including participants who had a complete response, PR or SD.  Any 
participant who had refractory or relapsed disease is eligible for study enrollment. 
Treatment populations are defined in Section 12. 
5. Participants who received adjuvant PD-1 therapy who then develop measurable disease 
are eligible.  However, they must have received their last dose of PD-1/PD-L1 blockade 
within two months of enrollment in this study.  They will be stratified with participants 
who have primary progressive disease.  
6. Life expectancy of greater than 3 months. 
7. Age ≥ 18 years old. 
8. ECOG performance status = 0 or 1 or Karnofsky Performance Status equivalent 
9. Participants must have adequate organ and marrow function as defined below: 
a. White blood cells (WBC) >2, 000/mcL 
b. Absolute neutrophil count >1,500/mcL 
c. Platelets >100,000/mcL 


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d. Hemoglobin > 9.0 g/dL  
e. Total bilirubin ≤ 1.5 X institution’s upper limit of normal 
f. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase)/alanine 
aminotransferase (ALT) (serum glutamic pyruvic transaminase) ≤ 2.5 X institution’s 
upper limit of normal for participants with no concurrent liver metastases, OR≤ 5 X 
institution’s upper limit of normal for participants with concurrent liver metastases 
g. Serum creatinine < 1.5x OR creatinine clearance of at least 40 
10. Women of childbearing potential must have a negative serum pregnancy test within 
24 hours prior to the start of study drug.  A woman of childbearing potential is defined as 
any female who has experienced menarche and who has not undergone surgical 
sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal.  
Menopause is defined clinically as 12 months of amenorrhea in a woman over age 50 in 
the absence of other biologic or physiologic causes.  
11. Women with child bearing potential and men with reproductive potential must be willing 
to practice acceptable methods of contraception. 
12. Ability to understand and the willingness to sign a written informed consent document.  
13. Willingness to undergo biopsy of metastatic site or site of unresectable disease prior to 
randomization.  
7.2 
Exclusion Criteria 
Participants meeting any of the following criteria are ineligible to participate in this study: 
1. Concurrent malignancies: 
a. Participants with a previously treated malignancy are eligible to participate if all 
treatment of that malignancy was completed at least 2 years before registration and 
the participant has no evidence of disease. 
b. Participants who have a concurrent malignancy that is clinically stable and does not 
require tumor-directed treatment are eligible to participate if the risk of the prior 
malignancy interfering with either safety or efficacy endpoints is very low (with 
agreement from the sponsor and PI). 
c. Other malignancies may be permitted if the risk of the prior malignancy interfering 
with either safety or efficacy endpoints is very low (with agreement from the sponsor 
and PI). 
2. Any major surgical procedures or external beam radiotherapy within 14 days prior to study 
drug administration.  
3. Use of other investigational drugs within 28 days prior to study drug administration.   
4. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.  
Treated brain metastases must have been stable for at least 1 month and require treatment 
with less than 10 mg/day prednisone equivalent for at least two weeks prior to study drug 
administration.   
5. Prior exposure to either ipilimumab or combined checkpoint blockade.  
6. Any diagnosis of autoimmune disease.  Participants with Type I diabetes mellitus, 
hypothyroidism only requiring hormone replacement, adrenal insufficiency on 
replacement dose steroids, skin disorders (such as vitiligo, psoriasis or alopecia) not 
requiring systemic treatment, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll.   
7. Pregnant women and lactating women.  


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8. History of uveal melanoma.  
9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C 
Virus (HCV) infection (with the exception of chronic or cleared HBV or HCV infection, 
which will be allowed).  Once-documented negative result for HIV, HBV, and HCV is 
sufficient.   
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
and psychiatric illness/social situations that would limit compliance with study 
requirements.   
11. Participants with a condition requiring systemic treatment with either corticosteroids 
(>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 
days of study drug administration.  Inhaled or topical steroids and adrenal replacement 
steroid doses >10 mg daily prednisone equivalent are permitted.  
12. Participants with history of any grade 4 toxicity during previous anti PD-1 treatment or 
history of Grade 3 or higher pneumonitis.  
13. Participants with a history of grade ≥2 neuropathy.  
14. Prisoners or participants who are involuntarily incarcerated.  
15. Children under the age of 18.   
16. Participants who require hemodialysis.  
17. Participants with a history of allergy to study drug components or history of a severe 
hypersensitivity reaction to any monoclonal antibody.   
7.3 
Withdrawal, Removal, and Replacement of Participants 
A participant may voluntarily withdraw or be withdrawn from the study at any time for reasons 
including, but not limited to, the following:  
• 
Progression of disease: Either unequivocal symptomatic progression necessitating a 
change in therapy in the opinion of the treating physician or radiologic progression as 
defined by cross-sectional imaging utilizing RECIST 1.1 criteria.   
• 
Treatment Cessation: Discontinuation criteria apply for all drug-related AEs attributed 
to nivolumab, ipilimumab or both.  Treatment with all study drugs should be 
permanently discontinued for the following:  
o 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 
o Any Grade 3 non-skin, drug-related AE, with the following exceptions: 
• Grade 3 diarrhea lasting <7 days 
• Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except 
Ø Grade 3 drug-related thrombocytopenia >7 days or associated with 
bleeding requires discontinuation 
Ø Any drug-related liver function test abnormality that meets the 
following criteria requires discontinuation: 
§ AST or ALT >8 x upper limit of normal (ULN) 
§ Total Bilirubin >5x ULN 
§ Concurrent AST or ALT and total bilirubin >2x ULN 
o Any Grade 4 drug-related AE or laboratory abnormality, except for the following 
events which do not require discontinuation. 


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• Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis. 
• Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset 
o Any dosing interruption lasting >6 weeks with the following exceptions: 
• Dosing interruptions to allow for prolonged steroid tapers to manage drug-
related AEs are allowed.   
• Dosing interruptions >6 weeks that occur for non-drug related may be allowed 
if approved by the primary Investigator 
o Any AE, laboratory abnormality or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued 
drug dosing.   
• 
Withdrawal of consent: Participant may withdraw consent at any time.   
• 
Death 
• 
Screening Failure: If, at any point after enrollment, the PI determines that the 
participant does not meet all inclusion criteria or meets any exclusion criteria. 
Rescreening is permitted. 
7.4 
Follow-Up for Drug Discontinuation/Participant Withdrawal from Study 
If a participant discontinues study treatment and is withdrawn from the study for any reason, 
the study site must immediately notify the medical monitor.  The date and the reason for study 
discontinuation must be recorded on the electronic case report form (eCRF).  Participants who 
withdraw prematurely are to attend an Early Termination Visit, if possible, and complete all 
assessments. 
In the event that a participant discontinues prematurely from the study due to a 
treatment-emergent adverse events (TEAE) or serious TEAE, the TEAE or serious TEAE will 
be followed until it resolves (returns to normal or baseline values) or stabilizes, or until it is 
judged by the Investigator to be no longer clinically significant.   
Once a participant is withdrawn from the study, the participant may not re-enter the study. 
8 
TREATMENTS 
Participants will be screened for enrollment.  If they meet all inclusion criteria and do not meet 
exclusion criteria, they will be referred for pre-treatment biopsy of either an unresectable lesion 
or a metastatic lesion.  After biopsy, each participant will be randomized either to Arm A 
(combination ipilimumab and nivolumab) or Arm B (ipilimumab alone). 
Arm A: 
• 
Participants will be required to start treatment within 14 days of their pre-treatment 
biopsy.  The pre-treatment biopsy is considered standard of care. 
• 
One dose of ipilimumab and nivolumab administered together constitutes one cycle; 
they will be administered in the manner described in Section 8.4. 
• 
Cycles will be administered every 21 days±4 days for up to 4 cycles.  


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• 
CT scans will be administered at weeks 12 and 18 and every 12 weeks for up to 2 years 
after study treatment begins.  These are considered standard of care. 
• 
Blood will be drawn at every cycle during treatment and during follow-up visits.  
Standard bloodwork, such as complete blood count (CBC) and comprehensive 
metabolic panel (CMP), are part of routine care.  Other bloodwork (approximately 
40 mL) will be drawn which is solely for the purpose of research. 
• 
An on-treatment biopsy will be required within 14 days ± 5 days of the start of Cycle 1.  
This is solely for the purpose of research.  All reasonable efforts will be made to biopsy 
the same lesion pre- and on-treatment.   
Arm B:  
• 
Participants will be required to start treatment within 14 days of their pre-treatment 
biopsy.  The pre-treatment biopsy is considered standard of care. 
• 
One dose of ipilimumab constitutes one cycle; it will be administered in the manner 
described in Section 8.4.  
• 
Cycles will be administered every 21±4 days for up to 4 cycles.  
• 
CT scans will be administered at weeks 12 and 18 and every 12 weeks for up to 2 years 
after study treatment begins.  These are considered standard of care. 
• 
Blood will be drawn at every cycle during treatment and during follow-up visits.  
Standard bloodwork, such as CBC and CMP, are part of routine care.  Other 
bloodwork (approximately 40 mL) will be drawn which is solely for the purpose of 
research.   
• 
An on-treatment biopsy will be required within 14 days ± 5 days of the start of Cycle 1.  
This is solely for the purpose of research.  All reasonable efforts will be made to biopsy 
the same lesion pre- and on-treatment.   
Basic information about the study treatments is provided in Table 2. 


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Table 2: Details of Study Treatments/Intervention 
Product Description 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label 
Type 
Secondary 
Packaging 
(Qty) /Label 
Type 
Appearance 
Storage 
Conditions 
(per label) 
Nivolumab 
BMS-936558-01 
Solution for 
Injectiona 
100 mg 
(10 
mg/mL) 
10 mL vial 5-10 vials per 
carton/ Open-
label 
Clear to 
opalescent 
colorless to pale 
yellow liquid. 
May contain 
particles 
2 to 8°C. 
Protect form 
light and 
freezing 
Ipilimumab 
Solution for 
Injection 
200 mg (5 
mg/mL) 
40 mL vial 4 vials per 
carton/Open-
label 
Clear, colorless to 
pale yellow liquid. 
May contain 
particles 
2 to 8°C. 
Protect from 
light and 
freezing. 
a Nivolumab may be labeled as BMS-936558-01 Solution for Injection 
If stored in a glass front refrigerator, vials should be stored in the carton.  Recommended safety 
measures for preparation and handling of nivolumab and ipilimumab include laboratory coats 
and gloves.  Please see Appendix 1 for further information.   
Storage Conditions and Handling: 
Ipilimumab injection may be stored undiluted, 200 mg/vial (5 mg/mL), or following dilution 
to concentrations between 1 mg/mL and 4 mg/mL in 0.9% Sodium Chloride Injection (USP), 
or 5% Dextrose Injection (USP) in PVC, non-PVC/ or glass containers for up to 24 hours in 
the refrigerator (2°C to 8°C) or at room temperature/room light.  For longer storage, 
ipilimumab should be kept refrigerated (2°C to 8°C) with protection 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.   
8.1 
Details of Study Treatments/Intervention 
8.1.1 Ipilimumab 
Mechanism of Action:  CTLA-4 is a negative regulator of T-cell activity.  Ipilimumab is a 
monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its 
ligands, CD80/CD86.  Blockade of CTLA-4 augments T-cell activation and proliferation, 
including the activation and proliferation of tumor infiltrating T-effector cells.  Inhibition of 
CTLA-4 can also reduce T-regulatory cell function, which may contribute to a general increase 
in T cell responsiveness, including the anti-tumor immune response.   
Storage and formulation:  Ipilimumab currently comes packaged in a concentrated form in 
either a 50 mg (5 mg/mL) or 200 mg (5 mg/mL) single use vial.  This concentrated solution 
should be diluted with 0.9% Sodium Chloride or 5% Dextrose Injection to prepare a diluted 


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solution with a final concentration ranging from 1 mg/mL to 2 mg/mL.  Ipilimumab must be 
stored at 2°-8°C.  Vials should be protected from light and should not be frozen.   
Pharmacokinetics:  The pharmacokinetics of ipilimumab were studied in 785 patients with 
unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 
three weeks for 4 doses.  Peak concentration (Cmax), trough concentration (Cmin), and area under 
the plasma concentration versus time curve (AUC) of ipilimumab increased dose 
proportionally within the dose range examined.  Upon repeated dosing every 3 weeks, the 
clearance (CL) of ipilimumab was found to be time-invariant, and systemic accumulation was 
1.5-fold or less.  Steady-state concentrations of ipilimumab were reached by the third dose; the 
mean Cmin at steady-state was 19.4 mcg/mL following repeated doses of 3 mg/kg.  The mean 
value for terminal half-life was 15.4 days and for CL was 16.8 mL/h.   
Administration:  Ipilimumab will be mixed, stored and administered as per commercial 
guidelines.   
8.1.2 Nivolumab 
Mechanism of Action:  Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor 
found on T-cells, inhibits T-cell proliferation and cytokine production.  Upregulation of PD-1 
ligands occur in some tumors and signaling through this pathway can contribute to inhibition 
of active T-cell immune surveillance of tumors.  Nivolumab is a human immunoglobulin G4 
monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and 
PD-L2, releasing the PD-1 pathway-mediated inhibition of the immune response, including the 
anti-tumor immune response.   
Storage and formulation:  Nivolumab currently comes packaged in a concentrated form in 
either a 40 mg (10 mg/mL) or 100 mg (10 mg/mL) single use vial.  This concentrated solution 
should be diluted with 0.9% Sodium Chloride or 5% Dextrose Injection to prepare a diluted 
solution with a final concentration ranging from 1 mg/mL to 10 mg/mL.  Nivolumab must be 
stored at 2°-8°C.  Vials should be protected from light and should not be frozen.  
Pharmacokinetics:  The pharmacokinetics of nivolumab was studied in 909 patients over a 
dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses every 2 or 
3 weeks.  The exposure to nivolumab increased dose proportionally over the dose range of 0.1 
to 10 mg/kg administered every 2 weeks.  The mean CL is 9.5 mL/h and mean elimination 
half-life is 25.7 days.  Steady-concentrations of nivolumab were reached by 12 weeks when 
administered at 3 mg/kg every 2 weeks and systemic accumulation was approximately 3-fold.   
Administration:  Nivolumab will be mixed, stored and administered as per commercial 
guidelines. 


