A Phase II Study of Combination Immunotherapy With Ipilimumab and Nivolumab in Patients With Advanced Non-small Cell Lung Cancer Resistant to Anti-PD-1-axis Therapy
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Yale University

Title: A phase II study of combination immunotherapy with ipilimumab and 
nivolumab in patients with advanced non-small cell lung cancer resistant to anti-
PD-1-axis therapy 
ClinicalTrials.gov ID: NCT03262779 
Last Approval Date: 4/1/2021 
Document: Protocol and SAP 

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HIC Protocol #: 2000020343
IND #: 133633
TITLE:  A phase II study of combination immunotherapy with ipilimumab and nivolumab in 
patients with advanced non-small cell lung cancer resistant to anti-PD-1-axis therapy
Coordinating Center:
Yale Cancer Center
Principal Investigator:
Scott Gettinger, M.D.
Section of Medical Oncology 
Yale Cancer Center
333 Cedar Street, FMP-127 
New Haven, CT 06520
Tel: (203) 737-6980
Fax: (203) 785-3788
Scott.Gettinger@Yale.edu
Co-Investigators:
Roy Herbst, M.D., Ph.D. 
Sarah Goldberg, M.D. 
Anne Chiang, M.D. 
Rogerio Lilenbaum, M.D.
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Statistician:
Study Coordinator:
Daniel Zelterman, PhD.
Kira Pavlik           
Yale Cancer Center for Analytical Sciences
Clinical Trials Office 
Yale School of Public Health
Yale Cancer Center
300 George Street, Suite 555
100 Church Street South, Suite A160
New Haven, CT 06519
New Haven, CT 06519
Tel: 203-785-5574
Tel: 203-785-6540
Daniel.Zelterman@yale.edu
Fax: 203-785-2677 
Kira.Pavlik@yale.edu
Responsible Research Nurse(s)
Heather Gerrish, R.N.
Elin Rowen, R.N.
100 Church Street South, Suite A160
100 Church Street South, Suite A160
New Haven, CT 06519
New Haven, CT 06519
203-836-4296
203-907-7735
Heather.gerrish@yale.edu
elin.rowen@yale.edu
Study Medications: Nivolumab, ipilimumab
Study Collaborators: Kurt Schalper, MD, PhD; Susan Kaech, PhD
Protocol Revision History:
Amendment Number
Date
Amendment 2
11-Mar-2021
Amendment 1
27-Mar-2019
Original
19-June-2017
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Contents
1.
OBJECTIVES AND ENDPOINTS................................................................................10
1.1.
Primary Objective/ Endpoint ...................................................................................................10
1.2.
Secondary Objectives/ Endpoints ............................................................................................10
2.
BACKGROUND ......................................................................................................10
2.1.
Introduction ............................................................................................................................10
2.2.
Study Rationale........................................................................................................................12
2.2.1.
Pre-Clinical Studies ..................................................................................................................12
2.2.2   Clinical Studies..........................................................................................................................13
2.2.3.  Rationale for Shorter Infusion Times.........................................................................................15
3.
PATIENT SELECTION ..............................................................................................15
3.1.
Inclusion Criteria......................................................................................................................15
3.2.
Exclusion Criteria .....................................................................................................................17
4.
TREATMENT PLAN.................................................................................................19
4.1.
Study Design............................................................................................................................19
4.1.1.
Tumor Biopsies and Pharmacodynamic Blood Draws..............................................................19
4.2.
Description, packaging, labeling and storage of study drugs ...................................................20
4.3.
Treatment Schedule and Dosing Plan......................................................................................20
4.3.1.
Dose Delay Criteria..................................................................................................................21
4.3.2.
Dose Reductions......................................................................................................................22
4.3.3.
Criteria to Resume Dosing.......................................................................................................22
4.3.3.1 Criteria to Resume Nivolumab Dosing.....................................................................................22
4.3.3.2 Criteria to Resume Ipilimumab Dosing ....................................................................................23
4.3.4.
Treatment Discontinuation Criteria .........................................................................................24
4.3.4.1. Nivolumab or Ipilimumab Dose Discontinuation........................................................................24
4.4.
Duration of Therapy ................................................................................................................26
4.5.
Criteria for Removal from Study..............................................................................................26
4.6.
Treatment Beyond Disease Progression..................................................................................26
4.7.
Duration of Follow Up .............................................................................................................27
4.8.
General concomitant therapy and management of safety concerns.......................................27
4.8.1.
Concomitant therapy...............................................................................................................27
4.8.2.
Management of Safety concerns.............................................................................................27
4.8.3.
Monitoring ..............................................................................................................................27
4.8.4.
Management for Immuno-Oncology Agent AEs ......................................................................27
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4.8.5.
Treatment of Nivolumab or Ipilimumab Infusion Reactions ....................................................28
5.
STUDY ASSESSMENTS AND PROCEDURES ..............................................................29
5.1.
Screening Period......................................................................................................................29
5.2.
On-Study Visits.........................................................................................................................29
5.3.
Follow-up Visits........................................................................................................................30
5.4.
STUDY CALENDAR....................................................................................................................32
6.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS......................................33
6.1
Safety Analysis.........................................................................................................................33
6.2
Definition of Adverse Event Terms ..........................................................................................33
6.3.
Toxicity Grading.......................................................................................................................41
6.4.
Toxicity Attribution..................................................................................................................41
6.5.
Yale Principal Investigator Safety Reporting Requirements.....................................................42
6.5.1
Expedited Reporting of Unexpected SAEs................................................................................42
6.5.2
Reporting to the Yale Human Investigation Committee ..........................................................42
6.5.3
Reporting to the Food and Drug Administration......................................................................42
6.5.4
Reporting to Bristol Myers Squibb...........................................................................................43
6.5.5.  Duration of Reporting of SAEs...................................................................................................44
6.6.
Yale Safety Reporting and Monitoring (DSMP)........................................................................44
6.7.
Pregnancies .............................................................................................................................45
6.8.
Warnings and Precautions.......................................................................................................45
7.
CORRELATIVE/SPECIAL STUDIES ............................................................................45
8.
CRITERIA FOR RESPONSE.......................................................................................46
9.
STATISTICAL CONSIDERATIONS .............................................................................46
Appendix 1:
NCI Common Terminology Criteria for Adverse Events (CTCAE)..................51
Appendix 2:
Eastern Cooperative Oncology Group (ECOG) Performance Status.............51
Appendix 3:
Response Evaluation Criteria in Solid Tumors (RECIST)...............................51
Appendix 4:
Immune-Related Response Criteria............................................................60
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PROTOCOL SYNOPSIS:
Title of Study: A phase II study of combination immunotherapy with ipilimumab and nivolumab 
in patients with advanced non-small cell lung cancer resistant to anti-PD-1-axis monotherapy
Primary Investigator: Scott Gettinger, MD
Study Center(s): Yale Cancer Center/Smilow Cancer Hospital and Yale Care Centers, New Haven, 
CT
Concept and Rationale:
Approximately 20 percent of unselected patients with advanced non-small cell lung cancer 
(NSCLC) and progression during or after standard first line chemotherapy will experience tumor 
response to nivolumab1-4. Treatment options for patients who are not responsive to 
programmed death 1 (PD-1) axis inhibitor therapy are limited, and the mechanisms of primary 
resistance are poorly understood.
The combination of nivolumab and ipilimumab is currently FDA approved for the treatment of 
advanced melanoma based on superiority to either agent alone5. The results of a phase I study 
evaluating combination therapy with nivolumab and ipilimumab in patients with advanced 
NSCLC (NCT01454102) were presented at the annual American Society of Clinical Oncology 
(ASCO) meeting in 20166. Dosing of nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg 
every 6 weeks yielded an objective response rate (ORR) by RECIST v1.1 of 39%, with one-year 
survival rate of 69% and grade 3-4 treatment-related adverse event rate of 33%. These results 
prompted an ongoing phase III study comparing this regimen to standard first line 
chemotherapy, nivolumab monotherapy or combination therapy with chemotherapy and 
nivolumab for patients with advanced NSCLC (NCT02477826).