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8.2 
Toxicities / Side Effects 
8.2.1 Ipilimumab 
Likely Side Effects:  Diarrhea, inflammation of the colon (colitis), increase in liver enzymes, 
fatigue, skin itchiness, skin rash, nausea, abdominal pain, decreased appetite, fever, vomiting, 
headache, constipation, adrenal gland abnormalities, and thyroid gland abnormalities.  
Less Likely Side Effects:  Chills, weakness, muscle pain, and redness of skin.  
Rare Side Effects:  Decrease or total loss of hormones of pituitary gland, allergic reactions, 
inflammation of the liver, inflammation of the pituitary gland, decreased red blood cells, loss 
of color (pigment) from areas of skin, decreased or blurry vision, or inflammation of the eye, 
numbness or tingling in your fingers or toes, inflammation or loss of the lining of the brain or 
spinal cord, inflammation of the kidneys, and joint pain.  
8.2.2 Ipilimumab and Nivolumab 
Likely Side Effects:  Diarrhea, inflammation of the colon (colitis), increase in liver enzymes, 
fatigue, swelling of the extremities, flu-like feeling, pain, skin itchiness, skin rash or xerosis 
(increased dryness), vitiligo (loss of pigment or color in the skin), nausea, abdominal pain, 
decreased appetite, fever, vomiting, constipation, flatulence, dry mouth, weight loss, cough, 
shortness of breath, headache, peripheral neuropathy (numbness or tingling of the fingers or 
toes), dizziness, change in sensation of taste, joint pain or stiffness, dehydration, increased 
blood sugar, low sodium levels, infections, inflammation of the optic disc, low blood pressure, 
and difficulty sleeping.   
Less Likely Side Effects:  inflammation of the pancreas, decreased movement of the intestines, 
inflammation of the thyroid, lung inflammation (pneumonitis), shortness of breath, joint 
swelling, muscle soreness, weakness, stiffness, or spasm, adrenal gland abnormalities, 
inflammation of the heart or lining of the heart, acute kidney injury or failure, and increase in 
inflammatory blood proteins.   
Rare Side Effects:  
• 
Myasthenia gravis, a nerve disease that may cause weakness of the eye, face, breathing 
and swallowing muscles.  One death in a patient who received the combination was 
considered due to myasthenia gravis and severe infection (sepsis) 
• 
A syndrome associated with fever, WBC activation and abnormal function (including 
destruction of other blood cells by WBCs), low blood cell counts, rash, and 
enlargement of the spleen. 
8.3 
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions 
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions.  However, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritus, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms.  
All Grade 3 or 4 infusion reactions should be reported as an serious adverse event (SAE) if 
criteria are met.  Infusion reactions should be graded according to National Cancer Institute 
(NCI) CTCAE 4.00 guidelines.  


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Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate:  
For Grade 1 symptoms: infusion interruption not indicated; intervention not indicated 
Remain at bedside and monitor participant until recovery from symptoms.  The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen 325 to 1000 mg at least 30 minutes before additional 
nivolumab administrations. 
For Grade 2 symptoms: requires therapy or infusion interruption but responds promptly to 
symptomatic treatment (e.g., antihistamines, non-steroidal anti-inflammatory drugs, narcotics, 
corticosteroids, bronchodilators, intravenous [IV] fluids); prophylactic medications indicated 
for 24 hours.  
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat 
the participant with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 
1000 mg; remain at bedside and monitor participant 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 participant closely.  If symptoms recur 
then no further nivolumab or ipilimumab will be administered at that visit.  Administer 
diphenhydramine 50 mg IV, and remain at bedside and monitor the participant until resolution 
of symptoms.  The amount of study drug infused must be recorded on the eCRF.  The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen 325 to 1000 mg should be administered at least 
30 minutes before additional nivolumab or ipilimumab 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: 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: life threatening; pressor or ventilatory support 
indicated.  
Immediately discontinue infusion of nivolumab or ipilimumab.  Begin an IV infusion of 
normal saline, and treat the participant 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.  Participant should be 
monitored until the Investigator is comfortable that the symptoms will not recur.  Nivolumab 
or ipilimumab will be permanently discontinued.  Investigators should follow their institutional 
guidelines for the treatment of anaphylaxis.  Remain at bedside and monitor participant until 
recovery from symptoms. In the case of late-occurring hypersensitivity symptoms (e.g., 
appearance of a localized or generalized pruritus within 1 week after treatment), symptomatic 
treatment may be given (e.g., oral antihistamine, or corticosteroids).   


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8.4 
Intervention 
8.4.1 Dosage and administration  
Both nivolumab and ipilimumab will be stored, mixed and administered as per published 
commercial guidelines (please see Appendix 1).  For participants in the combination arm, 
nivolumab will first be administered intravenously at a dose of 1 mg/kg of body weight over a 
period of approximately 60 minutes, once every 3 weeks for 4 doses.  Approximately 
30 minutes after the completion of each nivolumab infusion, participants will receive 3 mg/kg 
of ipilimumab over a period of approximately 30 minutes.  
In the ipilimumab monotherapy group, participants will receive 3 mg/kg of ipilimumab over a 
period of approximately 30 minutes once every 3 weeks for 4 doses.   
8.4.2 Monitoring and Dose Delay Criteria 
Participants should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and laboratory test values are acceptable.  If toxicity occurs as indicated 
below, participants in both study arms should have study drug(s) held.  In participants who are 
in the combined treatment arm, both drugs should be held for any toxicity.  Dose delays are 
designed to maximize treatment for those who derive clinical benefit from treatment while 
ensuring participant safety. Participants should follow timed assessments, and continuation on 
study is at the PI’s discretion.  
Nivolumab and/or ipilimumab administration should be delayed for the following reasons: 
• 
Grade ≥2 non-skin, drug-related AEs with the following exceptions: 
o Grade 2 drug-related fatigue or laboratory abnormalities do not require 
a treatment delay 
• 
Any Grade 3 skin, drug-related AE 
• 
Any Grade 3 drug-related laboratory abnormalities with the following exceptions for 
lymphopenia, leukopenia, AST, ALT or total bilirubin 
o Grade 3 lymphopenia or leukopenia does not require dose delay 
o If a participant has a baseline AST, ALT or total bilirubin that is 
within normal limits, delay dosing for drug-related Grade ≥2 toxicity 
o If a participant has a baseline AST, ALT or total bilirubin that is 
within the Grade 1 toxicity range, delay dosing for drug-related 
Grade ≥3 toxicity 
• 
Any AE, laboratory abnormalities, or intercurrent illness, which in the judgment of the 
Investigator warrants delaying the dose of study drug. 
8.4.3 Management Algorithms for Immune-related Adverse Events 
Immuno-oncology agents are associated with AEs that can differ in severity and duration from 
AEs caused by other therapeutic classes.  Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity.  Immune-related AEs will be 
managed as per published guidelines.  Please see Appendix 2 for further details. 
8.4.4 Dose Modifications 


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Nivolumab and ipilimumab dose reductions and escalations are not permitted in either study 
arm.   
8.4.5 Criteria to Resume Treatment 
Criteria to resume treatment apply for all drug-related AEs attributed to nivolumab, ipilimumab 
or both.  Participants may resume treatment with study drug(s) when the drug-related AEs 
resolve to Grade ≤1 or baseline value with the following exceptions: 
• 
Participants may resume treatment in the presence of Grade 2 fatigue 
• 
Participants who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity  
• 
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment 
• 
See Appendix 2 for detailed management algorithms of irAEs 
8.5 
Blinding 
Not Applicable.  
8.6 
Treatment Accountability and Compliance 
Administration of study drugs will be supervised by study personnel or assigned infusion room 
nursing staff, who will monitor compliance.  Study drugs accountability will be maintained in 
the Pharmacy Source documents i.e. accountability logs or in the study master file, as required.   
9 
STUDY PROCEDURES 
Table 3 outlines the timing of procedures, and assessments to be performed throughout the 
study.  See Sections 9.1 to 9.2.3 for additional details of study procedures.   
 


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Table 3: Schedule of Assessments 
  
Baseline/ 
Screeninga 
Cycle 1b 
Cycle 2 
Cycle 3 
Cycle 4 
Follow-up 
Visit 1 
and 2d 
Additional  
Follow-up 
Visitse 
Early 
Termination 
Visitf 
Obtain Informed Consent 
X 
  
  
  
  
  
  
 
Participant History 
X 
  
  
  
  
  
  
 
Inclusion/Exclusion 
criteria 
X 
  
  
  
  
  
  
 
Biopsy of Target Lesionc 
X 
 X 
  
  
  
 
  
 
Prior/concomitant 
medications 
Collected from Screening to Follow-up 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
 
X 
Performance status 
X 
X 
X 
X 
X 
X 
 
X 
Height/Weight 
X 
X 
X 
X 
X 
X 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
X 
Complete Blood Count 
X 
X 
X 
X 
X 
X 
 
X 
Complete Metabolic Panel, 
LDH 
X 
X 
X 
X 
X 
X 
 
X 
Thyroid function testingg 
X 
X 
X 
X 
X 
 X 
  
X 
Pregnancy test (serum) 
X 
 X 
 X 
 X 
 X 
 X 
  
X 
HCV, HBV, HIV Testing 
X 
  
  
  
  
  
  
 
CT scanh 
X 
  
  
  
X 
X 
  
X 
MRI Brain 
X 
 
 
 
 
 
 
 
ECG 
X 
  
  
  
  
  
  
 
Adverse Events 
Collected from consent to 100 days after drug discontinuation 
 
Drug Administration 
 
 X 
 X 
 X 
 X 
  
  
 
Research blood (~40mL) 
X 
X 
X 
X 
X 
X 
  
X 


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PD-L1 expression on 
banked tumor specimen if 
available 
X 
 
 
 
 
 
 
 
Survival Data 
  
  
  
  
  
X 
X 
X 
aScreening assessments are recommended to be performed within 28 days prior to treatment unless otherwise specified above 
bEach cycle=21 days±4 days  
cBiopsy at baseline for all participants within 14 days of Cycle 1, Day 1.  On-treatment biopsy must be performed within 14 days±5 days of 
first dose of study drug. 
dFollow up period begins when the last dose of study therapy is administered.  Follow-up visit 1=21 days from last dose ± 7 days.  Follow-up 
visit 2=42 days from last dose ± 7 days. If the participant completed follow-up visit 1 and follow-up visit 2 and has progressed, the participant 
is not required to have scans every 12 weeks. Survival could be assessed via calls every 3 months (±7 days). If a participant is off treatment and 
has not progressed, they would continue to visit the site and have scans every 12 weeks. 
eAdditional follow-up visits will be scheduled every 3 months ±7 days.  For participants who end treatment for toxicity, scans should continue 
every 12 weeks until progression of disease. After progression of disease, survival calls will occur every 3 months (±7 days). 
fFor participants who terminate the study early, follow-up will begin 21 days from the last dose (follow-up visit 1). 
gTSH will be checked at every visit and will reflex to check free T4 if abnormal. 
hPer standard of care to provide data for RECIST measurements as appropriate for each participant per the investigator physician. CT scans 
will be performed at baseline (-7 days), Week 12, Week 18, and every 12 weeks (±7 days) thereafter until progression of disease, death, or end 
of study for up to 2 years.  A CT scan of the chest, abdomen and pelvis or an MRI of the abdomen and pelvis plus a non-contrast CT of the 
chest are acceptable. 


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9.1 
Participant Informed Consent 
Prior to performing any study-related procedures, the Investigator (or his/her designated staff 
member) will obtain written informed consent from the participant.  After informed consent is 
obtained, the participant will be registered on study and begin “Screening/Baseline” 
evaluation.  They will be monitored for AEs and clinical progression.  They will continue to 
be followed periodically utilizing phone, email, fax, or postal mail for OS data for up to 2 years.   
9.2 
Procedures by Study Visit or Period 
9.2.1 Pretreatment Evaluation 
The following procedures and assessments must be performed prior to treatment start.  All 
intervals are defined with respect to Cycle 1, Day 1 of treatment.   
9.2.1.1 At any time prior to the start of the study drug 
• 
Histologic confirmation of melanoma by the institution’s pathologist.  
9.2.1.2 Within 4 weeks prior to the start of the study drug 
• Written Informed Consent 
• A contrast-enhanced CT or magnetic resonance imaging (MRI) of the brain as well as 
of the chest, abdomen and pelvis.  A CT scan of the chest, abdomen and pelvis or an 
MRI of the abdomen and pelvis plus a non-contrast CT of the chest are acceptable. 
• Electrocardiogram (ECG) 
9.2.2 Within 2 Weeks Prior to the Start of the Study 
• Updated medical history and physical examination including measurement of vital 
signs and ECOG performance status 
• Medication review 
• Complete blood count, comprehensive metabolic panel, thyroid stimulating hormone 
(TSH) and free T4 
• HIV enzyme-linked immunosorbent assay, HBV Core antibody, HBV surface 
antigen, HCV antibody.  HIV consent will be obtained and documented as per the 
institution’s guidelines. 
• Serum beta-human chorionic gonadotropin for women of child-bearing potential 
(defined as women less than 55 years of age) 
• Fresh core biopsy of target lesion that obtains a goal of 4 adequate cores, with 2-3 
considered acceptable or excisional biopsy.   
9.2.3 Unscheduled Visits 
The Investigator may at his/her discretion arrange for a participant to have an unscheduled 
assessment, especially in the case of AEs that require follow-up or an AE considered by the 
Investigator to be possibly related to the use of study drug.  The unscheduled visit page in the 
eCRF must be completed.   


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10 EFFICACY ASSESSMENTS 
10.1 Response in Solid Tumor Criteria 1.1 
10.1.1 Definitions of Measurable Disease 
Measurable disease is defined as at least 1 target lesion, i.e. one that can be accurately measured 
in at least 1 dimension (longest dimension to be recorded).  Each lesion must be 10 mm in 1 
short axis as measured on CT or MRI; lymph nodes must be at least 15 mm in short axis.  
10.1.2 Target” and “Non-Target” lesions 
10.1.2.1 Target Lesions 
All measurable lesions up to a maximum of 5 lesions representative of all involved organs 
should be identified as target lesions and recorded and measured at baseline.  Target lesions 
should be selected on the basis of their size (lesions with the longest dimension) and their 
suitability for accurate repetitive measurements.  
A sum of the longest dimension (LD) for all target lesions will be calculated and reported as 
the baseline sum LD.  The baseline sum LD will be used as reference to further characterize 
the objective tumor response of the measurable dimension of the disease. 
10.1.2.2 Non-Target Lesions 
All other lesions or sites of disease should be identified as non-target lesions and should also 
be recorded at baseline.  Measurements are not required and these lesions should be followed 
as “present” or “absent”.   
10.1.2.3 Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the 
nodes regress to below 10mm on study.  This means that when lymph nodes are included as 
target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of <10mm.  Case report forms or 
other data collection methods may therefore be designed to have target nodal lesions recorded 
in a separate section where, in order to qualify for CR, each node must achieve a short axis < 
10mm.  For PR, SD and PD, the actual short axis measurement of the nodes is to be included 
in the sum of target lesions. 
10.1.3 Baseline Evaluation 
Baseline disease status should be assessed with cross-sectional imaging (CT with contrast 
preferred) as close as possible to the start of therapy and never more than 28 days before the 
beginning of therapy.  If iodinated contrast dye is contraindicated, an MRI with gadolinium 
may substitute for the abdomen and pelvis, but a CT chest without contrast must also be 
performed.   
10.1.4 Repeat Evaluations 
Repeat Evaluations are periodic measurements of disease burden must be assessed utilizing 
the same cross-sectional imaging modalities as baseline.  Participants who do not undergo 


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repeat assessments within acceptable time frames will be removed from study and censored at 
the time of last evaluation.   
10.1.5 Best Response 
• Complete Response (CR): Disappearance of all target and non-target lesions and no 
evidence of new lesions documented by 2 disease assessments at least 4 weeks apart.   
• Partial Response (PR):  At least a 30% decrease in the in the longest dimension (LD) of 
all target lesions, taking as reference the baseline sum LD.  There can be no unequivocal 
progression of non-target lesions and no new lesions.  Documentation by 2 disease 
assessments at least 4 weeks apart is required.   
• Progressive Disease (PD):  At least a 20% increase in the sum of LD of target lesions, 
taking as reference the smallest sum LD or the appearance of new lesions within 8 
weeks of study entry.  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
• Stable Disease (SD):  Any condition not meeting the above criteria.   
• Inevaluable for response is defined as having no repeat tumor assessments following 
initiation of study therapy for reasons unrelated to symptoms or signs of disease.  
10.2 Quantifying Clinical Correlates of Response 
Outcome will be assessed as follows: 
• Objective Response Rate (ORR):  The proportion of participants with either (1) CR or (2) 
PR by RECIST 1.1 criteria.   
• Survival:  The observed length of life from first dose of study drug to death or the date of 
last contact.   
• TTF:  Is defined as the time from first study drug treatment until the participant is started 
on another line of systemic therapy or participant death, whichever occurs first.  
Participants who are alive and do not start another therapy will be censored at the time of 
last follow-up.   
11 SAFETY ASSESSMENTS 
Safety assessments (vital signs, physical examinations, performance status, height/weight, 
ECG recording, AEs, clinical laboratory results (routine hematology and biochemistry, and CT 
and MRI scans) are to be performed at protocol specified visits, as specified in the Schedule 
of Assessments, Table 3.  
11.1 Adverse Events 
11.1.1 Definition of Non-serious Adverse Events 
An AE is defined as any new untoward medical occurrence or worsening of a preexisting 
medical condition in a clinical investigation participant administered an investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of investigational product, 
whether or not considered related to the investigational product. 
A non-serious AE is an AE not classified as serious.  


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The collection of non-serious AE information will begin at initiation of study drug.  All 
non-serious AEs (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following the last 
dose of study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious.  Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate.  
The causal relationship to study drug is determined by a physician and should be used to assess 
all AE.  The casual relationship can be one of the following: 
UNRELATED:  This category applies to those AEs that are clearly and incontrovertibly due to extraneous 
causes (disease, environment, etc.). 
UNLIKELY:  This category applies to those AEs that are judged to be unrelated to the test drug, but for 
which no extraneous cause may be found.  An AE may be considered unlikely to be related to study drug if 
or when it meets 2 of the following criteria:  (1) it does not follow a reasonable temporal sequence from 
administration of the test drug; (2) it could readily have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the subject; (3) it does not follow a 
known pattern of response to the test drug; or (4) it does not reappear or worsen when the drug is re-
administered. 
POSSIBLY:  This category applies to those AEs for which a connection with the test drug administration 
appears unlikely but cannot be ruled out with certainty.  An AE may be considered possibly related if or 
when it meets 2 of the following criteria: (1) it follows a reasonable temporal sequence from administration 
of the drug; (2) it could not readily have been produced by the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; or (3) it follows a known pattern of response 
to the test drug. 
PROBABLY:  This category applies to those AEs that the investigator feels with a high degree of certainty 
are related to the test drug.  An AE may be considered probably related if or when it meets 3 of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose (note that there are exceptions when an AE does not disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists; for example, as in bone marrow depression, fixed drug eruptions, or 
tardive dyskinesia); or (4) it follows a known pattern of response to the test drug. 
DEFINITELY:  This category applies to those AEs that the investigator feels are incontrovertibly related to 
test drug.  An AE may be assigned an attribution of definitely related if or when it meets all of the following 
criteria: (1) it follows a reasonable temporal sequence from administration of the drug; (2) it could not be 
reasonably explained by the known characteristics of the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject; (3) it disappears or decreases on cessation or 
reduction in dose and recurs with re-exposure to drug (if rechallenge occurs); and (4) it follows a known 
pattern of response to the test drug. 
Classification of AEs by intensity should also be determined by a physician. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants 
should not be questioned regarding the specific occurrence of one or more AEs). 
11.1.2 Serious Adverse Events 
An AE is considered serious if it results in any of the following outcomes:  
• 
Death  
• 
A life-threatening AE  
• 
An AE that results in hospital admission or prolongation of existing hospitalization 


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• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events 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 participant or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
• 
Potential drug induced liver injury (DILI) is also considered an important medical 
event.  DILI is defined as the following: 
o ALT or AST elevation >3x ULN AND 
o Total bilirubin >2x ULN, without elevated serum alkaline phosphatase 
AND 
o No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, 
pre-existing chronic or acute liver disease, or the administration of other 
drug(s) known to be hepatotoxic.  
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via study 
drug is an SAE. 
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, 
these events must be handled as SAEs. 
Note: Hospital admission for elective pre-planned surgeries is not considered an SAE.   
Disease Progression is considered a non-reportable event. 
SAE reporting is required as soon as the participant signs consent and is registered.  SAE 
reporting is required for 100-days after the participant’s last investigational treatment or 
intervention.  Any events that occur after the 100-day period and that are at least possibly 
related to protocol treatment must be reported. 
inVentiv Health Clinical will manage SAEs using ARGUS, and all sites will send reports to 
inVentiv’s safety team via email.  Sites will not upload any reports directly into ARGUS.  
SAE Reporting to BMS and inVentiv 
Following the participant’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, must be collected, including those thought to be associated 
with protocol-specified procedures.  All AEs are to be followed until resolution, until a stable 
clinical endpoint is reached, or for 100 days after the last dose of study treatment, unless other 
anticancer therapy is initiated.  
All SAEs must be collected that occur during the screening period.  If applicable, SAEs must 
be collected that relate to any protocol-specified procedure (e.g., a follow-up skin biopsy).  The 
Investigator should report any SAE that occurs after these time periods that is believed to be 
related to study drug or protocol-specified procedure.  
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports should include the same Investigator term(s) initially reported.)  


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Sites should complete SAE reports and then submit the reports per their local IRB 
requirements. 
All SAEs should be followed to resolution or stabilization. 
The Sponsor will ensure that all SAEs in the clinical database are reported to BMS and any 
applicable health authority during the conduct of the study.  
11.1.3 Pregnancy 
Female participants of childbearing potential must have a negative pregnancy test at Screening.  
An acceptable form of contraception must be used for up to 5 months post last dose by all 
female participants and for 7 months post last dose by all male participants (as detailed in 
Appendix 4). Following administration of study drug, any known cases of pregnancy in female 
participants will be reported until the participant completes or withdraws from the study.  The 
pregnancy will be reported immediately by phone and by faxing/emailing a completed 
Pregnancy Report to the Sponsor (or designee) within 24 hours of knowledge of the event.  The 
Investigator will follow the participant until completion of the pregnancy and must assess the 
outcome in the shortest possible time but not more than 30 days after completion of the 
pregnancy.  The Investigator should notify the Sponsor (or designee) of the pregnancy outcome 
by submitting a follow-up Pregnancy Report on a Pregnancy Surveillance Form.  If the 
outcome of the pregnancy meets the criteria for immediate classification of an SAE (e.g., 
spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus is to 
be documented], stillbirth, neonatal death, or congenital anomaly), the Investigator will report 
the event by phone and by faxing a completed SAE form to the Sponsor (or designee) within 
24 hours of knowledge of the event.  
11.1.4 Overdose 
The Investigator must immediately notify the Sponsor of any occurrence of overdose with 
study drug.  Overdose is defined as any dose higher than the dose specified to be administered 
in accordance with the protocol. 
All overdoses should be reported to inVentiv as SAEs (see Section Error! Reference source 
not found.).  Details of signs and symptoms, clinical management, and outcome should be 
reported, if available.  Overdoses should also be captured as protocol deviations. 
11.1.5 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
Adverse Events or Serious Adverse Events 
Progression of the cancer under study, including deaths, as judged by the Investigator, is not 
considered a reportable event. Any suspected endpoint, which upon review from the 
Investigator, is not considered progression of the cancer under study must be reported as an 
SAE. Within 24 hours of determination that the event is not progression of the cancer under 
study, an SAE form should be forwarded to InVentiv Pharmacovigilance Group as described 
(see Section Error! Reference source not found.). 
All deaths will be recorded on the Death eCRF page. 


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11.2 Unanticipated Problems/Non-Compliance 
Unanticipated Problems 
An unexpected problem is any incident, experience, or outcome that meets all of the following 
criteria: 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
An incident, experience, or outcome that meets the three criteria above generally will warrant 
consideration of substantive changes in the research protocol or informed consent 
process/document or other corrective actions in order to protect the safety, welfare, or rights 
of subjects or others.   Examples of corrective actions or substantive changes that might need 
to be considered in response to an unanticipated problem include:  
• changes to the research protocol initiated by the investigator prior to obtaining IRB 
approval to eliminate apparent immediate hazards to subjects; 
• modification of inclusion or exclusion criteria to mitigate the newly identified risks; 
• implementation of additional procedures for monitoring subjects; 
• suspension of enrollment of new subjects; 
• suspension of research procedures in currently enrolled subjects; 
• modification of informed consent documents to include a description of newly 
recognized risks; and 
• provision of additional information about newly recognized risks to previously enrolled 
subjects. 
Only a small subset of AEs occurring in human subjects participating in research will meet 
these three criteria for an unanticipated problem.   Furthermore, there are other types of 
incidents, experiences, and outcomes that occur during the conduct of human subjects research 
that represent unanticipated problems but are not considered AEs.   For example, some 
unanticipated problems involve social or economic harm instead of the physical or 
psychological harm associated with AEs.   In other cases, unanticipated problems place 
subjects or others at increased risk of harm, but no harm occurs. 
It may be difficult to determine whether a particular AE is unexpected. This determination may 
require analysis of appropriate data on all subjects enrolled in the research.   In addition, 
unanticipated problems may become apparent during continuing renewals, protocol violations, 


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deviations, complaints, injuries, or deaths.   Investigators are required to promptly report to the 
IRB unanticipated problems involving risks to subjects or others.   A report for an unexpected 
event should contain a clear explanation of why the event(s) was determined to be an 
unanticipated problem and a description of any proposed protocol changes or other corrective 
actions to be taken by the investigators in response to the unanticipated problem. 
Non-Compliance 
All investigators should comply with all applicable local, state, and federal regulations in the 
conduct of research involving human subjects.   Non-compliance is defined as any violation of 
any regulation that governs human subject research, any deviation from the study protocol 
approved by the IRB, or any violation of any conditions imposed by the IRB on the approval 
of the study or conduct of the research.   Investigators will also be informed when allegations 
of non-compliance are made during the study.   Investigators are responsible for reporting in 
writing, all suspected incidents of non-compliance within 2 business days of 
discovery.   Reports should be sent to inVentiv Health and the MSKCC research team for 
submission to the IRB and should include the incident, date of the incident, individuals 
involved, whether the incident requires further action, and corrective actions and procedures.  
12 STATISTICAL ANALYSIS 
A Statistical Analysis Plan (SAP) will be prepared after the protocol is approved.  This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.  The SAP will serve as a compliment to the 
protocol and supersedes it in case of differences. 
The statistical evaluation will be performed using the Statistical Analysis Software (SAS®) 
Version 8.1 or higher (SAS Institute, Cary, NC).  All data will be listed, and summary tables 
will be provided.  Summary statistics will be presented by dose group.  For continuous 
variables, data will be summarized with the number of participants (N), mean, standard 
deviation, median, minimum, and maximum by treatment group.  For categorical variables, 
data will be tabulated with the number and proportion of participants for each category by 
treatment group. 
12.1 Determination of Sample size 
Twelve participants will be enrolled in each arm for a total of 24 participants.  A response rate 
of 10% or less would not be considered promising (null hypothesis) as the ipilimumab response 
rate in untreated patients is 10.9%.33  A response rate of at least 30% is promising (alternative 
hypothesis). Point estimates and 95% confidence intervals for the response rates will be 
reported. Alpha (probability of Type I error) for hypothesis tests will be 0.1. If 4 or more of 
12 participants in an arm respond (response rate of 33% or greater), the treatment will be 
considered promising for further investigation.     
12.2 Analysis Populations 
Evaluable participants for efficacy  
• 
All participants who receive at least 1 dose of study drug(s) will be evaluated for the 
primary endpoint.  Participants who develop rapid symptomatic disease progression 


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or drop out early due to death will be treated as non-responders.  Participants who 
develop early toxicities that require treatment delay or discontinuation will continue 
to be evaluable on study.   
• 
Participants may be replaced in either arm if they complete randomization but do not 
complete any cycles of therapy. 
Evaluable participants for toxicity 
Participants who have completed at least one treatment cycle on either arm will be considered 
evaluable for toxicity. 
12.3 Efficacy Analysis 
12.3.1 Analysis of Primary Efficacy Endpoint 
• The primary endpoint is objective response (CR and PR) as defined by RECIST criteria 
by Week 18.  Objective response rates will be estimated as proportions with 95% CIs 
estimated using an exact procedure. 
12.3.2 Analysis of Secondary Efficacy Endpoints 
• DCR, defined as participants who achieve SD, PR or complete response at Week 12 
and/or Week 18 as measured by RECIST v1.1 will be estimated as proportions with 
95% CIs estimated using an exact procedure.  
• Participants will be followed for duration of response (in those participants who derive 
clinical benefit), TTF and OS for two years; these will be estimated and demonstrated 
using Kaplan Meier approaches.  
12.3.3 Analysis of Exploratory Efficacy Endpoints 
• All research samples for exploratory endpoints will be analyzed at a Parker Institute 
for Cancer Immunotherapy selected testing center.  Please see Appendix 3 for further 
information. 
• Peripheral lymphocyte phenotype changes throughout treatment, including Treg cells, 
defined as CD4+FOX3P+ cells, will be expressed using descriptive statistics at pre and 
post treatment time points.  These will be assed via flow cytometry of PBMCs. 
• Changes in quantities of MDSCs, defined as CD14+HLA-DRlow cells, throughout 
treatment will be expressed using descriptive statistics at pre and post treatment time 
points.  
• nCounter immune profiling of the tumor before treatment will be expressed using 
descriptive statistics at pre and post treatment time points and will be correlated with 
clinical response also using logistic regression models. 
• Tumor neoepitopes and mutational burden will be correlated with clinical response also 
using logistic regression models. 
• Summary statistics will be generated and differences between mutation burden or neo-
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• IHC will be used to assess PD-L1 expression on both immune cells and tumor cells.  
PDL-1 expression will be assessed pre-treatment and on-treatment.  A participant will 
be PD-L1 + if >1% of cells express PD-L1.  If response data permit, the tumor positivity 
of PD-L1 expression will be compared in the pre- and post-treatment biopsies using a 
Wilcoxon signed rank test. 
• Pre- and on- treatment PD-L1 expression and will be correlated with clinical response 
also using logistic regression models.  
• IHC will be used to quantify cytotoxic and Tregs, including stains for CD3, CD4, CD8, 
FOXP3, ICOS and Lag3.  Associations from pre to post treatment will be assessed 
using the Wilcoxon signed rank test for paired comparisons (e.g., the continuous 
measure, density of cells per high powered field). 
12.4 Safety Analysis 
Adverse events and toxicity data will be tabulated and summarized using descriptive statistics. 
12.5 Data Review Team 
The study will be closely monitored and data will be reviewed on an ongoing basis. In order 
to ensure the safety and well-being of participating subjects, as well as, the validity of data 
during the study, a Data Review Team (DRT) will review the safety and further emerging data 
on a regular basis.  During these meetings, aggregated safety data and individual participant 
data derived from medical data listing reviews will be presented, reviewed, and discussed.  The 
DRT team will consist of team members from the Sponsor, inVentiv, the Coordinating PI, and 
all active PIs.   
13 STUDY MANAGEMENT 
13.1 Approval and Consent 
13.1.1 Regulatory Guidelines 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, Subpart D, of 
Title 21 of the Code of Federal Regulations (CFR), and in compliance with good clinical 
practice (GCP) guidelines. 
13.1.2 Institutional Review Board/Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted Independent Ethics 
Committee (IEC)/IRB.  Approval is required for the study protocol, investigational drug 
brochure, protocol amendments, informed consent forms (ICFs), and participant information 
sheets.   
13.1.3 Informed Consent 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study.  Participants will also be informed that they are free to withdraw 