We propose a trial to evaluate if the addition of ipilimumab to nivolumab after primary 
resistance to anti-PD-1 axis therapy can lead to objective radiographic tumor regression. It is 
hypothesized that ipilimumab will enable more effective immune priming in some patients, 
resulting in the trafficking of tumor-specific cytotoxic T cells to the tumor, as well as depletion of 
tumor-permissive T regulatory cells. With concurrent nivolumab, PD-1 inhibition in the tumor 
will enable effective anti-tumor attack by tumor-specific T cells. Serial tumor biopsies and blood 
collections will allow interrogation of changes in the tumor microenvironment (and periphery) 
that support this hypothesis. 
We will primarily enroll patients who have experienced progression of NSCLC after anti-PD-1- 
axis therapy without initial response to such therapy (‘primary resistance’). A smaller cohort of 
patients with acquired resistance to anti-PD-1 axis therapy (i.e. progression after initial 
response) will additionally be accrued.
Primary Objective/ Endpoint:
-
To determine the objective response rate (ORR) using RECIST v1.1 to nivolumab and 
ipilimumab when administered in combination to patients with pre-treated advanced
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NSCLC who have experienced primary resistance to anti-PD-1 axis therapy as their last 
line of systemic therapy.
Secondary Objective(s)/ Endpoint(s):
-
To determine the objective response rate (ORR) using immune related Response Criteria 
(irRC) to nivolumab and ipilimumab when administered in combination to patients with 
pre-treated advanced NSCLC who have experienced primary resistance to anti-PD-1 axis 
therapy as their last line of systemic therapy.
-
To determine progression-free (RECIST v1.1 and irRC) and overall survival with 
nivolumab and ipilimumab when administered in combination to patients with pre- 
treated advanced NSCLC who have experienced primary resistance to anti-PD-1 axis 
therapy as their last line of systemic therapy.
-
To determine ORR and progression free survival (PFS) by RECIST v1.1 and irRC, and 
overall survival, with nivolumab and ipilimumab in patients with pre-treated advanced 
NSCLC who have experienced acquired resistance to anti-PD-1 axis therapy as their last 
line of systemic therapy.
-
To characterize the safety profile of nivolumab and ipilimumab when administered in 
combination, and feasibility of sequential biopsies, in patients with pre-treated 
advanced NSCLC who have experienced primary or acquired resistance to anti-PD-1 axis 
therapy as their last line of systemic therapy.
-
To evaluate changes in the tumor microenvironment and blood after adding ipilimumab 
to nivolumab in patients with primary and acquired resistance to anti-PD-1-axis as their 
last line of systemic therapy.
Study Design:
This a phase II study employing a Simon two-stage design to evaluate the primary endpoint of 
ORR by RECIST v1.1 to combination therapy with nivolumab 3 mg/kg administered 
intravenously (IV) every 2 weeks, with ipilimumab 1 mg/kg administered IV every 6 weeks, in 
patients with advanced NSCLC and primary resistance to anti-PD-1 axis therapy. If there is at 
least one response or prolonged stability (> 24 weeks) using irRC appreciated in the first 10 
patients who initiate trial therapy, a total of 40 patients will be enrolled. An additional 10 
patients with acquired resistance to anti-PD-1 axis therapy will be enrolled in an exploratory 
cohort receiving the same therapy.
Tumor biopsies (and blood collection for pharmacodynamic studies) will be performed just prior 
to initiating trial therapy, and 9 to 10 weeks after receiving first dose of trial therapy.
Main Criteria for Inclusion/Exclusion:
Inclusion
-
Age ≥18 years
-
Histologically or cytologically documented, locally advanced or metastatic (i.e., Stage IIIB 
not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC (per the 
American Joint Committee /AJCC staging system)
-
ECOG performance status of 0 to 2
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-
Anti- PD-1 Axis therapy (anti-PD-1 or anti-PD-L1, e.g. nivolumab, pembrolizumab, 
atezolizumab, durvalumab, avelumab) must be the most recent systemic anti-tumor 
treatment received in all patients, with documented progressive disease:
a.
Patients to be enrolled to the primary cohort (primary resistance) must have had 
progressive disease or stable disease less than 24 weeks as the best clinical response 
to anti-PD-1-axis therapy.
b.
Patients to be enrolled to the exploratory cohort (acquired resistance) must have 
had stable disease for at least 24 weeks, partial response, or complete response as 
the best clinical response to anti-PD-1-axis therapy, with subsequent progression of 
disease.
-
Chemotherapy naive and treated patients will be eligible, with no limit on number of 
prior therapies. Patients with NSCLC known to harbor an ALK rearrangement, or EGFR 
mutation known to be sensitive to FDA approved tyrosine kinase inhibitors (TKI), are 
only eligible after experiencing disease progression (during or after treatment) or 
intolerance to an FDA approved EGFR TKI or ALK TKI, respectively:
a.
Patients with TKI treated EGFR mutant NSCLC harboring the secondary EGFR T790M 
tumor must have received prior osimertinib.
b.
Patients with crizotinib treated ALK rearranged NSCLC must have received a next 
generation ALK inhibitor (e.g. ceritinib, alectinib or brigatinib).
-
At least one tumor amenable to incisional, excisional, core or forceps (transbronchial) 
biopsy. Patients must be willing to undergo tumor biopsies before starting trial therapy, 
and 9 to 10 weeks after initiation of therapy:
a.
If the initial biopsy will be excisional, the excised tumor cannot be counted as a 
target lesion and there must be another lesion amenable to incisional, excisional, 
core or forceps biopsy. In this scenario, the second biopsy can only be excisional if 
the lesion to be excised is not a target lesion.
b.
Cytology tumor specimens (e.g. from fine-needle biopsies, or drainage of pleural/ 
pericardial or ascites fluid) are not acceptable. Biopsies of bone lesions that do not 
have a soft tissue component are also not acceptable (i.e. decalcified tumor samples 
are not acceptable).
-
Adequate hematologic and end-organ function
Exclusion
-
Subjects must not have a history of life-threatening toxicity related to prior anti-PD-1 
axis therapy:
a.   Subjects with history of anti-PD-1 axis therapy toxicities that are unlikely to recur 
with standard countermeasures (e.g., hormone replacement after adrenal crisis) are 
eligible.
-
Prior treatment with anti-CTLA-4 therapeutic antibodies
-
Symptomatic or untreated CNS metastases. Patients with a history of treated 
asymptomatic CNS metastases are eligible, provided they meet all of the following 
criteria:
a.   No evidence of interim progression between the completion of CNS-directed 
therapy and the start of trial therapy.
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b.
No ongoing requirement for dexamethasone as therapy for CNS disease; 
anticonvulsants at a stable dose are allowed.
c.
Completed stereotactic radiosurgery at least 1 week prior to Cycle 1, Day 1 or 
whole-brain radiation at least 2 weeks prior to Cycle 1, Day 1.
-
History of leptomeningeal carcinomatosis
-
Prior palliative radiotherapy outside the CNS within 2 weeks of the first dose of study 
drug
-
Treatment with systemic immunosuppressive medications (including but not limited to, 
dexamethasone at doses > 2 mg daily (or equivalent dose of other corticosteroids), 
cyclophosphamide, tacrolimus, sirolimus, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor [anti-TNF] agents) within 2 weeks prior to initiating trial 
therapy (Inhaled or topically applied steroids, and acute and chronic standard-dose 
NSAIDs are permitted. Replacement steroids are also permitted).
Intervention and Mode of Delivery:
Nivolumab 3 mg/kg IV every 2 weeks and Ipilimumab 1 mg/kg IV every 6 weeks
Duration of Intervention and Evaluation:
Combination therapy with ipilimumab and nivolumab will be continued until disease progression 
or unacceptable toxicity. Patients with progression of disease by RECIST v1.1 without decline in 
performance status will be allowed to continue trial therapy if their treating physician believes 
they are deriving clinical benefit from study therapy.
Both RECIST v1.1 and immune-related response criteria (irRC) will be used to assess response to 
therapy. All patients who receive at least one dose each of ipilimumab and nivolumab will be 
considered evaluable.
Tumor response will be based on tumor assessments at screening, every 9 weeks from the first 
dose (for the first 24 weeks) and thereafter every 12 weeks until investigator-assessed initial 
disease progression.
Statistical Methods:
For the primary endpoint of objective response rate (ORR) by RECIST v1.1 among patients with 
primary resistance to anti-PD-1-axis therapy, a Simon two-stage design will be employed.  The 
design is based on our intuition for a very low anticipated response rate and not on any specific 
experimental evidence.  The study will terminate early if there are no responses or prolonged 
stability (> 24 weeks) using irRC among the first 10 patients enrolled. Otherwise we will enroll a 
maximum of 40 patients with primary resistance and reject the null hypothesis of no objective 
response if we observe 4 or more positive responses. For a null hypothesis with a 5% ORR and 
alternative with a 19% ORR, this criterion has significance level 0.1 and power greater than 85%. 