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from the study at any time.  All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate.  This consent form meets the requirements of the CFR 
and the IRB/Privacy Board of this Center.  The consent form will include the following:  
• The nature and objectives, potential risks and benefits of the intended study.  
• The length of study and the likely follow-up required. 
• Alternatives to the proposed study. (This will include available standard and 
investigational therapies.  In addition, participants will be offered an option of 
supportive care for therapeutic studies.) 
• The name of the Investigator(s) responsible for the protocol. 
• The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of participant privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all participants must agree to the Research 
Authorization component of the ICF. 
Each participant and consenting professional will sign the consent form.  The participant must 
receive a copy of the signed ICF. 
13.2 Research Participant Registration 
Participant eligibility will be confirmed as defined in the Sections 7.1 and 7.2.  Informed 
consent will be obtained by following procedures defined in Section 13.1.3 entitled Informed 
Consent.  During the registration process registering individuals will be required to complete 
a protocol specific Eligibility Checklist.   
Registrations must be submitted via the ALMAC Interactive Voice Response System.   
13.3 Data Handling 
A Study Coordinator (SC) or equivalent will be assigned to the study.  The responsibilities of 
the SC include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. 
The data collected for this study will be entered into a secure database.  Source documentation 
will be available to support the computerized participant record. 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be 
identified at the start of the study.  Data reported on the eCRF that are derived from source 
documents should be consistent with the source documents, or the discrepancies must be 
explained. 
Clinical data will be entered on eCRFs for transmission to the Sponsor.  Data on eCRFs 
transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site, unless the study site makes direct data entry to the 
databases for which no other original or source documentation is maintained.  In such cases, 
the study site should document which eCRFs are subject to direct data entry and should have 
in place procedures to obtain and retain copies of the information submitted by direct data 


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entry.  All study forms and records transmitted to the Sponsor must carry only coded identifiers 
such that personally identifying information is not transmitted.  The primary method of data 
transmittal is via the secure, internet-based electronic data capture (EDC) system maintained 
by inVentiv Health Clinical.  Access to the EDC system is available to authorized users via the 
study’s Internet web site, where an assigned username and password are required for access. 
Any changes made to data after collection will be made through the use of Data Clarification 
Forms.  eCRFs will be considered complete when all missing and/or incorrect data have been 
resolved. 
13.4 Source Documents 
Source documents are considered to be all information in original records and certified copies 
of original records of clinical findings, observations, data or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. 
13.5 Record Retention 
Study records and source documents must be preserved for at least 15 years after the 
completion or discontinuation of/withdrawal from the study or 2 years after the last approval 
of a marketing application in an International Conference on Harmonization region, whichever 
is the longer time period. 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of participant health information, including, but not limited 
to, the Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 
(the Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy Regulation).  
The Investigator shall ensure that study participants authorize the use and disclosure of 
protected health information in accordance with HIPAA Privacy Regulation and in a form 
satisfactory to the Sponsor. 
13.6 Monitoring 
The study will be monitored to ensure that it is conducted and documented properly according 
to the protocol, GCP, and all applicable regulatory requirements.  
On-site monitoring visits will be made at appropriate times during the study.  Clinical monitors 
must have direct access to source documentation in order to check the completeness, clarity, 
and consistency of the data recorded in the eCRFs/CRFs for each subject.   
The Investigator will make available to the clinical monitor source documents and medical 
records necessary to complete eCRFs/CRFs.  In addition, the Investigator will work closely 
with the clinical monitor and, as needed, provide them appropriate evidence that the conduct 
of the study is being done in accordance with applicable regulations and GCP guidelines.  
 
inVentiv Health Clinical will perform remote monitoring and will also visit the clinical sites 
every 16 weeks. An experienced medical team will be reviewing the emerging data and will 
also be available to participating centers to address any clinical questions including 


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safety-related questions. Both participant level data and aggregated data will be routinely 
reviewed to ensure no unexpected events are observed.  
13.7 Quality Control and Quality Assurance 
Weekly registration reports will be generated to monitor participant accruals and completeness 
of registration data.  Routine data quality reports will be generated to assess missing data and 
inconsistencies.  Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action. 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
13.8 Protocol Amendment and Protocol Deviation  
13.8.1 Protocol Amendment 
Any changes to the protocol will require a formal amendment. This includes substantial 
changes, as well as those that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no impact 
on the safety of participants or the conduct of the study. All protocol amendments will be 
submitted to the IRB/IEC and, as required, to the appropriate Regulatory Authorities.   
13.8.2 Protocol Deviations 
Should a protocol deviation occur, the Sponsor must be informed.  Protocol deviations and/or 
violations and the reasons they occurred will be included in the clinical study report.  It is the 
investigator’s responsibility to report protocol deviations inVentiv Health and the MSKCC 
research team for submission to the HRPP office in accordance with applicable Regulatory 
Authority mandates. Prospective deviation requests will not be allowed. 
13.9 Ethical Considerations 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, Subpart D, of 
Title 21 of the CFR, and in compliance with GCP guidelines. 
IRBs/IECs will review and approve this protocol and the ICF.  All participants are required to 
give written informed consent prior to participation in the study.   
13.10 Financing and Insurance 
Prior to the study commencing, the Sponsor (or its designee) and the Investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study.  This agreement 
will be documented in a financial agreement that will be signed by the Investigator (or the 
institution signatory) and the Sponsor (or its designee).  
The Investigator is required to have adequate current insurance to cover claims for its 
negligence and/or malpractice.  The Sponsor, or the manufacturer of the study drug, will 
provide insurance coverage for the clinical study as required by national regulations. 


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13.11 Study and Site Closure 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Reasons for terminating the study 
may include, but are not limited to the following: 
• Discontinuation of further stud intervention development 
• The incidence or severity of adverse events in this or other studies indicate the potential 
hazard to participants 
• Participant enrollment is unsatisfactory 
The Sponsor will notify the Investigator if the Sponsor decides to discontinue the study. 
Reasons for early closure of a study site by the Sponsor or investigator may include, but are 
not limited to: 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or GCP guidelines 
• No study activity (ie, all participants have completed the study and all obligations have 
been fulfilled) 
13.12 Publication Policy / Disclosure of Data  
Both the use of data and the publication policy are detailed within the clinical study agreement.  
Intellectual property rights (and related matters) generated by the Investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will 
be agreed between the Institution and the Sponsor or their designee.   


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5. Bajetta E, Di Leo A, Zampino MG, et al. Multicenter randomized trial of dacarbazine 
alone or in combination with two different doses and schedules of interferon alfa-2a in 
the treatment of advanced melanoma. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology. 1994;12(4):806-811. 
6. Middleton MR, Lorigan P, Owen J, et al. A randomized Phase 3 study comparing 
dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in 
advanced melanoma. British journal of cancer. 2000;82(6):1158-1162. 
7. Chapman PB, Einhorn LH, Meyers ML, et al. Phase 3 multicenter randomized trial of 
the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 1999;17(9):2745-2751. 
8. Middleton MR, Grob JJ, Aaronson N, et al. Randomized Phase 3 study of 
temozolomide versus dacarbazine in the treatment of patients with advanced metastatic 
malignant melanoma. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2000;18(1):158-166. 
9. Rao RD, Holtan SG, Ingle JN, et al. Combination of paclitaxel and carboplatin as 
second-line therapy for patients with metastatic melanoma. Cancer. 2006;106(2):375-
382. 
10. Hersh EM, O'Day SJ, Ribas A, et al. A Phase 2 clinical trial of nab-paclitaxel in 
previously treated and chemotherapy-naive patients with metastatic melanoma. 
Cancer. 2010;116(1):155-163. 
11. Flaherty KT, Lee SJ, Zhao F, et al. Phase 3 trial of carboplatin and paclitaxel with or 
without sorafenib in metastatic melanoma. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. 2013;31(3):373-379. 
12. Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. 
Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the 
Eastern Cooperative Oncology Group Trial EST 1684. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. 1996;14(1):7-17. 
13. Kirkwood JM, Manola J, Ibrahim J, et al. A pooled analysis of eastern cooperative 
oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. 
Clinical cancer research : an official journal of the American Association for Cancer 
Research. 2004;10(5):1670-1677. 


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14. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon alfa-2b in 
high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. 
2000;18(12):2444-2458. 
15. Eggermont AM, Suciu S, Santinami M, et al. Adjuvant therapy with pegylated 
interferon alfa-2b versus observation alone in resected Stage III melanoma: final results 
of EORTC 18991, a randomised Phase 3 trial. Lancet. 2008;372(9633):117-126. 
16. Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients 
with high-risk melanoma: a systematic review and meta-analysis. Journal of the 
National Cancer Institute. 2010;102(7):493-501. 
17. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy 
for patients with metastatic melanoma: analysis of 270 patients treated between 1985 
and 1993. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 1999;17(7):2105-2116. 
18. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 
therapy in patients with metastatic melanoma: long-term survival update. The cancer 
journal from Scientific American. 2000;6 Suppl 1:S11-14. 
19. Hamid O, Schmidt H, Nissan A, et al. A prospective Phase 2 trial exploring the 
association between tumor microenvironment biomarkers and clinical activity of 
ipilimumab in advanced melanoma. Journal of translational medicine. 2011;9:204. 
20. Ng Tang D, Shen Y, Sun J, et al. Increased frequency of ICOS+ CD4 T cells as a 
pharmacodynamic biomarker for anti-CTLA-4 therapy. Cancer immunology research. 
2013;1(4):229-234. 
21. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by 
inhibiting adaptive immune resistance. Nature. 2014;515(7528):568-571. 
22. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination 
blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within 
B16 melanoma tumors. Proceedings of the National Academy of Sciences of the United 
States of America. 2010;107(9):4275-4280. 
23. Simpson TR, Li F, Montalvo-Ortiz W, et al. Fc-dependent depletion of tumor-
infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against 
melanoma. The Journal of experimental medicine. 2013;210(9):1695-1710. 
24. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma 
without BRAF mutation. The New England journal of medicine. 2015;372(4):320-330. 
25. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
anti-PD-1 antibody in cancer. The New England journal of medicine. 
2012;366(26):2443-2454. 
26. Grosso J, Horak CE, Inzunza D, et al. Association of tumor PD-L1 expression and 
immune biomarkers with clinical activity in patients (pts) with advanced solid tumors 
treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538). ASCO Meeting 
Abstracts. 2013;31(15_suppl):3016. 
27. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-
PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563-567. 
28. Ribas A, Robert C, Hodi FS, et al. Association of response to programmed death 
receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an interferon-


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inflammatory 
immune 
gene 
signature. 
ASCO 
Meeting 
Abstracts. 
2015;33(15_suppl):3001. 
29. Taube JM, Young GD, McMiller TL, et al. Differential Expression of Immune-
Regulatory Genes Associated with PD-L1 Display in Melanoma: Implications for PD-
1 Pathway Blockade. Clinical Cancer Research. 2015. 
30. Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and 
anti-self responses in a Phase 1 trial with the anti-cytotoxic T lymphocyte-associated 
antigen 4 monoclonal antibody CP-675,206. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. 2005;23(35):8968-8977. 
31. Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody 
blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated 
cancer patients. Proceedings of the National Academy of Sciences of the United States 
of America. 2008;105(8):3005-3010. 
32. Weber JS, O’Day S, Urba W, et al. Phase 1/2 Study of Ipilimumab for Patients With 
Metastatic Melanoma. Journal of Clinical Oncology. 2008;26(36):5950-5956. 
33. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in 
patients with metastatic melanoma. The New England journal of medicine. 
2010;363(8):711-723. 
34. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus Dacarbazine for Previously 
Untreated 
Metastatic 
Melanoma. 
New 
England 
Journal 
of 
Medicine. 
2011;364(26):2517-2526.  
35. Schadendorf D, Hodi FS, Robert C, et al. Pooled Analysis of Long-Term Survival Data 
From Phase II and Phase 3 Trials of Ipilimumab in Unresectable or Metastatic 
Melanoma. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2015;33(17):1889-1894. 
36. Robert C, Schadendorf D, Messina M, Hodi FS, O'Day S, investigators MDX. Efficacy 
and safety of retreatment with ipilimumab in patients with pretreated advanced 
melanoma who progressed after initially achieving disease control. Clinical cancer 
research : an official journal of the American Association for Cancer Research. 
2013;19(8):2232-2239. 
37. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member 
of the immunoglobulin gene superfamily, upon programmed cell death. The EMBO 
journal. 1992;11(11):3887-3895. 
38. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory 
receptor by a novel B7 family member leads to negative regulation of lymphocyte 
activation. The Journal of experimental medicine. 2000;192(7):1027-1034. 
39. Keir ME, Liang SC, Guleria I, et al. Tissue expression of PD-L1 mediates peripheral T 
cell tolerance. The Journal of experimental medicine. 2006;203(4):883-895. 
40. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and Activity of Anti–PD-L1 
Antibody in Patients with Advanced Cancer. New England Journal of Medicine. 
2012;366(26):2455-2465. 
41. Topalian SL, Sznol M, McDermott DF, et al. Survival, Durable Tumor Remission, and 
Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab. 
Journal of Clinical Oncology. 2014;32(10):1020-1030. 


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42. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment 
with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised 
dose-comparison cohort of a Phase 1 trial. Lancet. 2014;384(9948):1109-1117. 
43. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced 
Melanoma. New England Journal of Medicine. 2015;372(26):2521-2532.  
44. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. The New England journal of medicine. 2013;369(2):122-133. 
45. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus 
ipilimumab in untreated melanoma. The New England journal of medicine. 
2015;372(21):2006-2017.  1 
46. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab 
or Monotherapy in Untreated Melanoma. The New England journal of medicine. 2015. 
2 
47. Weber JS, Minor D, D'Angelo S, Hodi FS, Gutzmer R, Larkin J. A Phase 3 randomized, 
open-labe study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with 
advanced melanoma after prior anti-CTLA-4 thearpy. European Society of Medical 
Oncology Congress; September 26-30, 2014; Madrid, Spain.   
 


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15 APPENDICES 
15.1 Appendix 1: Product Information and Pharmacy Manuals 
PRODUCT INFORMATION TABLE 
Table 
Product Description 
Product 
Description 
and Dosage 
Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label 
Type 
Secondary 
Packaging 
(Qty) /Label 
Type 
Appearance 
Storage 
Conditions 
(per label) 
Nivolumab 
BMS-936558-
01 Solution 
for Injectiona 
100 mg 
(10 
mg/mL) 
10 mL vial 5-10 vials 
per carton/ 
Open-label 
Clear to 
opalescent 
colorless to 
pale yellow 
liquid. May 
contain 
particles 
2 to 8°C. 
Protect form 
light and 
freezing 
Ipilimumab 
Solution for 
Injection 
200 mg 
(5 
mg/mL) 
40 mL vial 4 vials per 
carton/Open-
label 
Clear, colorless 
to pale yellow 
liquid. May 
contain 
particles 
2 to 8°C. 
Protect from 
light and 
freezing. 
a Nivolumab may be labeled as BMS-936558-01 Solution for Injection 
 
If stored in a glass front refrigerator, vials should be stored in the carton. Recommended 
safety measures for preparation and handling of nivolumab and ipilimumab include 
laboratory coats and gloves. 
Nivolumab and ipilimumab will be given together every 3 weeks for 4 doses.  
 
Nivolumab dose = 1 mg/kg 
 
Ipilimumab dose = 3 mg/kg 
When study drugs (ipilimumab or nivolumab) are to be administered on the same day, 
separate infusion bags and filters must be used for each infusion.  It is recommended that 
nivolumab be administered first.  The second infusion will always be ipilimumab and will 
start approximately 30 minutes after completion of the nivolumab infusion. 
BMS-936558 (nivolumab) is to be administered approximately as a 60-minute IV infusion. 
Ipilimumab should be administered approximately as a 30-minute infusion following. 
Ipilimumab and nivolumab may be diluted in 0.9% Sodium Chloride Solution or 5% 
Dextrose solution.  
The dosing calculations should be based on body weight, which will be assessed at Screening 
and Day 1 of each cycle. Dose adjustments are not required unless the participant has a 10% 
change compared with their initial weight on Cycle 1, Day 1. Drug should be measured 
according to institutional guidelines. 
 
 
 


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Nivolumab (BMS-936558) Pharmacy Reference Material 
As this is provided for guidance only, please see Investigator’s Brochure (IB) for 
additional information regarding preparation and administration 
Nivolumab has a concentration of 10 mg/mL and is provided in a 10 mL vial.  Ten or 5 vials 
are provided in a carton. 
 
Storage Conditions & Handling: 
• Store at 2-8°C (36-46°F), protect from light, freezing, and shaking. 
• If any temperature excursions are encountered during storage, please report these to BMS 
for assessment via the Temperature Excursion Response Form.    
• As with all injectable drugs, care should be taken when handling and preparing nivolumab. 
Whenever possible, nivolumab should be prepared in a laminar flow hood or safety cabinet 
using standard precautions for the safe handling of IV agents applying aseptic technique.  
• Partially used vials should be disposed at the site following procedures for the disposal of 
anticancer drugs.  
 
After final drug reconciliation, unused nivolumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs.  For further information, please either discuss 
with your BMS CSR&O protocol manager or refer to your site IP Destruction policies and 
procedures  
 
Use Time/Stability: Please refer to the appropriate section of the current IB or Addendum.  
Due to parameters surrounding the use time of nivolumab and ipilimumab, the time of 
preparation should be noted in the Pharmacy Source documents [accountability logs] or in 
study files as required for investigator sponsored research [FDA and GCP]. 
 
The administration of BMS-936558-01 injection prepared for dosing nivolumab infusion 
must be completed within 24 hours of preparation.  If not used immediately, the infusion 
solution may be stored up to 20 hours in a refrigerator at under refrigeration conditions 
(2°-8°C (36°-46°F) and used within 24 hours, and a maximum of 8 hours of the total 
24 hours can be at room temperature (20°-25°C, 68°-77°F) and under room light.  The 
maximum 4-hour period under room temperature and room light conditions for undiluted and 
diluted solutions of BMS-936558-01 injection in the IV bag includes the product 
administration period. 
 
Preparation and Administration: 
1. 
Visually inspect the drug product solution for particulate matter and discoloration prior to 
administration.  Discard if solution is cloudy, if there is pronounced discoloration (solution 
may have a pale-yellow color), or if there is foreign particulate matter other than a few 
translucent-to-white, amorphous particles. Note: Mix by gently inverting several times.  Do 
not shake. 
2. 
Aseptically withdraw the required volume of nivolumab solution into a syringe and 
dispense into an IV bag.  If multiple vials are needed for a participant, it is important to use 
a separate sterile syringe and needle for each vial to prevent problems such as dulling of 
needle tip, stopper coring, repeated friction of plunger against syringe barrel wall.  Do not 


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enter into each vial more than once.  Do not administer study drug as an IV push or bolus 
injection 
3. 
Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose 
Injection solution. It is acceptable to add nivolumab solution from the vials into an 
appropriate pre-filled bag of diluent. 
4. 
Note: Nivolumab infusion concentration must be at or above the minimum allowable 
concentration of 0.35 mg/mL [IBV13 Addendum Section 3.2.2] 
5. 
Note: It is not recommended that so-called “channel” or tube systems are used to transport 
prepared infusions of nivolumab. 
6. 
Attach the IV bag containing the nivolumab solution to the infusion set and filter. 
7. 
At the end of the infusion period, flush the line with a sufficient quantity of approved 
diluents. 
 
Ipilimumab Pharmacy Reference Material 
Ipilimumab vials (40 mL) are shipped in quantities of four.  
Ipilimumab (BMS-734016) Injection (5 mg/ml) must be stored refrigerated (2-8°C, 36-46°F) 
with protection from light and from freezing.  Ipilimumab may be stored in IV infusion bags 
(PVC, non-PVC/non-DEHP) or glass infusion containers for up to 24 hours at room 
temperature (20-25°C, 68-77°F) or refrigerated (2-8°C, 36-46°F).  This would include any time 
in transit and the total time for infusion.  Drug must be completely delivered within 24 hours 
of preparation. 
 
Storage Conditions & Handling: 
Ipilimumab injection may be stored undiluted, 200 mg/vial (5 mg/mL), or following dilution 
to concentrations between 1 mg/mL and 4 mg/mL in 0.9% Sodium Chloride Injection (USP), 
or 5% Dextrose Injection (USP) in PVC, non-PVC/ or glass containers for up to 24 hours in 
the refrigerator (2°C to 8°C) or at room temperature/room light.  For longer storage, 
ipilimumab should be kept refrigerated (2°C to 8°C) with protection 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.  
Preparation and Administration 
As this is provided for guidance only, please see IB for additional information 
regarding preparation and administration. 
1. As ipilimumab is stored long term at refrigerated temperatures (2-8ºC) and protected 
from light, allow the appropriate number of vials of ipilimumab to stand at room 
temperature for approximately five minutes. 
2. Ensure that the ipilimumab solution is clear colorless, essentially free from particulate 
matter on visual inspection.  If multiple vials are needed for a participant, it is important 
to use a separate sterile syringe and needle for each vial to prevent problems such as 


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dulling of needle tip, stopper coring, repeated friction of plunger against syringe barrel 
wall, etc. 
3. Aseptically transfer the required volume of ipilimumab solution into a syringe. [Note: 
A sufficient excess of ipilimumab is incorporated into each vial to account for 
withdrawal losses].  
4. Do not draw into each vial more than once. Discard partially used vials or empty vials. 
5. Ipilimumab solution should be added to an appropriate size infusion container to 
accommodate the calculated final volume. 
Dose calculations should be based on body weight, which will be assessed at Screening 
and Day 1 of each cycle. Dose adjustments are not required unless the participant has 
a 10% change compared with their initial weight on Cycle 1, Day 1. Drug should be 
measured according to institutional guidelines. 
Mix by GENTLY inverting several times. DO NOT shake. 
Ipilimumab injection may be diluted in 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP. 
6. Visually inspect the final solution.  If the initial diluted solution or final solution for 
infusion is not clear or contents appear to contain precipitate, the solution should be 
discarded. 
7. Immediately after the infusion is complete, flush with an adequate amount of 0.9% 
Sodium Chloride injection (USP) or 5% Dextrose injection (USP) to completely flush 
the residual fluid (dead space) in your administration set (approximately 30-50 mL); 
this will ensure that all active drug is delivered to the study participant. 
8. Safely discard any unused portion of the infusion solution. Do not store for reuse. 
 
Ipilimumab should be administered under the supervision of a physician experienced in the 
use of IV agents.  Ipilimumab is administered as an IV infusion only. 
 
 
 


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15.2 Appendix 2:  Management Algorithms for Immuno-Oncology Agents 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered 
immuno-oncology agents in this protocol. Management algorithms have been developed to 
assist investigators in assessing and managing the following groups of AEs: Gastrointestinal, 
Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, and Neurological.  
 
Early recognition and intervention are recommended according to the management algorithms; 
and in addition include ophthalmologic evaluations for any visual symptoms in order to 
evaluate for nivolumab or ipilimumab related uveitis. 
 
The recommendations are to follow the algorithms in the nivolumab IB for immune related 
events; while the ipilimumab IB contains similar algorithms, the algorithms in the nivolumab 
brochure have been aligned to accommodate combinations as well as nivolumab monotherapy.   
 
Therefore, the algorithms recommended for utilization are attached for reference. 
For participants expected who require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider the following recommendations. 
 
• Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent 
opportunistic infections such as Pneumocystis jiroveci and fungal infections. 
• Early consultation with an infectious disease specialist should be considered. 
Depending on the presentation, consultation with a pulmonologist for bronchoscopy or 
a gastroenterologist for endoscopy may also be appropriate. 
• In participants who develop recurrent AEs in the setting of ongoing or prior 
immunosuppressant use, an opportunistic infection should be considered in the 
differential diagnosis. 
Additional details on the safety of nivolumab and ipilimumab, including results from clinical 
studies, are available in the IB. 


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15.3 Appendix 3: Laboratory Procedures 
A variety of factors that could potentially predict clinical response to ipilimumab alone 
or in combination with nivolumab will be investigated in peripheral blood and in tumor 
specimens taken both pre- and post-treatment.  All samples collected and banked may 
also be used for future exploratory analyses. 
 
All sites will send samples, collected in the kits that are provided by Parker Institute 
for Cancer Immunotherapy, to a centralized biorepository location.  The samples will 
be shipped from the biorepository to a centralized testing location for analysis.  Sites 
will not be required to do any exploratory testing unless they have been identified as a 
testing site and the budgeting for that will be established separately. 
 
Tumor tissue specimens 
 
Pre- and on- treatment tumor specimens will be obtained on all eligible participants.  
Tumor specimens collected may include (1) 4 core biopsy specimens or (2) an excision 
biopsy or (3) a specimen from surgical resection of a tumor.  In the case of the core 
biopsy specimens, 3 core biopsies will be snap frozen and 1 biopsy will be formalin 
fixed and preserved in paraffin embedded blocks (FFPE).  In the case of excisional or 
surgical specimens, approximately ½ of the specimen will be snap frozen and the other 
½ will be formalin fixed and paraffin embedded.   
 
Analysis of immune infiltrate 
Analysis of immune infiltrate will be performed using IHC and/or flow cytometry. 
Populations of cells analyzed may include, but will not be limited to, CD4, CD8, Treg 
populations, B cells, MDSC, monocytes, dendritic cells and expression of biologically 
relevant/phenotypic markers thereof.  Standard established institutional protocols will 
be applied.  Changes to these methods may be adapted depending upon the most recent, 
generally accepted protocols.   
 
PD-L1 Expression 
 
PD-L1 expression will be assessed on both pre-treatment and on-treatment tumor 
biopsies in the form of formalin fixed paraffin embedded block or unstained slides.  
PD-L1 stained tissue sections will be assessed by a pathologist and membranous PD-
L1 expression scored in tumor and immune cells.  PD-L1 expression will be graded as 
positive for negative, according to the most up to date standards for the assay in use.  
Changes to these methods may be adapted depending upon the most recent, generally 
accepted protocols. 
 
Gene Expression Profiling: 
Gene expression profiling on tumor samples will be run using different methodologies.  
Genes of interest include but are not limited to cell surface makers such as CD4 and 
CD8, checkpoint molecules such as LAG3 and genes relevant to the interferon 
pathway.  Standard established institutional protocols will be applied.  Changes to these 
methods may be adapted depending upon the most recent, generally accepted protocol.   


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RNA and DNA Preparation 
Core biopsies will be used to extract DNA or RNA.  Whole blood samples will be 
collected in a lavender top tube for purification of RNA/DNA.  Standard established 
institutional protocols will be applied.  Changes to the methods for RNA and DNA 
preparation may be adapted depending upon the most recent, generally accepted 
protocols.   
 
Exome sequencing of Tumor DNA and matched Normal DNA from Blood 
Exome sequencing will be carried out on Illumina Hiseq 2100 to a mean target 
coverage of 150X using 500 ng of genomic DNA from frozen tissue as input.  Changes 
to the methods for exome sequencing may be adapted depending upon the most recent, 
generally accepted protocols. 
 
Transcriptome Sequencing of Tumor RNA 
RNA-Seq analysis will be performed on samples with sufficient material.  Sequencing 
libraries will be prepared from total RNA with the Illumina TruSeq mRNA library kit 
(v2) and then sequenced on the HiSeq 2500 with 2x50bp paired reads, yielding 47-60M 
reads per sample. The RNA reads will be aligned using the STAR aligner after which 
Cufflinks was used for gene quantification (FPKM). Changes to these methods may be 
adapted depending on the most recent, generally accepted protocols. 
 
Somatic Mutation Identification and Verification 
 
Raw sequencing data will be mapped to the human reference genome.  Alignment, 
base-quality score recalibration, duplicate-read removal, and exclusion of germline 
variants will be performed using the Genome Analysis Toolkit (GATK). Known single 
nucleotide polymorphisms will be eliminated. Mutations will be annotated using 
SnpEffect, called with Somatic Sniper, VarScan, Strelka and MuTect then filtered and 
manually reviewed using IGV.  Insertion and deletions (indels) will be called using 
Strelka. 
 
Changes to these methods may be adapted depending on the most recent, generally 
accepted protocols. 
 