The null and alternative hypothesis rates are not motivated by experimental evidence but rather, 
are examples of one pair of hypotheses that can be tested using this design.  
Progression-free survival will be estimated with derivation of the corresponding 95% CI, plotted 
using the Kaplan-Meier method. Overall survival will be plotted using the Kaplan-Meier method. 
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Time-to-event endpoints (PFS, OS) will be analyzed using the Kaplan-Meier plots.  We will 
correlate OSS and PFS with ORR using Cox proportional hazards regression methods.No 
formal statistical analyses will be conducted on the 10 additional patients with acquired 
resistance, though the finding of immune related response in 1 or more patients would be 
unexpected, and should prompt further study.
Funding, Regulatory, and Feasibility Issues:
-
Ipilimumab and nivolumab will be supplied by Bristol Myers Squibb Company.
-
Bristol Myers Squibb Company will provide additional trial funding, including 
funding of serial biopsies.
-
IND for trial therapy to be held by Scott Gettinger.
Patient Acceptability/Ethics and Consent Issues:
None anticipated
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1.
OBJECTIVES AND ENDPOINTS
1.1.
Primary Objective/ Endpoint
To determine the objective response rate (ORR) using RECIST v1.1 to nivolumab and ipilimumab 
when administered in combination to patients with pre-treated advanced NSCLC who have 
experienced primary resistance to anti-PD-1 axis therapy as their last line of systemic therapy.
1.2.
Secondary Objectives/ Endpoints
A.
To determine the objective response rate (ORR) using immune related Response Criteria 
(irRC) to nivolumab and ipilimumab when administered in combination to patients with pre- 
treated advanced NSCLC who have experienced primary resistance to anti-PD-1 axis therapy 
as their last line of systemic therapy.
B.
To determine progression-free (RECIST v1.1 and irRC) and overall survival with nivolumab 
and ipilimumab when administered in combination to patients with pre-treated advanced 
NSCLC who have experienced primary resistance to anti-PD-1 axis therapy as their last line 
of systemic therapy.
C.
To determine ORR and progression free survival (PFS) by RECIST v1.1 and irRC, and overall 
survival, in patients with pre-treated advanced NSCLC who have experienced acquired 
resistance to anti-PD-1 axis therapy as their last line of systemic therapy
D. To characterize the safety profile of nivolumab and ipilimumab when administered in 
combination, and feasibility of sequential biopsies, in patients with pre-treated advanced 
NSCLC who have experienced primary or acquired resistance to anti-PD-1 axis therapy as 
their last line of systemic therapy
E.
To evaluate changes in the tumor microenvironment and blood after adding ipilimumab to 
anti- PD-1 axis therapy in patients with primary and acquired resistance to anti-PD-1-axis as 
their last line of systemic therapy
2.
BACKGROUND
2.1.
Introduction
Lung cancer remains the most common cancer worldwide7, and is the leading cause of cancer related 
deaths in the United States, with an estimated 159,000 deaths in 20148. Non-small cell lung cancer 
(NSCLC), which is the largest subgroup of lung cancer (~80%), is most often diagnosed at an advanced 
stage when standard first line systemic therapies result in a median survival of only 10-12 months in 
the healthiest patients, with one year survival rates of 40-50%9. Second line therapies are less 
effective, with associated median survival of 8 months, and one-year survival rate of approximately 
30%10,11. Currently, no more than 2 lines of chemotherapy are recommended/FDA approved for 
advanced NSCLC, with lack of clear survival benefit.
A small percentage of patients with advanced NSCLC (approximately 15%) are found to have tumors 
driven by an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) 
rearrangement. Treatment of such patients with small molecule EGFR tyrosine kinase inhibitors (TKI) 
or ALK TKIs respectively, can lead to high response rates; however, the majority of patients will 
experience progression of disease within a year of starting therapy.
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Programmed death 1 (PD-1) is an inhibitory receptor up-regulated on activated T cells, which 
suppresses T cell effector function upon binding to one of its two ligands, PD ligand 1 (PD-L1) or PD 
ligand 2 (PD-L2). PD-L1 is broadly expressed on hematopoietic cells, while PD-L2 expression is mainly 
found on dendritic cells. PD-1 inhibition in certain situations can protect against an excessive 
inflammatory response and the development of clinically apparent autoimmunity; however, in the 
setting of cancer, can be co-opted by tumors to suppress anti-tumor immunity at the site of the 
tumor. Indeed, PD-L1 upregulation has been demonstrated on several tumors, and has generally 
been associated with a poorer prognosis. Over the last 5 years, durable anti-tumor responses have 
been appreciated with a number of PD-1 and PD-L1 antagonist antibodies in clinical trials across a 
number of solid malignancies, including NSCLC.
Nivolumab, an IgG4 antagonist antibody against PD-1, is currently FDA approved for use in patients 
with advanced NSCLC who have experienced disease progression after standard platinum-based 
doublet chemotherapy. In patients with advanced squamous NSCLC, nivolumab was found to be 
superior to standard salvage docetaxel, with median over survival of 9.2 vs. 6 months (HR 0.59, 95% 
CI 0.44 to 0.79; p<0.001); and response rate of 20% vs 9%. Median duration of response was not 
reached with nivolumab, and 8.4 months with docetaxel2. In similar trial enrolling only patients with 
non-squamous NSCLC, nivolumab also improved overall survival compared to docetaxel with median 
survival of 12.2 months vs. 9.4 months (HR 0.73, 95% CI 0.59 to 0.89; p=0.002) with response rates 
of 19% vs. 12%. Duration of response was 17.2 months with nivolumab, compared to 5.6 months 
with docetaxel12. Nivolumab is also FDA approved for use in unresectable or metastatic melanoma, 
advanced renal cell carcinoma after anti-angiogenic therapy and classical Hodgkins disease that has 
relapsed or progressed after autologous hematopoietic stem cell transplantation and post- 
transplantation brentuximab vedotin.
Pembrolizumab, another IgG4 antagonist antibody to PD-1, is also approved for use in patients with 
advanced NSCLC and progressive disease after standard platinum based doublet chemotherapy. 
However, unlike nivolumab which is FDA approved regardless of tumor PD-L1 expression, 
pembrolizumab can only be prescribed to patients with tumor PD-L1 protein expression (i.e. at least 
1% of tumor cells showing PD-L1 expression). Initial approval was based on a large phase I trial which 
reported a response rate of 45% in 73 patients with high PD-L1 expression, with median duration of 
response of 12.5 months. Among the 57 patients with previously treated advanced NSCLC, response 
rate was 44%. A subsequent phase III trial randomized 1034 patients with advanced pre-treated 
NSCLC with at least 1% of tumor cells demonstrating PD-L1 expression to salvage pembrolizumab 
(2mg/ kg or 10 mg/kg dose) versus docetaxel. Overall survival and response rates were higher with 
the pembrolizumab arms; median survival/response rates were 10.4 months/ 18% (2mg/kg dose) 
and 12.7 months/ 18% (10 mg/kg dose) versus 8.5 months/ 9% for the docetaxel treated group [HR 
0.71, 95% CI 0.58-0.88 and  0.61, 95% CI 0.49-0.75, respectively]13.  In  October 2016, the FDA 
additionally approved the use of pembrolizumab in the first-line setting for patients with advanced 
NSCLC with high PD-L1 tumor expression (i.e. at least 50% of tumor cells expressing PD-L1). Approval 
was based on a Phase III trial demonstrating improvement in progression-free and overall survival 
with pembrolizumab compared to standard platinum-based doublet chemotherapy in patients with 
untreated advanced PD-L1 high tumors, with median of PFS 10.3 months versus 6 months (HR 0.50, 
95% CI 0.37 to 0.68; p<0.001) and estimated rate of overall survival at 6 months of 80% in the
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pembrolizumab group versus 72.4% in the chemotherapy group (HR 0.60, 95% CI 0.41 to 0.89; 
p=0.005)14.
Cytotoxic T lymphocyte antigen 4 (CTLA-4) is another immune checkpoint inhibitor receptor which 
is upregulated on naïve T cells when presented with antigen. It is also constitutively expressed on T 
regulatory cells. Upon engagement with CD80 or CD86 expressed on antigen presenting cells, it 
delivers an inhibitors signal resulting in downregulation of immune responses. Antagonist antibodies 
to CTLA-4 have shown activity across tumor types in early studies, including advanced NSCLC.
Ipilimumab, an IgG1 antagonist antibody against CTLA-4, was initially FDA-approved for use as 
monotherapy in patients with unresectable or metastatic melanoma on the basis of an OS advantage 
found in comparison with an investigational tumor vaccine and placebo as part of a randomized, 
double-blind, double-dummy trial15. It was later approved as adjuvant monotherapy for patients 
with completely resected cutaneous melanoma with lymph node involvement. Recently, ipilimumab 
was approved for use in combination with nivolumab for patients with unresectable or metastatic 
melanoma based on a phase III trial demonstrating an improvement in progression free survival 
compared to either ipilimumab or nivolumab alone. The combination was associated with more 
toxicity; grade 3 or 4 treatment related adverse events were reported in 16%, 27% and 55% of 
patients treated with nivolumab alone, ipilimumab alone, or combination therapy, respectively5.
The combination of nivolumab and ipilimumab is currently being evaluated in patients with 
advanced NSCLC, with results from a phase I reported at the annual American Society of Clinical 
Oncology (ASCO) meeting in 2016 (see Section 2.2.2). Based on promising results, a phase III trial 
was initiated randomizing patients with PD-L1 positive tumors to standard platinum based doublet 
chemotherapy, nivolumab alone or combination of nivolumab and ipilimumab. Patients with PD-L1 
negative tumors are randomized to combination therapy with nivolumab and ipilimumab to 
standard platinum doublet chemotherapy with or without concurrent nivolumab.
2.2.
Study Rationale
It is hypothesized that pharmacologic antagonism of CTLA-4 can overcome resistance to anti-PD-1- 
axis monotherapy in subjects with advanced NSCLC by enabling more effective tumor immune 
priming and/or releasing immune suppression mediated by T regulatory cells. This approach is 
supported by preclinical studies, and clinical studies in advanced melanoma demonstrating 
superiority of combination therapy with nivolumab and ipilimumab compared to either agent alone. 
Preliminary results from large phase I/dose expansion clinical trials evaluating combination therapy 
with anti-CTLA-4 and anti-PD-1 axis therapy in advanced NSCLC further support evaluation of 
combination therapy NSCLC6,16. We propose a trial to evaluate whether the addition of ipilimumab 
to nivolumab after primary resistance to anti-PD-1-axis therapy can lead to objective radiographic 
tumor regression. Serial tumor biopsies (and blood collections) will allow interrogation of changes 
in the tumor microenvironment (and periphery) that support this hypothesis.
2.2.1. Pre-Clinical Studies
In vitro combinations of nivolumab plus ipilimumab increase IFN-γ production 2- to 7-fold over 
either agent alone in a mixed lymphocyte reaction. Increased antitumor activity of the combination 
was also observed in 3 of 5 syngeneic murine cancer models. In a murine melanoma vaccine
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model, blockade with either CTLA-4 or PD-1 antibodies increased the proportion of CTLA-4 and PD- 
1-expressing CD4/CD8 tumor infiltrating T effector cells, and dual blockade increased tumor 
infiltration of T effector cells and decreased intratumoral T regulatory cells, as compared to either 
agent alone17.
2.2.2   Clinical Studies
The combination of nivolumab and ipilimumab is currently FDA approved for use in patients with 
unresectable or metastatic melanoma. Approval was based on a phase III study randomizing 945 
previously untreated stage III or IBV melanoma to nivolumab alone, nivolumab combined with 
ipilimumab, or ipilimumab alone. Progression free survival (co-primary endpoint with overall 
survival) was 11.5 months with nivolumab plus ipilimumab (95% CI, 8.9 to 16.7), as compared to 2.9 
months (95% CI 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 
99.5% CI, 0.31 to 0.57; P<0.001) and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for 
the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). Overall response rates were 
44% (nivolumab alone), 58% (nivolumab plus ipilimumab) and 19% (ipilimumab alone). Although the 
trial was not powered to compare treatments by PD-L1 expression, both nivolumab alone and in 
combination with ipilimumab resulted in a similar prolongation of progression free survival 
compared to ipilimumab alone in patients with PD-L1 positive tumors (with overall response rate 
slightly higher numerically with combination therapy at 72% % compared to nivolumab alone at 
58%)5.
The combination of nivolumab and ipilimumab has been evaluated as first line therapy for patients 
with advanced NSCLC with promising activity. Safety and efficacy results from two combination arms 
varying the schedule of ipilimumab (nivolumab 3mg/kg every 2 weeks with ipilimumab 1 mg/kg 
administered either once every 6 or 12 weeks), are shown below (Table 2.2.1 & 2.2.2, Figure 2.2.1). 
Also shown below is another arm of the trial evaluating first line nivolumab monotherapy (3mg/kg 
every 2 weeks) in patients with advanced NSCLC. Therapy in all arms was continued until disease 
progression or unacceptable toxicity. Patients were allowed to continue therapy despite progression 
of disease if they were felt to be deriving clinical benefit without worsening of their performance 
status. The primary endpoint of all arms was safety and tolerability, with secondary endpoints of 
ORR (RECIST v1.1) and PFS at 24 weeks.
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TABLE 2.2.1: Nivolumab Plus Ipilimumab in First-line NSCLC: Safety Summary
FIGURE 2.2.1: Nivolumab Plus Ipilimumab in First-line NSCLC: Treatment-related Select AEs
TABLE 2.2.2: Nivolumab Plus Ipilimumab in First-line NSCLC: Summary of Efficacy
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2.2.3.  Rationale for Shorter Infusion Times
Previous clinical studies of nivolumab monotherapy and ipilimumab monotherapy and the 
combination of nivolumab and ipilimumab have used a 60-minute infusion duration for nivolumab 
and 90-minute infusion duration for ipilimumab (1-3 mg/kg dosing for both). However, both 
nivolumab and ipilimumab have been administered at up to 10 mg/kg with the same infusion 
duration.
In Study CA209010 (a Phase 2, randomized, double-blinded, dose-ranging study of nivolumab in 
subjects with advanced/metastatic clear cell RCC), a dose association was observed for infusion site 
reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). 
All the events were Grade 1-2 and were manageable. An infusion duration of 30 minutes for 3 mg/kg 
nivolumab (30% of the dose provided at 10 mg/kg) would not be expected to present any safety 
concerns compared to the prior experience at 10 mg/kg nivolumab dose infused over a 60-minute 
duration.
Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In the CA184022 
study, where ipilimumab was administered  up  to  a dose of 10 mg/kg, on-study drug  related 
hypersensitivity events (Grade 1-2) were reported in 1 (1.4%) subject in the 0.3 mg/kg and in 2 (2.8%) 
subjects in the 10 mg/kg group. There were no drug-related hypersensitivity events reported in the 
3 mg/kg group. Across the 3 treatment groups, no Grade 3-4 drug-related hypersensitivity events 
were reported, and there were no reports of infusion reactions. Ipilimumab 10 mg/kg monotherapy 
has also been safely administered as 90-minute infusion in large Phase 3 studies in prostate cancer 
(CA184043) and as adjuvant therapy for stage 3 melanoma (CA184029), with infusion reactions 
occurring in subjects. Administering 1 mg/kg of ipilimumab represents one-tenth of the 10 mg/kg 
dose.
Infusion reactions including high-grade hypersensitivity reactions have been uncommon across 
nivolumab or ipilimumab clinical studies or the combination of nivolumab and ipilimumab. A 30- 
minute break after the first infusion for combination cohort will ensure the appropriate safety 
monitoring before the start of the second  infusion. Overall, a change in  safety profile is not 
anticipated with 30-minute infusion of nivolumab, ipilimumab or combination.
3.
PATIENT SELECTION
3.1.
Inclusion Criteria
A. Signed Informed Consent
B. Ability to comply with the protocol
C.
Age ≥18 years
D. Histologically or cytologically documented, locally advanced or metastatic (i.e., Stage IIIB 
not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC (per the 
American Joint Committee /AJCC staging system)
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E.
ECOG performance status of 0 to 2
F.
Measurable disease, as defined by RECIST v1.1. Previously irradiated lesions can be 
counted as target lesions if clearly progressing after radiation.