Neoantigen Prediction 
 
For each somatic SNV appearing in expressed genes, reference and mutated peptide 
sequences are generated.  Each variant is linked to its corresponding coding DNA 
sequence (CDS) from Ensembl based on its B37 coordinates. The CDS is re-translated 
with the mutated DNA residue producing the mutated peptide product. NetMHCCons 
v1.1 generates a predicted binding affinity for all 8 to 11mers containing the mutated 
amino acid and all peptides with an IC50 score below 500nM are considered predicted 
neoepitopes. Changes to these methods may be adapted depending upon the most 
recent, generally accepted protocols.   
 


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Exploratory Serum and Plasma Biomarkers 
 
Blood samples for exploratory serum and plasma biomarker analyses will be drawn at 
the time points indicated in Table 3.  Changes to these methods may be adapted 
depending upon the most recent, generally accepted protocols.   
 
Peripheral blood analysis 
 
Analysis of peripheral blood populations will be performed using flow cytometry 
and/or computational approaches (deconvolution) based upon RNA sequencing data 
analysis.  Populations of cells analyzed may include, but will not be limited to, CD4, 
CD8, Treg populations, B cells, MDSC, monocytes, dendritic cells and expression of 
biologically relevant/phenotypic markers thereof. Standard established institutional 
protocols will be applied.  Changes to these methods may be adapted depending upon 
the most recent, generally accepted protocols.  
 
 


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15.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information 
Definitions 
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
o Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
 
Contraception Guidance: 
 
Male Participants 
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
In addition, male participants must refrain from donating sperm for the duration of the study 
and for 7 months after the last dose of study intervention. 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration during the protocol-defined time frame and for 7 months after the last dose of 
study intervention. 


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Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
below. 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb  
• Oral  
• Intravaginal  
• Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral  
• Injectable 
Highly Effective Methods That Are User Independenta 
Implantable progestogen only hormonal contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. 


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NOTES:  
a) Typical use failure rates may differ from those when used consistently and correctly. 
Use should be consistent with local regulations regarding the use of contraceptive 
methods for participants participating in clinical studies.  
b) Hormonal contraception may be susceptible to interaction with the study intervention, 
which may reduce the efficacy of the contraceptive method. In this case, 2 highly 
effective methods of contraception should be utilized during the treatment period and 
for at least 5 months after the last dose of study intervention. 
 
Pregnancy Testing 
• WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test within 24 hours of first dose. 
• Additional pregnancy testing should be performed every 3 cycles during the treatment 
period. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
Collection of Pregnancy Information 
 
Male Participants with Partners who Become Pregnant 
• The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female Participants who Become Pregnant 
• The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on 
the appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of 
the pregnancy. The investigator will collect follow-up information on the participant 
and the neonate and the information will be forwarded to the Sponsor. Generally, 
follow-up will not be required for longer than 6 to 8 weeks beyond the estimated 
delivery date. Any termination of pregnancy will be reported, regardless of fetal 
status (presence or absence of anomalies) or indication for the procedure. 


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• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported 
as such. Any post-study pregnancy related SAE considered reasonably related to the 
study intervention by the investigator will be reported to the Sponsor as described in 
Section 11.1.3. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
 

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan 
 
Protocol Number: PICI0001 
 
Protocol Title: A Randomized, Phase 2 Study of Ipilimumab Vs Ipilimumab plus 
Nivolumab in Patients with Stage III-IV Melanoma Who Have Progressed or 
Relapsed on PD-1 Inhibitor Therapy 
 
 
 
NCT Number: 
NCT02731729 
 
Sponsor: 
Parker Institute for Cancer Immunotherapy (PICI) 
1 Letterman Drive 
Suite D3500 
San Francisco, CA 94129 
Tel: 
415-985-7311 
Fax: 
415-872-5305 
 
 
Date Final 
12-APR-2019 
 
 
 
 
 


 
1 
 
 
 
Statistical Analysis Plan for 
Protocol Number:  PICI0001 
 
Protocol Title:  A Randomized, Phase 2 Study of Ipilimumab vs Ipilimumab 
plus Nivolumab in Patients with Stage III-IV Melanoma Who Have 
Progressed or Relapsed on PD-1 Inhibitor Therapy 
 
IND Number: 
Not Applicable 
Name of Products: 
Ipilimumab and Nivolumab 
Phase of Development: 
2 
Indication: 
Stage III-IV Melanoma 
Sponsor: 
Parker Institute for Cancer Immunotherapy 
1 Letterman Drive, Suite D3500 
San Francisco, CA 94129 
Tel: 
415-985-7311 
Fax: 415-872-5305 
Date Final: 
12-APR-2019 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Parker Institute for 
Cancer Immunotherapy.  Any unauthorized copying or use of this document is prohibited. 




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Statistical Analysis Plan for PICI0001 Protocol 
 
 
 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ................................................................................................ 3 
List of TABLES ..................................................................................................... 4 
List of FIGURES .................................................................................................... 4 
2 
INTRODUCTION ........................................................................................................... 5 
3 
STUDY DESIGN ............................................................................................................ 5 
3.1 
Protocol Synopsis .................................................................................................6 
3.2 
Study Objectives ...................................................................................................6 
3.2.1 
Primary Objective ..................................................................................6 
3.2.2 
Secondary Objectives .............................................................................6 
3.2.3 
Exploratory Objectives ..........................................................................6 
3.3 
Study Endpoints ....................................................................................................6 
3.3.1 
Primary Endpoint ...................................................................................6 
3.3.2 
Secondary Endpoints .............................................................................7 
3.3.3 
Exploratory Endpoints ...........................................................................7 
3.4 
Determination of Sample Size ..............................................................................7 
3.5 
Analysis Timing ....................................................................................................8 
4 
STUDY CONDUCT ........................................................................................................ 8 
4.1 
Randomization Details ..........................................................................................8 
4.2 
Data Monitoring ....................................................................................................8 
5 
STATISTICAL METHODS ............................................................................................ 8 
5.1 
Analysis Populations .............................................................................................8 
5.1.1 
Efficacy-Evaluable Population ..............................................................8 
5.1.2 
Safety-Evaluable Population ..................................................................8 
5.2 
Analysis of Study Conduct ...................................................................................9 
5.3 
Analysis of Treatment Group Comparability .......................................................9 
5.4 
Efficacy Analysis ..................................................................................................9 
5.4.1 
Primary Efficacy Endpoint ..................................................................10 
5.4.2 
Secondary Efficacy Endpoints .............................................................10 
5.4.3 
Exploratory Efficacy Endpoints ...........................................................11 
5.4.4 
Sensitivity Analyses .............................................................................11 
5.5 
Safety Analysis ...................................................................................................11 


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5.5.1 
Exposure of Study Medication .............................................................11 
5.5.2 
Adverse Events ....................................................................................11 
5.5.3 
Laboratory Data ...................................................................................12 
5.5.4 
Vital Signs ............................................................................................12 
5.5.5 
Physical Examinations .........................................................................12 
5.6 
Missing Data .......................................................................................................12 
5.6.1 
Missing and Partial Missing Adverse Event Dates ..............................12 
5.6.2 
Partial Missing Death Dates .................................................................12 
5.6.3 
Partial Missing Treatment Failure Dates .............................................12 
5.7 
Interim Analyses .................................................................................................13 
6 
DIFFERENCES COMPARED TO PROTOCOL ......................................................... 13 
7 
REFERENCES .............................................................................................................. 14 
8 
APPENDICES ............................................................................................................... 15 
8.1 
Protocol Synopsis ...............................................................................................15 
8.2 
Schedule of Assessments ....................................................................................21 
 
LIST OF TABLES 
Table 1: Confidence Intervals for the True Proportion of Responders ...................................7 
 
LIST OF FIGURES 
Figure 1: Study Schema ............................................................................................................6 


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2 
INTRODUCTION 
The purpose of this document is to provide details of the planned analyses for Study PICI0001. 
The primary analyses described in the main body of this document will be performed after all 
participants have completed the 2-year follow-up period in the study or discontinued early, and 
all corresponding data have been entered into the database, reviewed, and verified and the 
database locked. No changes to the SAP will be allowed at the time of or subsequent to 
database lock. 
The analyses specified in this document supersede the high-level analysis plan described in the 
protocol.  
Statistical analyses will be performed using SAS or R statistical software. 
3 
STUDY DESIGN 
Study PICI0001 is a multi-center, randomized, Phase 2 study of ipilimumab vs ipilimumab 
plus nivolumab in participants with unresectable Stage III or Stage IV melanoma who were 
refractory to PD-1 inhibitor monotherapy.  
There will be two treatment arms in this study: 
Arm A: Participants will receive combination checkpoint blockade with ipilimumab and 
nivolumab.  
Arm B: Participants will receive ipilimumab alone. 
Participants who are eligible will be required to have a pre-treatment biopsy and then will be 
randomized to either ipilimumab alone or ipilimumab in combination with nivolumab. 
Participants will receive treatment for up to 4 cycles followed by an observation phase. 
The primary objective is to determine the response rate of combination ipilimumab/nivolumab 
and ipilimumab alone in participants previously treated with a PD-1 inhibitor by Week 18 of 
therapy. The total planned enrollment is 24 total participants, with 12 participants randomly 
allocated to each arm. Participants will be assessed for the primary endpoint at Week 18. They 
will then be followed for time to treatment failure (TTF) and overall survival (OS) for up to 2 
years.  
The study design is depicted in Figure 1. 


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Figure 1: 
Study Schema 
 
Note: The on-treatment biopsy has a window of ±5 days.  
 
3.1 
Protocol Synopsis 
The Protocol Synopsis is included as Appendix 1. The Schedule of Assessments is included 
as Appendix 2. 
3.2 
Study Objectives  
3.2.1 Primary Objective  
The primary objective is to assess response rates of combination ipilimumab/nivolumab and 
ipilimumab alone in participants previously treated with a PD-1 inhibitor by Week 18 of 
therapy. 
3.2.2 Secondary Objectives  
The secondary objectives are: 
• To assess clinical benefit of combination ipilimumab/nivolumab and ipilimumab alone. 
• To evaluate time to treatment failure (TTF) and overall survival (OS) for each arm. 
• To assess safety and tolerability of ipilimumab alone and in combination with 
nivolumab in previously treated participants. 
3.2.3 Exploratory Objectives  
The exploratory objectives for this study are listed in Appendix 1. 
3.3 
Study Endpoints 
3.3.1 Primary Endpoint 


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The primary endpoint is the response to ipilimumab/nivolumab and ipilimumab alone by Week 
18, defined as having achieved a complete response (CR) or partial response (PR) as measured 
by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria or a PR/CR at any 
time prior to Week 18. 
3.3.2 Secondary Endpoints 
The secondary endpoints are: 
• The disease control rate (DCR) by RECIST v1.1 criteria of overall tumor burden at 
Week 12, where DCR is defined as participants who achieve stable disease (SD), PR, 
or CR. 
• DCR at Week 18, where DCR is defined as participants who achieve SD, PR, or CR. 
• TTF up to two years, where TTF is defined as the time from first study drug treatment 
until the participant is started on another line of systemic therapy or participant death, 
whichever occurs first. Participants who are alive and do not start another therapy will 
be censored at the time of last follow-up. 
• OS up to two years, where OS is defined as the time from first study drug treatment 
until death from any cause. Participants without documentation of death will be 
censored on the date of last contact. 
• Safety and tolerability, as measured by: 
o Incidence and severity of adverse events, with severity determined through the 
use of the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. 
o Change from baseline in physical examination findings, vital signs, and clinical 
laboratory results. 
3.3.3 Exploratory Endpoints 
The exploratory endpoints for this study are listed in Appendix 1. 
3.4 
Determination of Sample Size 
This study is not intended or powered for hypothesis testing. The study is intended to provide 
preliminary estimates of adverse events, response rates, effect sizes and confidence intervals. 
A sample size of approximately twelve participants in each arm, for a total of 24 participants, 
will provide these preliminary estimates. The study protocol incorrectly states that a Simon 2-
stage design will be implemented for this study. A 2-stage design was not implemented; rather, 
a single-stage design was used. 
Table 1 provides 95% exact confidence intervals for the proportion of responders per treatment 
arm. These confidence intervals provide information needed for the design of future studies. 
Table 1: 
Confidence Intervals for the True Proportion of Responders 
Observed responder rate 
95% Confidence Interval  
(n = 12) 
8.3% (1/12) 
(0.2%, 38.5%) 
16.7% (2/12) 
(2.1%, 48.4%) 
25.0% (3/12) 
(5.5%, 57.2%) 
33.3% (4/12) 
(9.9%, 65.1%) 


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41.7% (5/12) 
(15.2%, 72.3%) 
50.0% (6/12) 
(21.1%, 78.9%) 
3.5 
Analysis Timing 
The analysis of complete data for the study, including data from the follow-up period, will be 
performed when all participants have either (i) completed two years of follow-up, (ii) 
discontinued early from the study, or (iii) died, and all data from the study are in the database 
and the database is locked.  
4 
STUDY CONDUCT 
4.1 
Randomization Details 
Randomization will be managed centrally using an interactive voice response system (IVRS). 
Participants will be randomized following their pre-treatment biopsy at the Screening/Baseline 
Visit. Participants will be stratified based on their previous response to PD-1 therapy.   
4.2 
Data Monitoring 
The study will be closely monitored, and data will be reviewed on an ongoing basis. In order 
to ensure the safety and well-being of participating subjects, as well as the validity of data 
during the study, a Data Review Team (DRT) will review the safety and further emerging data 
on a regular basis.  During these meetings, aggregated safety data and individual participant 
data derived from medical data listing reviews will be presented, reviewed, and discussed.  The 
DRT team will consist of team members from the Sponsor, the Contract Research Organization 
(CRO), the Coordinating Principal Investigator (PI), and all active PIs.   
5 
STATISTICAL METHODS 
Summary statistics will be presented by treatment arm.  For continuous variables, data will be 
summarized with the number of participants (N), mean, standard deviation, median, minimum, 
and maximum. For categorical variables, data will be tabulated with the number and proportion 
of participants for each category. 
5.1 
Analysis Populations 
5.1.1 Efficacy-Evaluable Population 
The efficacy-evaluable population will include all participants who were randomly allocated 
to receive either combination ipilimumab/nivolumab or ipilimumab alone and received at least 
one dose of any study intervention (ipilimumab or nivolumab). For analyses based on this 
population, participant treatment groups will be defined according to the treatment that was 
assigned at randomization (ipilimumab/nivolumab or ipilimumab alone). 
5.1.2 Safety-Evaluable Population 
The safety-evaluable population, also referred to as the toxicity-evaluable population in the 
study protocol, will include all participants who received at least one dose of any study 
intervention (ipilimumab or nivolumab). Note that this is a more conservative definition than 