G. Chemotherapy-naive and treated patients will be eligible, with no limit on number of 
prior therapies. Patients with NSCLC known to harbor an ALK rearrangement, or EGFR 
mutation known to be sensitive to FDA-approved tyrosine kinase inhibitors (TKI), are 
only eligible after experiencing disease progression (during or after treatment) or 
intolerance to an FDA approved EGFR TKI or ALK TKI, respectively.
a.
Patients with TKI-treated EGFR mutant NSCLC harboring the secondary EGFR 
T790M tumor must have received prior osimertinib
b.
Patients with crizotinib-treated ALK rearranged NSCLC must have received a 
next generation ALK inhibitor (e.g. ceritinib, alectinib or brigatinib)
H. Prior palliative radiotherapy must have been completed at least 2 weeks before the first 
dose of study drug.
I.
Anti- PD-1 Axis therapy (anti-PD-1 or anti-PD-L1, e.g. nivolumab, pembrolizumab, 
atezolizumab, durvalumab, avelumab) must be the most recent systemic anti-tumor 
treatment received in all patients, with documented progressive disease. Last 
administration of anti-PD-1 axis therapy must have been at least 3 weeks before the first 
dose of study drug. 
a.
Patients to be enrolled to the primary cohort (primary resistance) must have 
had progressive disease or stable disease less than 24 weeks as the best clinical 
response to anti-PD-1-axis monotherapy
b.
Patients to be enrolled to the exploratory cohort (acquired resistance) must 
have had stable disease for at least 24 weeks, partial response, or complete 
response as the best clinical response to anti-PD-1-axis monotherapy, with 
subsequent progression of disease
J.
At least one tumor amenable to incisional, excisional, core or forceps (transbronchial) 
biopsy. Patients must be willing to undergo tumor biopsies before starting trial therapy, 
and 9 to 10 weeks after initiation of therapy.
a.
If the initial biopsy will be excisional, the excised tumor cannot be counted as a 
target lesion and there must be another lesion amenable to incisional, 
excisional, core or forceps biopsy. In this scenario, the second biopsy can only be 
excisional if the lesion to be excised is not a target lesion.
b.
Cytology tumor specimens (e.g. from fine-needle biopsies, or drainage of pleural/ 
pericardial or ascites fluid) are not acceptable. Biopsies of bone lesions that do not 
have a soft tissue component are also not acceptable (i.e. decalcified tumor 
samples are not acceptable).
K.
For female patients of childbearing potential and male patients with partners of 
childbearing potential, agreement (by patient and/or partner) to use a highly effective 
form(s) of contraception (i.e., one that results in a low failure rate [‹1% per year] when 
used consistently and correctly) and to continue its use for 6 months after the last dose of 
trial therapy. Highly effective contraception is one with a failure rate of ‹0.1%. Birth 
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control pills on their own do not achieve that rate.
a.
Women of childbearing potential must have a negative pregnancy test (serum 
or urine) within 72 hours of the start of study drug administration
b.
Women who have recently given birth must no longer be breastfeeding
L.
Adequate hematologic and end-organ function, defined by the following laboratory 
results obtained within 14 days prior to the first study treatment:
-
Neutrophils ≥1500 cells/µL (without granulocyte colony-stimulating factor support 
within 2 weeks prior to Cycle 1, Day 1)
-
Platelets ≥75,000/µL (transfusion to achieve this level is not permitted within 2 
weeks of the first study drug administration)
-
Hemoglobin ≥9.0 g/dL
-
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x 
institutional upper limit of normal (ULN) with the following exceptions: Patients 
with documented liver metastases: AST and/or ALT≤5 x ULN
-
Serum bilirubin ≤1.5 x ULN (Patients with known Gilbert disease who have serum
bilirubin level ≤3 x ULN may be enrolled)
-
Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min
3.2.
Exclusion Criteria
A. Has an active autoimmune disease requiring systemic treatment within the past 3 months 
or a documented history of clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved 
childhood asthma/atopy would be an exception to this rule. Subjects who require 
intermittent use of inhaled steroids or local steroid injections would not be excluded from 
the study. Subjects with hypothyroidism stable on hormone replacement, or psoriasis not 
requiring systemic therapy (within the past 3 years) will not be excluded from the study.
B.
Interstitial lung disease that is symptomatic or may interfere with the detection or 
management of suspected drug-related pulmonary toxicity
C.
Subjects must not have a history of life-threatening toxicity related to prior anti-PD-1 axis 
therapy
a.
Subjects with history of anti-PD-1 axis therapy toxicities that are unlikely to recur 
with standard countermeasures (e.g., hormone replacement after adrenal crisis) 
are eligible.
D. Prior treatment with anti-CTLA-4 therapeutic antibodies
E.
Symptomatic or untreated CNS metastases. Patients with a history of treated asymptomatic 
CNS metastases are eligible, provided they meet all of the following criteria:
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a.
No evidence  of  interim  progression  between  the  completion  of  CNS-directed 
therapy and the start of trial therapy.
b.
No   ongoing   requirement   for   dexamethasone   as   therapy   for   CNS   disease; 
anticonvulsants at a stable dose are allowed.
c.
Completed stereotactic radiosurgery at least 1 week prior to Cycle 1, Day 1 or whole- 
brain radiation at least 2 weeks prior to Cycle 1, Day 1
F.
History of leptomeningeal carcinomatosis
G. Prior palliative radiotherapy outside the CNS within 2 weeks of the first dose of study drug.
H. Treatment with systemic immunosuppressive medications (including but not limited to, 
dexamethasone at doses > 2 mg daily (or equivalent dose of other corticosteroids), 
cyclophosphamide, tacrolimus, sirolimus, azathioprine, methotrexate, thalidomide, and 
antitumor necrosis factor [anti-TNF] agents) within 2 weeks prior to initiating trial therapy 
(Inhaled or topically applied steroids, and acute and chronic standard-dose NSAIDs are 
permitted. Replacement steroids are also permitted).
I.
Subjects must not have received vaccines containing live virus for prevention of infectious 
diseases within 12 weeks prior to the first dose of study drug.
a.
The use of inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted 
on study without restriction.
J.
Any approved systemic anti-cancer therapy, within 3 weeks prior to initiation of study 
treatment; the following exception is allowed:
-
TKIs approved for treatment of NSCLC discontinued > 7 days prior to Cycle 1, Day 1.
The baseline scan must be obtained after discontinuation of prior TKIs.
K.
Treatment with any other investigational agent or participation in another clinical trial with 
therapeutic intent within 21 days prior to enrollment; the following exceptions are allowed:
-
Unapproved/experimental TKIs discontinued 14 days prior to Cycle 1, Day 1
L.
Known infection with HIV, HBV or HCV. Patients with prior exposure to hepatitis, but no 
evidence of active or chronic infection, may be eligible.
-
Subjects with positive hepatitis C antibody and negative quantitative hepatitis C by 
polymerase chain reaction are eligible.
M. Active systemic infection requiring systemic antibiotic treatment within 72 hours prior to 
first dose of study treatment
N. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart 
failure, unstable angina pectoris, or psychiatric illness/social situations that would limit 
compliance with study requirements
O. Major surgery or traumatic injury within 4 weeks of starting study drug
P.
Women who are pregnant or lactating.
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Q. Any underlying medical condition that in the Principal Investigator’s opinion will make the 
administration of study drug hazardous to the patient or would obscure the interpretation 
of adverse events.
4.
TREATMENT PLAN
4.1.
Study Design
This is a phase II study employing a 2-stage design to evaluate the primary endpoint of ORR to 
combination therapy with nivolumab 3 mg/kg administered intravenously (IV) every 2 weeks with 
ipilimumab 1 mg/kg administered IV every 6 weeks in patients with advanced NSCLC and primary 
resistance to anti-PD-1 axis therapy. If there is at least 1 response or prolonged stability (> 24 weeks) 
using irRC appreciated in the first 10 patients who initiate trial therapy, an additional 30 patients will 
be enrolled to a total of 40 patients. An additional 10 patients with acquired resistance to anti-PD-1 
axis therapy will be enrolled in an exploratory cohort receiving the same therapy.
4.1.1. Tumor Biopsies and Pharmacodynamic Blood Draws
A trial tumor biopsy will be required of all enrolled patients before starting treatment. A second 
mandatory tumor biopsy will be performed between day 56 and 70 of trial therapy (9-10 weeks 
after initiation of therapy). These on-trial tumor biopsies must be collected via core, forceps, or 
incision/ excision. Although the second biopsy will generally be obtained from the same site as the 
first one, there may be circumstances when another tumor site would alternatively be biopsied 
(e.g. lesion initially biopsied becomes too small to safely and/or effectively biopsy). 
Optional biopsies may be performed at sites of response (including partial response, or stable 
disease at least 24 weeks) or progression while on treatment. We anticipate that such biopsies will 
help to characterize changes in the tumor immune microenvironment that play a role in mitigating 
response or resistance to treatment, respectively.
If archived tumor tissue from a biopsy performed prior to enrollment is available, unstained slides 
or block will be requested for additional analysis of biomarkers (as consented to in the informed 
consent document).
Blood draws to characterize the peripheral anti-tumor immunologic milieu will be collected prior to 
the initiation of combination therapy. Serial draws will be performed 2 weeks, 4 weeks, 6 weeks, 
and 9 weeks after the initiation of therapy (should correspond with timing of on-treatment biopsy) 
as well as at the time of disease progression.
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4.2.
Description, packaging, labeling and storage of study drugs
Table 4.2:
Study Drugs
Product Description / 
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage 
Conditions 
(per label)
Nivolumab Solution for 
Injection
100 mg (10
mg/mL)
10 mL per 
vial/ Open- 
label
5 
per 
carton/ 
Open-label
Clear to 
opalescent 
colorless to 
pale yellow 
liquid. May 
contain 
particles
2 to 8° C.
Protect 
from light 
and freezing
Ipilimumab Solution for 
Injection
200 mg 
(5mg/mL)
40 mL
vial/Open- 
label
4 vials per 
carton/Open- 
label
Clear to 
opalescent 
colorless to 
pale yellow 
liquid. May 
contain 
particles
2 to 8° C.
Protect 
from light 
and freezing
4.3.
Treatment Schedule and Dosing Plan
Enrolled subjects will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 
weeks and ipilimumab 1 mg/kg as a 30-minute infusion every 6 weeks, starting on Day 1, until 
progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs 
first.
When nivolumab and ipilimumab are to be administered on the same day, separate infusion bags 
and filters must be used for each infusion. Nivolumab is to be administered first. The second 
infusion will always be ipilimumab and will start no sooner than 30 minutes after completion of the 
nivolumab infusion.
Nivolumab and ipilimumab may be diluted in 0.9% Sodium Chloride Solution or 5% Dextrose 
solution.
Dosing calculations should be based on the body weight assessed. If the subject’s weight on the 
day of dosing differs by >10% from the weight used to calculate the prior dose, the dose must be 
recalculated. All doses should be rounded to the nearest milligram. There will be no dose 
modifications allowed.
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Subjects may be dosed with nivolumab no less than 12 days from the previous dose. There are no 
premedications recommended.
Subjects should be carefully monitored for infusion reactions. If an acute infusion reaction is noted, 
subjects should be managed according to Section 4.8.5.
Doses of nivolumab and/or ipilimumab may be interrupted, delayed, or discontinued depending on 
how well the subject tolerates the treatment.
4.3.1. Dose Delay Criteria
Dose delay criteria apply to all drug-related AEs. Treatment delays are allowable up to 6 weeks
for nivolumab and 12 weeks for ipilimumab from the last dose (any dose delays greater than this
will require approval from the medical monitor).
Tumor assessments for all subjects should continue as per protocol even if dosing is delayed.
Nivolumab and ipilimumab administration should be delayed for the following:
-
Grade 2 non-skin, drug-related adverse event, except for fatigue and laboratory abnormalities
-
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
-
Grade 3 skin, drug-related AE
-
Grade 3 drug-related laboratory abnormality with the following exceptions:
-
Grade 3 lymphopenia or asymptomatic amylase or lipase elevation does not require dose 
delay
-
Grade ≥ 3 AST, ALT, Total Bilirubin will require dose discontinuation
-
Any AE, laboratory abnormality or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
Participants who have drug-related toxicities that meet the criteria for dose delay should have both 
drugs (ipilimumab and nivolumab) delayed until retreatment criteria are met. (Exceptions apply to 
the retreatment criteria after dose delay of ipilimumab and nivolumab for Grade ≥ 3 amylase and 
lipase abnormalities that are not associated with symptoms or clinical manifestations of pancreatitis 
and that are attributed to ipilimumab alone.)
Rescheduling:
Nivolumab may be delayed until the next planned ipilimumab dose if the next ipilimumab dose is 
scheduled within the next 12 days. This will permit periodic ipilimumab dosing to be synchronized 
with nivolumab dosing.
Ipilimumab should be dosed at the specified interval regardless of any delays in intervening 
nivolumab doses. However, in order to maintain periodic synchronized dosing of ipilimumab and 
nivolumab, the dosing days of nivolumab (every 2 weeks   days) and ipilimumab (every 6 weeks 
  days) may be adjusted within the permitted  5 day window, as long as consecutive nivolumab 
doses are given at least 12 days apart. Ipilimumab may be delayed beyond the 5 day window if 
needed to synchronize with the next nivolumab dose.
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A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 4/ 1/ 2 0 2 1
2 2
If a n  i pili m u m a b d os e  is d el ay e d  b ey o n d  6  w e eks  fr o m t h e pri or  i pili m u m a b d os e,  t h e n s u bs e q u e nt 
i pili m u m a b d os es  s h o ul d b e  r esc h e d ul e d t o m ai nt ai n  t h e 6 w e ek  i nt erv al b et w e e n  c o ns ec utiv e 
i pili m u m a b d os es.
A  d os e  d el ay  of  i pili m u m a b w hic h  r es ults i n n o  i pili m u m a b d osi n g  f or >  1 2  w e eks  r e q uir es 
i pili m u m a b disc o nti n u ati o n, wit h  exc e pti o ns  as  n ot e d i n S ecti o n 4. 3. 3. 2.
4. 3. 2.
D os e  R e d ucti o ns
T h er e  will  b e  n o  d os e  r e d ucti o ns f or niv ol u m a b  or  i pili m u m a b
4. 3. 3.
Crit eri a  t o R es u m e  D osi n g
4. 3. 3. 1 Crit eri a  t o R es u m e  Ni v ol u m a b  D osi n g
S u bj ects  m a y  r es u m e tr e at m e nt wit h  niv ol u m a b  w h e n  t h e dr u g-r el at e d  A E(s)  r es olv e(s) t o Gr a d e  ≤
1  or  b as eli n e,  wit h t h e  f oll o wi n g exc e pti o ns:
-
S u bj ects  m a y  r es u m e tr e at m e nt i n t h e pr es e nc e  of Gr a d e  2  f ati g u e.
-
S u bj ects  w h o  h av e  n ot  ex p eri e nc e d  a  Gr a d e  3  dr u g-r el at e d  ski n A E  m a y  r es u m e tr e at m e nt i n t h e 
pr es e nc e  of  Gr a d e  2  ski n t oxicity.
- 
F or s u bj ects wit h Gr a d e 2 A S T, AL T, or T ot al bilir u bi n el ev ati o ns, d osi n g m a y r es u m e w h e n 
l a b or at or y v al u es r et ur n t o b as eli n e a n d m a n a g e m e nt wit h c ortic ost er oi ds, if n e e d e d, is 
c o m pl et e.
- 
S u bj ects wit h c o m bi n e d Gr a d e 2 A S T/ AL T A N D t ot al bilir u bi n v al u es m e eti n g disc o nti n u ati o n 
p ar a m et ers (s e e p ac k a g e i ns ert) s h o ul d h av e tr e at m e nt p er m a n e ntl y disc o nti n u e d.
-
Dr u g-r el at e d  p ul m o n ary  t oxicity, di arr h e a,  or  c olitis m ust  h av e  r es olv e d t o b as eli n e  b ef or e  
tr e at m e nt is r es u m e d. S u bj ects  wit h  p ersist e nt  Gr a d e  1  p n e u m o nitis  aft er  c o m pl eti o n of  a  
st er oi d t a p er ov er  at  l e ast 1  m o nt h  m a y  b e  eli gi bl e  f or r etr e at m e nt if disc uss e d  wit h  a n d  
a p pr ov e d  by  t h e PI.