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the toxicity-evaluable population defined in the Protocol, which includes all participants who 
completed at least one cycle on either treatment arm. For analyses based on this population, 
participant treatment groups will be defined according to the treatment that was assigned at 
randomization. However, if a participant received the incorrect study drug for the entire period 
of treatment, the participant’s treatment group will be defined as the incorrect drug the 
participant actually received. 
5.2 
Analysis of Study Conduct 
The number of participants randomized will be tabulated by treatment arm. Participant 
disposition (the number of participants randomized, receiving at least one cycle of study drug 
during the treatment period, and completing the 4-cycle treatment period) and time on study 
will be tabulated by treatment arm. Reasons for premature discontinuation from study 
treatment and reasons for premature discontinuation from the study, including the 2-year 
follow-up period, will be summarized. 
5.3 
Analysis of Treatment Group Comparability 
Demographic and baseline characteristics, including but not limited to age, sex, race, ethnicity, 
melanoma subtype, melanoma disease stage, previous response to anti-PD-1 therapy, time 
since last anti-PD-1 treatment, baseline Eastern Cooperative Oncology Group (ECOG) 
performance status, and baseline lactate dehydrogenase (LDH) levels will be summarized for 
the efficacy-evaluable population by treatment arm using descriptive statistics. The baseline 
measurement used for the analysis of treatment group comparability is assumed to be from the 
Baseline/Screening Visit.  
5.4 
Efficacy Analysis  
Efficacy analyses will be conducted on the efficacy-evaluable population (see Section 5.1.1), 
with participants grouped according to the treatment assigned at randomization. 
Per the intention-to-treat principle, data from all randomized and dosed participants, regardless 
of adherence to study drug or to the protocol, will be included in the efficacy analyses. Efficacy 
summaries will include data from participants who discontinued study drug early but continued 
with study assessments and may include data collected at unscheduled visits, early termination 
visits, or follow-up visits. 
Comparisons of Interest 
This study is not powered for statistical comparisons between arms.  
Type I Error Management 
This study is not intended or powered for hypothesis testing. Due to the exploratory nature of 
this study, no control of type I error will be applied for any of the endpoints. 
Covariate Adjustment 
Unless otherwise noted, analyses of primary and secondary efficacy endpoints will be adjusted 
for the following covariate: 
• Previous response to PD-1 therapy (primary refractory disease, progressive disease) 


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Given that the above covariate is the stratification factor used when randomly allocating 
participants, no missing data of this baseline covariate is expected. 
5.4.1 Primary Efficacy Endpoint 
The primary endpoint is the response to ipilimumab/nivolumab and ipilimumab alone by Week 
18, defined as having achieved CR or PR as measured by RECIST v1.1 criteria, or a PR/CR at 
any time prior to Week 18.  
The objective response rate (ORR) is defined as the number of participants whose best 
objective response (BOR) is CR or PR divided by the total number of participants in the 
population of interest. Participants with a BOR of stable disease (SD), progressive disease (PD) 
or without a post-baseline tumor assessment will be considered non-responders and, thus, will 
be counted in the denominator of the ORR calculation.  
The BOR is defined as the best response designation, as determined by the investigator, 
recorded between the date of randomization and the date of subsequent anticancer therapy 
(including tumor-directed radiotherapy and tumor-directed surgery). For participants without 
subsequent anticancer therapy, all available response designations through Week 19 (Week 18 
+7 day window) will contribute to the BOR assessment.  
The ORR will be estimated within each treatment arm and 95% confidence intervals (CIs) will 
be estimated using the Clopper-Pearson method. 
This study is not powered for statistical comparisons between arms. To aid in interpretation, 
each arm will be indirectly compared to the historical ipilimumab ORR of 10.9% (Hodi et al. 
2010). 
5.4.2 Secondary Efficacy Endpoints 
Disease Control Rate  
DCR is defined as the proportion of participants who achieve SD, PR, or CR as measured by 
RECIST v1.1. That is, DCR is the number of participants whose BOR is SD, PR, or CR divided 
by the total number of participants in the population of interest. For SD, measurements must 
have met the SD criteria per RECIST v1.1 at least once after study entry, with disease 
assessment occurring at least 8 weeks after first study drug treatment. 
DCR will be assessed at Week 12 (+7 days) and Week 18 (+7 days). DCR will be estimated 
within each treatment arm and 95% confidence intervals (CIs) will be estimated using the 
Clopper-Pearson method. 
This study is not powered for statistical comparisons between arms. To aid in interpretation, 
each arm will be indirectly compared to the historical ipilimumab DCR of 28.5% (Hodi et al. 
2010).  
Time to Treatment Failure 
TTF is defined as the time from first study drug treatment until the participant is started on 
another line of systemic therapy or participant death, whichever occurs first. Participants who 
are alive and do not start another therapy will be censored at the date of last follow-up. Time 
to event distributions will be estimated using Kaplan-Meier techniques. 


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Overall Survival 
OS is defined as the time from first study drug treatment until death from any cause. 
Participants without documentation of death will be censored on the date of last contact. Time 
to event distributions will be estimated using Kaplan-Meier techniques.  
5.4.3 Exploratory Efficacy Endpoints 
Exploratory endpoints defined in the protocol are outside the scope of this SAP.  
5.4.4 Sensitivity Analyses 
No sensitivity analyses are planned for this study. 
5.5 
Safety Analysis  
Safety will be assessed through the summary of adverse events (AEs), serious adverse events 
(SAEs), laboratory test results (hematology and serum chemistry), vital signs, and physical 
examinations. Safety summaries will include endpoints as described in Section 3.3.2. This may 
include data collected at unscheduled visits, early termination visits, or follow-up visits. 
Safety outcomes will be summarized based on the safety-evaluable population (see Section 
5.1.2). Safety summaries will be presented by treatment arm. 
5.5.1 Exposure of Study Medication 
Exposure to study drug will be summarized by treatment arm assigned at randomization.  
The number of doses of study drug received will be summarized using descriptive statistics.  
5.5.2 Adverse Events 
Each AE will be coded using MedDRA dictionary version 19.1 and graded using the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  
AEs with relationship to study drug of “Possible”, “Probable”, “Definite”, or unknown 
(missing) will be considered drug-related. 
Treatment-emergent adverse event (TEAE) is defined as an AE occurring on or after Day 1 of 
study treatment and having been absent pre-treatment or that has worsened relative to the pre-
treatment state, and no later than 100 days following the last day of study treatment. Events 
with an onset prior to Day 1 will constitute pre-treatment events. Any AE deemed related to 
study drug will also be considered as a TEAE regardless of elapsed time since last study 
treatment.  
Listings for all AEs, SAEs, and TEAEs will be presented. Summaries of treatment-emergent 
events by treatment arm will be provided for each of the following categories: 
• AEs 
• AEs by most extreme severity 
• AEs assessed as related to study drug by the investigator 
• SAEs 
• AEs leading to discontinuation of study treatment 
In addition, participant deaths and the primary cause of death will be listed, as well as any 
cases of pregnancy.  


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5.5.3 Laboratory Data 
Routine clinical laboratory findings will be summarized using descriptive statistics for each 
treatment group. Changes from baseline to each visit will be determined for quantitative 
variables. 
5.5.4 Vital Signs 
Vital signs at each visit and change from baseline to each post-baseline visit will be 
summarized using descriptive statistics for each treatment arm. 
5.5.5 Physical Examinations 
Physical examination data will not be summarized because any significant findings should be 
captured and summarized as adverse events. 
5.6 
Missing Data 
5.6.1 Missing and Partial Missing Adverse Event Dates 
Partially missing data of AE onset date may be imputed in order to avoid eliminating 
information from summary tables of TEAEs. If the day of an AE onset date is missing but both 
the month and year are available, the AE will be flagged as treatment-emergent if the date is 
conservatively estimated to be within 100 days after the last dose of study drug administration. 
Any AE deemed related to study drug will also be considered a TEAE regardless of elapsed 
time since last study drug administration. There will be no attempt to impute missing or 
partially missing dates for the listing of AEs. 
5.6.2 Partial Missing Death Dates 
For death dates, the following conventions will be used for imputing partial dates: 
• If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. The imputed date will be compared to the last known date alive plus 1 
day, and the maximum will be considered as the death date. 
• If the month or the year is missing, the death date will be imputed as the last known 
date alive plus 1 day. 
• If the date is completely missing but the reason for death is present, the death date will 
be imputed as the last known date alive plus 1 day. 
5.6.3 Partial Missing Treatment Failure Dates 
For date of treatment failure, the following conventions will be used for imputing partial dates: 
• If only the day of the month is missing, the 1st of the month will be used to replace the 
missing day. In cases where the date of death is present and complete, the imputed 
treatment failure date will be compared to the date of death. The minimum of the 
imputed treatment failure date and date of death will be considered as the date of 
treatment failure. 
• If the day and month are missing or a date is completely missing, it will be considered 
as missing. 


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5.7 
Interim Analyses  
No formal interim analysis is planned for this study. 
6 
DIFFERENCES COMPARED TO PROTOCOL 
• Section 3.4 (Determination of Sample Size): SAP provides additional justification for 
the selection of sample size.  
• Section 3.4 (Determination of Sample Size): The study protocol incorrectly states that 
a Simon 2-stage design will be implemented for this study. The SAP clarifies that a 2-
stage design was not implemented. 
• Section 5.1.2 (Safety-Evaluable Population): The toxicity-evaluable population 
referred to in the Protocol has been modified and renamed the safety-evaluable 
population in the SAP. All safety analyses will be conducted on the safety-evaluable 
population and not the toxicity-evaluable population. 
• Section 5.4.4 (Safety Analysis): Although the Protocol lists physical examination 
findings as a secondary safety endpoint, physical examination data will not be 
summarized because any significant findings should be captured and summarized as 
adverse events. 
• Section 6.1.2 (Randomization): Although the protocol states that participants will be 
stratified based on melanoma subtype, this stratification factor was not implemented 
into the IVRS. Participants were only stratified on their previous response to PD-1 
therapy (primary refractory vs progressive disease). 
• Section 12 (Statistical Analysis): SAP clarifies that the statistical analyses may be 
performed using SAS or R statistical software. 


Parker Institute for Cancer Immunotherapy 
PICI0001 
Statistical Analysis Plan for Protocol PICI0001 
 
 
 
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7 
REFERENCES 
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients 
with metastatic melanoma. The New England journal of medicine. 2010;363(8):711-723. 
 


Parker Institute for Cancer Immunotherapy 
PICI0001 
Statistical Analysis Plan for Protocol PICI0001 
 
 
 
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8 
APPENDICES 
8.1 
Protocol Synopsis 
Title of Study: 
A Randomized, Phase 2 Study of Ipilimumab vs Ipilimumab plus 
Nivolumab in Participants with Stage III-IV Melanoma Who Have 
Progressed or Relapsed on PD-1 Inhibitor Therapy 
Protocol Number: 
PICI0001 
Investigators/Study Sites: 
This study will be conducted at multiple sites in the United States.   
Phase of Development: 
2 
Objectives: 
Primary Objectives:   
To assess response rates of combination ipilimumab/nivolumab and 
ipilimumab alone in participants previously treated with a programmed 
death receptor (PD-1) inhibitor by Week 18 of therapy.  
Secondary Objectives:   
• 
To assess clinical benefit of combination ipilimumab/nivolumab and 
ipilimumab alone 
• 
To evaluate time to treatment failure and overall survival (OS) for 
each arm 
• 
To assess safety and tolerability of ipilimumab alone and in 
combination with nivolumab in previously treated participants 
Exploratory Objectives:   
• 
To evaluate peripheral lymphocyte phenotype changes throughout 
treatment 
• 
To evaluate changes in quantities of myeloid derived suppressor cells 
(MDSCs), defined as CD14+HLA-DRlow cells, and Treg cells, defined 
as CD4+FOX3P+ cells, throughout treatment 
• 
To evaluate nCounter immune profiling of the tumor before treatment  
• 
To explore tumor neoepitopes and mutational burden via whole gene 
and exome sequencing on pre-treatment tumor biopsy and correlation 
with clinical response 
• 
To stratify clinical response rate by PD-L1 expression on 
pre-treatment biopsies 
• 
To evaluate the tumor immune microenvironment on pre- and 
on-treatment tumor biopsies 
Study Design: 
This is a multi-center, randomized Phase 2 study of ipilimumab vs 
ipilimumab plus nivolumab in participants previously treated with a PD-1 
inhibitor by Week 18 of therapy.  There will be 2 arms in the study.   
Arm A: Participants will receive combination checkpoint blockade with 
ipilimumab and nivolumab.   
Arm B: Participants in this arm will receive ipilimumab alone.   
A Simon 2-stage design will be implemented in each arm, allowing for 
early stopping for futility.  Participants who are eligible will be required to 
have a pre-treatment biopsy and then will be randomized to either 
ipilimumab alone or ipilimumab in combination with nivolumab.  
Participants will be required to have an on-treatment biopsy within 
14±5 days of their first dose of treatment.  Participants will receive up to 
4 cycles of treatment followed by observation phase.   
Participants will be assessed for the primary endpoint at 18 weeks and then 
be followed for time to treatment failure (TTF) and OS for up to 2 years.   


Parker Institute for Cancer Immunotherapy 
PICI0001 
Statistical Analysis Plan for Protocol PICI0001 
 
 
 
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Selection of Participants: 
Main Inclusion Criteria:   
1. AJCC (2009) Stage IV cutaneous melanoma or Stage III cutaneous, 
acral or mucosal melanoma that is judged inoperable.  Participants 
with a history of uveal melanoma are not eligible.   
2. Measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm with conventional techniques or as >10 mm 
with computerized tomography (CT) scan.  Participants must have at 
least one measurable lesion by Response Evaluation Criteria in Solid 
Tumors (RECIST) and a separate lesion amenable to biopsy.   
3. Histologic proof of melanoma reviewed and confirmed by the 
enrolling site.  
4. Previous treatment with a PD-1 or PD-L1 inhibitor with documented 
progression of disease on most recent CT scan.  Progression of 
disease is defined as 1) the appearance of a new measurable lesion 
(>10 mm) on cross-sectional imaging or physical examination OR 2) 
enlargement of previously detected lesions on two consecutive 
imaging studies OR 3) enlargement of a previously detected lesion 
with correlative symptomatology on one cross-sectional imaging 
study.  Participants remain eligible if they had a previous response to 
a PD-1 inhibitor, including participants who had a complete response, 
partial response or stable disease (SD).  Any participant who had 
refractory or relapsed disease is eligible for study enrollment. 
Treatment populations are defined in Section 12. 
5. Participants who received adjuvant PD-1 therapy who then develop 
measurable disease are eligible.  However, they must have received 
their last dose of PD-1/PD-L1 blockade within two months of 
enrollment in this study.  They will be stratified with participants who 
have primary progressive disease.  
6. Life expectancy of greater than 3 months. 
7. Age ≥ 18 years old. 
8. Eastern Cooperative Oncology Group performance status = 0 or 1 or 
Karnofsky Performance Status equivalent.   
9. Participants must have adequate organ and marrow function as 
defined below: 
a. 
White blood cells >2, 000/mcL 
b. Absolute neutrophil count >1,500/mcL 
c. 
Platelets >100,000/mcL 
d. Hemoglobin > 9.0 g/dL  
e. 
Total bilirubin ≤ 1.5 X institution’s upper limit of normal 
f. 
Aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase)/alanine aminotransferase (serum glutamic pyruvic 
transaminase) ≤ 2.5 X institution’s upper limit of normal for 
participants with no concurrent liver metastases, OR ≤ 5 X 
institution’s upper limit of normal for participants with 
concurrent liver metastases 
g. Serum creatinine < 1.5x OR creatinine clearance of at least 40 
10. Women of childbearing potential must have a negative serum 
pregnancy test within 24 hours prior to the start of study drug.  A 
woman of childbearing potential is defined as any female who has 
experienced menarche and who has not undergone surgical 
sterilization (hysterectomy or bilateral oophorectomy) or is not 
postmenopausal.  Menopause is defined clinically as 12 months of 
amenorrhea in a woman over age 50 in the absence of other biologic 
or physiologic causes.  