- 
S u bj ects wit h Gr a d e 1- 3 dr u g-r el at e d e n d ocri n o p at hi es a d e q u at el y c o ntr oll e d wit h o nl y 
p h ysi ol o gic h or m o n e r e pl ac e m e nt m a y r es u m e tr e at m e nt aft er c o ns ult ati o n wit h t h e PI
-
S u bj ects  w h o  r ec eiv e d syst e mic c ortic ost er oi ds f or m a n a g e m e nt  of  a ny  dr u g-r el at e d  t oxicity 
m ust  b e  off  c ortic ost er oi ds or  h av e  t a p er e d d o w n  t o a n  e q uiv al e nt  d os e  of  pr e d nis o n e ≤ 1 0 
m g/ d ay.
-
P artici p a nts w h o d el ay st u dy tr e at m e nt d u e t o a ny Gr a d e  3 a myl as e or li p as e a b n or m ality t h at 
is n ot ass oci at e d wit h sy m pt o ms or cli nic al m a nif est ati o ns of p a ncr e atitis, a n d t h at is ass ess e d by 
t h e i nv esti g at or t o b e r el at e d t o i pili m u m a b a n d n ot t o niv ol u m a b, m ay r es u m e niv ol u m a b w h e n 
t h e a myl as e or li p as e a b n or m ality h as r es olv e d t o Gr a d e < 3. T h e PI s h o ul d b e c o ns ult e d pri or t o 
r es u mi n g niv ol u m a b i n s uc h p artici p a nts.
-
D os e  d el ay of  niv ol u m a b t h at  r es ults i n tr e at m e nt i nt err u pti o n of >  6  w e eks  r e q uir es tr e at m e nt 
disc o nti n u ati o n,  wit h exc e pti o ns  as  n ot e d i n S ecti o n  4. 3. 4.
- 
O n e exc e pti o n t o n ot e is w h e n i pili m u m a b a n d niv ol u m a b d os es ar e d el a y e d d u e t o dr u g-r el at e d 
Gr a d e ≥ 3 a m yl as e or li p as e a b n or m aliti es n ot ass oci at e d 
wit h s y m pt o ms or cli nic al 
m a nif est ati o ns of p a ncr e atitis. If t h e i nv esti g at or ass ess es t h e Gr a d e  3 a m yl as e or li p as e 
a b n or m alit y t o b e r el at e d t o i pili m u m a b a n d n ot r el at e d t o niv ol u m a b, niv ol u m a b m a y b e 
A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 4/ 1/ 2 0 2 1

A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 4/ 1/ 2 0 2 1
2 3
r es u m e d w h e n t h e a m yl as e or li p as e a b n or m alit y r es olv es t o Gr a d e < 3 b ut i pili m u m a b m a y o nl y 
b e r es u m e d w h e n t h e a m yl as e or li p as e a b n or m alit y r es olv es t o Gr a d e 1 or b as eli n e. I nv esti g at or 
attri b uti o n of t his t oxicit y t o t h e i pili m u m a b d osi n g m ust b e cl e arl y n ot e d i n t h e p artici p a nt’s 
m e dic al c h art. T h e PI s h o ul d b e c o ns ult e d pri or t o r es u mi n g niv ol u m a b i n s uc h p artici p a nts.
-
If a ny  of  t h e a b ov e  m e nti o n e d  sy n dr o m es occ ur  o nly  aft er  a d mi nistr ati o n  of  niv ol u m a b  wit h  
i pili m u m a b a n d  n ot  aft er  niv ol u m a b- o nly  d os es,  a n d  t h e i nv esti g at or f e els t h at i pili m u m a b is t h e 
c a us e, niv ol u m a b  m a y  b e r es u m e d if t h e a b ov e  crit eri a ar e  m et
4. 3. 3. 2 Crit eri a  t o R es u m e  I pili m u m a b D osi n g
S u bj ects  m a y  r es u m e tr e at m e nt wit h i pili m u m a b w h e n dr u g-r el at e d A E(s)  r es olv e(s) t o Gr a d e 1  or  
b as eli n e  v al u e,  wit h t h e  f oll o wi n g exc e pti o ns:
- 
P artici p a nts m a y r es u m e tr e at m e nt i n t h e pr es e nc e of Gr a d e 2 f ati g u e. 
- 
P artici p a nts w h o h av e n ot ex p eri e nc e d a Gr a d e 3 dr u g-r el at e d s ki n A E m a y r es u m e tr e at m e nt i n 
t h e pr es e nc e of Gr a d e 2 s ki n t oxicit y.
- 
P artici p a nts wit h b as eli n e Gr a d e 1 A S T/ AL T or t ot al bilir u bi n el ev ati o ns w h o r e q uir e d os e d el a ys 
f or r e as o ns ot h er t h a n a 2- gr a d e s hift i n A S T/ AL T or t ot al bilir u bi n m a y r es u m e tr e at m e nt i n t h e 
pr es e nc e of Gr a d e 2 A S T/ AL T or t ot al bilir u bi n.
- 
P artici p a nts wit h c o m bi n e d Gr a d e 2 A S T/ AL T a n d t ot al bilir u bi n v al u es m e eti n g disc o nti n u ati o n 
p ar a m et ers ( S ecti o n 4. 3. 4) s h o ul d h av e tr e at m e nt p er m a n e ntl y disc o nti n u e d.
- 
Dr u g-r el at e d p ul m o n ar y t oxicit y, di arr h e a or c olitis m ust h av e r es olv e d t o b as eli n e b ef or e 
tr e at m e nt is r es u m e d. S u bj ects wit h p ersist e nt Gr a d e 1 p n e u m o nitis aft er c o m pl eti o n of a 
st er oi d t a p er ov er at l e ast 1 m o nt h m a y b e eli gi bl e f or r etr e at m e nt if disc uss e d wit h a n d 
a p pr o v e d b y t h e PI.
- 
P artici p a nts w h o r ec eiv e d s yst e mic c ortic ost er oi ds f or m a n a g e m e nt of a n y dr u g-r el at e d t oxicit y 
m ust b e off c ortic ost er oi ds or h av e t a p er e d d o w n t o a n e q uiv al e nt d os e of pr e d nis o n e ≤ 1 0 
m g/ d a y.
- 
S u bj ects wit h Gr a d e 1- 3 dr u g-r el at e d e n d ocri n o p at hi es a d e q u at el y c o ntr oll e d wit h o nl y 
p h ysi ol o gic h or m o n e r e pl ac e m e nt m a y r es u m e tr e at m e nt aft er c o ns ult ati o n wit h t h e PI.
- 
D os e d el a y of i pili m u m a b w hic h r es ults i n n o i pili m u m a b d osi n g f or > 1 2 w e e ks r e q uir es 
i pili m u m a b disc o nti n u ati o n, wit h exc e pti o ns as n ot e d i n S ecti o n 4. 3. 4. Alt h o u g h t h er e is ov erl a p 
a m o n g t h e disc o nti n u ati o n crit eri a, if disc o nti n u ati o n crit eri a ar e m et f or i pili m u m a b, b ut n ot 
f or ni v ol u m a b, tr e at m e nt wit h niv ol u m a b m a y c o nti n u e if i pili m u m a b is disc o nti n u e d.
I pili m u m a b m a y n ot b e r es u m e d s o o n er t h a n 6 w e e ks (  5 d a ys) aft er t h e pri or i pili m u m a b d os e.
I n g e n er al, p artici p a nts w h o m e et crit eri a t o r es u m e i pili m u m a b will als o h av e m et crit eri a t o r es u m e 
ni v ol u m a b, s o it s h o ul d b e f e asi bl e t o s y nc hr o niz e d osi n g of b ot h dr u gs w h e n r es u mi n g i pili m u m a b. I n 
or d er t o f acilit at e t his, t h e d osi n g d a ys of niv ol u m a b a n d i pili m u m a b m a y b e a dj ust e d wit hi n t h e 
p er mitt e d ± 5 d a y wi n d o w, as l o n g as c o ns ec utiv e niv ol u m a b d os es ar e giv e n at l e ast 1 2 d a ys a p art.