Parker Institute for Cancer Immunotherapy 
PICI0001 
Statistical Analysis Plan for Protocol PICI0001 
 
 
 
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11. Women with child bearing potential and men with reproductive 
potential must be willing to practice acceptable methods of 
contraception. 
12. Ability to understand and the willingness to sign a written informed 
consent document.  
13. Willingness to undergo biopsy of metastatic site or site of 
unresectable disease prior to randomization.  
 
Main Exclusion Criteria: 
1. Concurrent malignancies: 
a. Participants with a previously treated malignancy are eligible to 
participate if all treatment of that malignancy was completed at 
least 2 years before registration and the participant has no 
evidence of disease. 
b. Participants who have a concurrent malignancy that is clinically 
stable and does not require tumor-directed treatment are eligible 
to participate if the risk of the prior malignancy interfering with 
either safety or efficacy endpoints is very low (with agreement 
from the sponsor and principal investigator). 
c. Other malignancies may be permitted if the risk of the prior 
malignancy interfering with either safety or efficacy endpoints is 
very low (with agreement from the sponsor and principal 
investigator). 
2. Any major surgical procedures or external beam radiotherapy within 
14 days prior to study drug administration.  
3. Use of other investigational drugs within 28 days prior to study drug 
administration.   
4. Symptomatic or untreated leptomeningeal or brain metastases or 
spinal cord compression. Treated brain metastases must have been 
stable for at least 1 month and require treatment with less than 
10mg/day prednisone equivalent for at least 2 weeks prior to study 
drug administration.   
5. Prior exposure to either ipilimumab or combined checkpoint 
blockade.  
6. Any diagnosis of autoimmune disease.  Participants with Type I 
diabetes 
mellitus, 
hypothyroidism 
only 
requiring 
hormone 
replacement, adrenal insufficiency on replacement dose steroids, skin 
disorders (such as vitiligo, psoriasis or alopecia) not requiring 
systemic treatment, or conditions not expected to recur in the absence 
of an external trigger are permitted to enroll.   
7. Pregnant women and lactating women.  
8. History of uveal melanoma.  
9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus 
(HBV), or Hepatitis C Virus (HCV) infection (with the exception of 
chronic or cleared HBV or HCV infection, which will be allowed). 
Once-documented negative result for HIV, HBV, and HCV is 
sufficient.   
10. Uncontrolled intercurrent illness including, but not limited to, 
ongoing or active infection and psychiatric illness/social situations 
that would limit compliance with study requirements.   
11. Participants with a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalent) or other 
immunosuppressive medications within 14 days of study drug 
administration.  Inhaled or topical steroids and adrenal replacement 
steroid doses > 10 mg daily prednisone equivalent are permitted.  


Parker Institute for Cancer Immunotherapy 
PICI0001 
Statistical Analysis Plan for Protocol PICI0001 
 
 
 
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12. Participants with history of any grade 4 toxicity during previous anti 
PD-1 treatment or history of Grade 3 or higher pneumonitis.  
13. Participants with a history of Grade ≥2 neuropathy.  
14. Prisoners or participants who are involuntarily incarcerated.  
15. Children under the age of 18.   
16. Participants who require hemodialysis.  
17. Participants with a history of allergy to study drug components or 
history of a severe hypersensitivity reaction to any monoclonal 
antibody.   
Planned Sample Size: 
Twelve participants will be enrolled in each arm for a total of 
24 participants.   
Investigational Therapy: 
Not Applicable 
Reference Therapy: 
Arm A: Nivolumab (1 mg/kg of body weight) in combination with 
ipilimumab (3 mg/kg), both once every 3 weeks for 4 doses administrated 
intravenously.   
Or  
Arm B: ipilimumab (3 mg/kg) alone, once every 3 weeks for 4 doses 
administrated intravenously.   
Treatment Duration: 
Participants on both arms will receive treatment for up to 4 cycles (each 
cycle is of 21 days±4 days) and then be observed for up to 2 years in the 
follow up period.   
Participants will undergo screening and, if eligible, will undergo 
intervention in the selected arm of the study up to 4 cycles.   
Criteria for Evaluation: 
Efficacy:  Therapeutic response and outcome assessment will be done in 
this study using the international criteria proposed by the RECIST 
version 1.1 Committee.  Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the 
RECIST criteria.  Lesions are either measurable or non-measurable.  
“Target” and “Non-Target” lesions will be identified and recorded at 
baseline.  Responses will be assessed as follows: 
• 
Complete Response (CR): Disappearance of all target and non-target 
lesions and no evidence of new lesions documented by 2 disease 
assessments at least 4 weeks apart.   
• 
Partial Response (PR):  At least a 30% decrease in the in the longest 
dimension (LD) of all target lesions, taking as reference the baseline 
sum LD.  There can be no unequivocal progression of non-target 
lesions and no new lesions.  Documentation by 2 disease assessments 
at least 4 weeks apart is required.  Progressive Disease (PD):  At least 
a 20% increase in the sum of LD of target lesions, taking as reference 
the smallest sum LD or the appearance of new lesions within 8 weeks 
of study entry. In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.   
• 
Stable Disease (SD):  Any condition not meeting the above criteria.   
• 
Inevaluable for response is defined as having no repeat tumor 
assessments following initiation of study therapy for reasons 
unrelated to symptoms or signs of disease.  
Outcome will be assessed as follows: 
• 
Objective Response Rate (ORR):  The proportion of participants with 
either (1) CR or (2) PR by RECIST 1.1 criteria.   
• 
Survival:  The observed length of life from first dose of study drug to 
death or the date of last contact.   
• 
Time to treatment failure:  Is defined as the time from first study drug 
treatment until the participant is started on another line of systemic 
therapy or participant death, whichever occurs first.  Participants who 


Parker Institute for Cancer Immunotherapy 
PICI0001 
Statistical Analysis Plan for Protocol PICI0001 
 
 
 
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are alive and do not start another therapy will be censored at the time 
of last follow-up.   
Safety:  Safety assessments (vital signs, physical examinations, 
performance status, height/weight, electrocardiogram (ECG) recording, 
adverse events (AEs), clinical laboratory results (routine hematology and 
biochemistry, and CT and magnetic resonance imaging [MRI] scans) are 
to be performed at protocol-specified visits. 
Study Endpoints: 
Primary endpoints:  
• 
The response to combination ipilimumab/nivolumab and ipilimumab 
alone at Week 18 defined as having achieved a complete response or 
PR as measured by RECIST 1.1 criteria or a PR/complete response 
at any time prior to Week 18.   
Secondary endpoints:  
• 
Disease control rate (DCR) by RECIST v1.1 criteria of overall tumor 
burden at Week 12 and Week 18.  DCR is defined as participants who 
achieve SD, PR or complete response. 
• 
TTF and OS up to 2 years.  
• 
Safety and tolerability measured via metrics such as laboratory tests, 
vital signs, physical examinations as well as toxicity as graded by 
Common Terminology Criteria for Adverse Events v4.0.  
Exploratory endpoints:  
• 
All research samples for exploratory endpoints will be analyzed at a 
Parker Institute for Cancer Immunotherapy selected testing center.   
• 
Peripheral lymphocyte phenotype changes throughout treatment, 
including Treg cells, defined as CD4+FOX3P+ cells, will be expressed 
using descriptive statistics at pre and post treatment time points. 
These will be assessed via flow cytometry of peripheral blood 
mononuclear cells. 
• 
Changes in quantities of MDSCs, defined as CD14+HLA-DRlow 
cells, throughout treatment will be expressed using descriptive 
statistics at pre and post treatment time points.  
• 
nCounter immune profiling of the tumor before treatment will be 
expressed using descriptive statistics at pre and post treatment time 
points and will be correlated with clinical response also using logistic 
regression models. 
• 
Tumor neoepitopes and mutational burden will be correlated with 
clinical response also using logistic regression models. 
• 
Summary statistics will be generated and differences between 
mutation burden or neo-antigen score as they relate to PD-L1 
expression 
• 
Immunohistochemistry (IHC) will be used to assess PD-L1 
expression on both immune cells and tumor cells.  PDL-1 expression 
will be assessed pretreatment and on-treatment.  A participant will be 
PD-L1 + if >1% of cells express PD-L1. If response data permit, the 
tumor positivity of PD-L1 expression will be compared in the pre- 
and post-treatment biopsies using a Wilcoxon signed rank test. 
• 
Pre- and on- treatment PD-L1 expression and will be correlated with 
clinical response also using logistic regression models.  
• 
IHC will be used to quantify cytotoxic and regulatory T-cells, 
including stains for CD3, CD4, CD8, FOXP3, inducible 
co-stimulatory and Lag3.  Associations from pre to post treatment 
will be assessed using the Wilcoxon signed rank test for paired 


Parker Institute for Cancer Immunotherapy 
PICI0001 
Statistical Analysis Plan for Protocol PICI0001 
 
 
 
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comparisons (e.g., the continuous measure, density of cells per 
high powered field). 
Statistical Methods and 
Planned Analyses: 
This is a multi-center, randomized, Phase 2 study of ipilimumab and 
combined checkpoint blockade with ipilimumab and nivolumab.  
Randomization will be performed via a central process.  In each arm, an 
optimal Simon 2-stage design will be implemented.  A response rate of 
10% or less would not be considered promising (null hypothesis) as the 
ipilimumab response rate in untreated participants is 10.9%.  A response 
rate of at least 30% is promising (alternative hypothesis).  Point estimates 
and 95% confidence intervals for the response rates will be reported. Alpha 
(probability of Type I error) for hypothesis tests will be 0.1.  If 4 or more 
of 12 participants in an arm respond (response rate of 33% or greater), the 
treatment will be considered promising for further investigation. 
Efficacy evaluable population:  All participants who receive at least 
1 dose of study drug(s) will be evaluated for the primary endpoint.  
Participants who develop rapid symptomatic disease progression or drop 
out early due to death will be treated as non-responders.  Participants who 
develop early toxicities that require treatment delay or discontinuation will 
continue to be evaluable on study.  Participants may be replaced in either 
arm if they complete randomization but do not complete any cycles of 
therapy.   
The toxicity evaluable population:  Participants who have completed at 
least 1 treatment cycle on either arm will be considered evaluable for 
toxicity. 
Preferable treatment arm will be decided as follows:   
• 
If both arms have comparable response rates, the investigators will 
perform a comprehensive review of both the response data and 
toxicity data to decide which study arm is the preferable treatment 
moving forward.   
 
 
 


Parker Institute for Cancer Immunotherapy 
PICI0001 
Statistical Analysis Plan for Protocol PICI0001 
 
 
 
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8.2 
Schedule of Assessments 
  
Baseline/ 
Screeninga 
Cycle 1b 
Cycle 2 
Cycle 3 
Cycle 4 
Follow-up 
Visit 1 
and 2d 
Additional  
Follow-up 
Visitse 
Early 
Termination 
Visitf 
Obtain Informed Consent 
X 
  
  
  
  
  
  
 
Participant History 
X 
  
  
  
  
  
  
 
Inclusion/Exclusion 
criteria 
X 
  
  
  
  
  
  
 
Biopsy of Target Lesionc 
X 
X 
  
  
  
 
  
 
Prior/concomitant 
medications 
Collected from Screening to Follow-up 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
 
X 
Performance status 
X 
X 
X 
X 
X 
X 
 
X 
Height/Weight 
X 
X 
X 
X 
X 
X 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
X 
Complete Blood Count 
X 
X 
X 
X 
X 
X 
 
X 
Complete Metabolic Panel, 
LDH 
X 
X 
X 
X 
X 
X 
 
X 
Thyroid function testingg 
X 
X 
X 
X 
X 
X 
  
X 
Pregnancy test (serum) 
X 
X 
X 
X 
X 
X 
  
X 
HCV, HBV, HIV Testing 
X 
  
  
  
  
  
  
 
CT scanh 
X 
  
  
  
X 
X 
  
X 
MRI Brain 
X 
 
 
 
 
 
 
 
ECG 
X 
  
  
  
  
  
  
 
Adverse Events 
Collected from consent to 100 days after drug discontinuation 
 
Drug Administration 
 
X 
X 
X 
X 
  
  
 
Research blood (~40mL) 
X 
X 
X 
X 
X 
X 
  
X 


Parker Institute for Cancer Immunotherapy 
PICI0001 
Statistical Analysis Plan for Protocol PICI0001 
 
 
 
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PD-L1 expression on 
banked tumor specimen if 
available 
X 
 
 
 
 
 
 
 
Survival Data 
  
  
  
  
  
X 
X 
X 
aScreening assessments are recommended to be performed within 28 days prior to treatment unless otherwise specified above 
bEach cycle=21 days±4 days  
cBiopsy at baseline for all participants within 14 days of Cycle 1, Day 1.  On-treatment biopsy must be performed within 14 days±5 days of 
first dose of study drug. 
dFollow up period begins when the last dose of study therapy is administered.  Follow-up visit 1=21 days from last dose ± 7 days.  Follow-up 
visit 2=42 days from last dose ± 7 days. If the participant completed follow-up visit 1 and follow-up visit 2 and has progressed, the participant 
is not required to have scans every 12 weeks. Survival could be assessed via calls every 3 months (±7 days). If a participant is off treatment and 
has not progressed, they would continue to visit the site and have scans every 12 weeks. 
eAdditional follow-up visits will be scheduled every 3 months ±7 days.  For participants who end treatment for toxicity, scans should continue 
every 12 weeks until progression of disease. After progression of disease, survival calls will occur every 3 months (±7 days). 
fFor participants who terminate the study early, follow-up will begin 21 days from the last dose (follow-up visit 1). 
gTSH will be checked at every visit and will reflex to check free T4 if abnormal. 
hPer standard of care to provide data for RECIST measurements as appropriate for each participant per the investigator physician. CT scans 
will be performed at baseline (-7 days), Week 12, Week 18, and every 12 weeks (±7 days) thereafter until progression of disease, death, or end 
of study for up to 2 years.  A CT scan of the chest, abdomen and pelvis or an MRI of the abdomen and pelvis plus a non-contrast CT of the 
chest are acceptable.