O n e exc e pti o n  t o n ot e is w h e n i pili m u m a b a n d niv ol u m a b d os es ar e d el a y e d d u e t o dr u g-r el at e d 
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2 4
Gr a d e ≥ 3 a m yl as e or li p as e a b n or m aliti es n ot ass oci at e d wit h s y m pt o ms or cli nic al m a nif est ati o ns of 
p a ncr e atitis. If t h e i nv esti g at or ass ess es t h e Gr a d e  3 a m yl as e or li p as e a b n or m alit y t o b e r el at e d t o 
i pili m u m a b a n d n ot r el at e d t o niv ol u m a b, niv ol u m a b m a y b e r es u m e d w h e n t h e a m yl as e or li p as e 
a b n or m alit y r es olv es t o Gr a d e < 3 b ut i pili m u m a b m a y o nl y b e r es u m e d w h e n t h e a m yl as e or li p as e 
a b n or m alit y r es olv es t o Gr a d e 1 or b as eli n e. I nv esti g at or attri b uti o n of t his t oxicit y t o t h e i pili m u m a b 
d osi n g m ust b e cl e arl y n ot e d i n t h e p artici p a nt’s m e dic al c h art. T h e PI s h o ul d b e c o ns ult e d pri or t o 
r es u mi n g niv ol u m a b i n s uc h p artici p a nts.
4. 3. 4.
Tr e at m e nt  Disc o nti n u ati o n  Crit eri a
F or all  s u bj ects, gl o b al  d et eri or ati o n of  h e alt h  st at us r e q uiri n g disc o nti n u ati o n of  tr e at m e nt wit h o ut  
o bj ectiv e  evi d e nc e  of dis e as e  pr o gr essi o n at  t h at ti m e s h o ul d b e r e p ort e d as ‘sy m pt o m atic 
d et eri or ati o n’  i n t h e s o urc e d at a.  Ev ery eff ort  s h o ul d b e  m a d e  t o d oc u m e nt  o bj ectiv e  pr o gr essi o n  
(i. e., r a di o gr a p hic c o nfir m ati o n) ev e n aft er  disc o nti n u ati o n  of tr e at m e nt.
4. 3. 4. 1.
Ni v ol u m a b  or I pili m u ma b D os e  Disc o nti n u ati o n
Tr e at m e nt  wit h  niv ol u m a b  or i pili m u m a b m ust b e  p er m a n e ntly  disc o nti n u e d f or  a ny  of  t h e f oll o wi n g:
-
A ny  Gr a d e  2  dr u g-r el at e d uv eitis  or  ey e  p ai n  or bl urr e d visi o n  t h at d o es  n ot  r es p o n d t o t o pic al 
t h er a py a n d d o es  n ot  i m pr ov e t o Gr a d e  1  s ev erity wit hi n t h e r e-tr e at m e nt p eri o d O R r e q uir es 
syst e mic tr e at m e nt
- 
A n y Gr a d e 3 n o n-s ki n, dr u g-r el at e d a dv ers e ev e nt l asti n g > 7 d a ys, or r ec urs wit h t h e f oll o wi n g 
exc e pti o ns f or l a b or at or y a b n or m aliti es, 
di arr h e a, dr u g-r el at e d 
uv eitis, p n e u m o nitis, 
br o nc h os p as m, h y p ers e nsitivit y r e acti o ns, i nf usi o n r e acti o ns, a n d e n d ocri n o p at hi es:
- 
Gr a d e 3 dr u g-r el at e d di arr h e a, c olitis, n e ur ol o gic t oxicit y, uv eitis, p n e u m o nitis, 
br o nc h os p as m, h y p ers e nsitivit y r e acti o n, or i nf usi o n r e acti o n of a n y d ur ati o n r e q uir es 
disc o nti n u ati o n
- 
Gr a d e 3 dr u g-r el at e d e n d ocri n o p at hi es, a d e q u at el y c o ntr oll e d wit h o nl y p h ysi ol o gic 
h or m o n e r e pl ac e m e nt d o n ot r e q uir e disc o nti n u ati o n. A dr e n al i ns uffici e nc y r e q uir es 
disc o nti n u ati o n r e g ar dl ess of c o ntr ol wit h h or m o n e r e pl ac e m e nt.
- 
Gr a d e 
3 
dr u g-r el at e d l a b or at or y 
a b n or m aliti es 
d o 
n ot r e q uir e tr e at m e nt 
disc o nti n u ati o n exc e pt:
• 
Gr a d e 3  dr u g-r el at e d t hr o m b oc yt o p e ni a > 7 d a ys or ass oci at e d wit h bl e e di n g 
r e q uir es disc o nti n u ati o n.
• 
A n y  dr u g-r el at e d liv er f u ncti o n t est (L F T) a b n or m alit y t h at m e ets t h e f oll o wi n g 
crit eri a r e q uir e disc o nti n u ati o n:
• 
Gr a d e ≥ 3 dr u g-r el at e d 
A S T, 
AL T or T ot al Bilir u bi n r e q uir es 
disc o nti n u ati o n. I n m ost c as es of Gr a d e 3 A S T or AL T el ev ati o n, st u d y 
dr u g(s) 
will 
b e 
p er m a n e ntl y 
disc o nti n u e d. If t h e i nv esti g at or 
d et er mi n es a p ossi bl e f av or a bl e b e n efit/ris k r ati o t h at w arr a nts 
c o nti n u ati o n of st u d y dr u g(s), a disc ussi o n b et w e e n t h e i nv esti g at or 
a n d t h e PI m ust occ ur.
• 
C o nc urr e nt  A S T or AL T > 3 x UL N a n d t ot al bilir u bi n > 2x UL N
- 
A n y Gr a d e 4 dr u g-r el at e d a dv ers e ev e nt or l a b or at or y a b n or m alit y (i ncl u di n g b ut n ot li mit e d t o 
cr e ati ni n e, A S T, AL T, or T ot al Bilir u bi n), exc e pt f or t h e f oll o wi n g ev e nts w hic h d o n ot r e q uir e 
disc o nti n u ati o n:
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-
Grade 4 neutropenia ≥ 7 days
-
Grade 4 lymphopenia or leukopenia
-
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset
-
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, or 
glucose intolerance, which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, 
may not require discontinuation after discussion with and approval from the PI.
-
Any Grade ≥ 2 drug-related pneumonitis or interstitial lung disease that does not resolve with 
dose delay and systemic steroids (also see package insert for Pulmonary Adverse Event 
Management)
-
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continued nivolumab/ 
ipilimumab dosing.
-
Any event that leads to delay in dosing lasting > 6 weeks (or 12 weeks for ipilimumab) from 
the previous dose requires discontinuation, with the following exceptions:
1.
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed.
2.
Dosing delays lasting > 6 weeks (or 12 weeks for ipilimumab) from the previous dose that 
occur for non-drug-related reasons may be allowed if approved by the PI.
-
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of 
this event. In most cases, the study drug will be permanently discontinued in an appropriate 
manner (eg, dose tapering if necessary for participant safety). Please contact the Sponsor or 
designee within 24 hours of awareness of the pregnancy. If the investigator determines a 
possible favorable benefit/risk ratio that warrants continuation of study drug, a discussion 
between the investigator and the PI must occur.
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 weeks (or 12 weeks 
for ipilimumab), the PI must be consulted. Tumor assessments should continue as per protocol 
even if dosing is delayed. Periodic study visits to assess safety and laboratory studies should also 
continue every 6 weeks or more frequently if clinically indicated during such dosing delays.
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of ipilimumab. Although there is overlap among the discontinuation 
criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued.
If a participant meets criteria for discontinuation and investigator is unable to determine whether 
the event is related to both or one study drug, the participant should discontinue both nivolumab 
and ipilimumab and be taken off the treatment phase of the study. Continuation of ipilimumab 
after discontinuation of nivolumab is not allowed on study.
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4.4.
Duration of Therapy
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies:
1
Disease progression (PD by RECIST 1.1 with exception discussed in section 4.6
2
Symptomatic deterioration of health status without objective evidence of disease progression. 
Every effort should be made to document objective progression of disease in such cases.
3
Unmanageable toxicity attributed to trial therapy (see section 4.9)
4
Development of intercurrent illness limiting the ability to comply with study or the 
development of uncontrolled concurrent illness that prevents further administration of treatment or 
confound the ability to interpret data
6
General or specific changes in the patient’s condition rendering the patient unacceptable for 
further treatment in the judgment of the investigator
7
Patient request for discontinuation, patient withdrawal from study, or patient lost to 
follow up
8
Death
9
Study termination
4.5.
Criteria for Removal from Study
Patients will be removed from study when any of the criteria listed in Section 4.4 applies. The 
reason for study removal and the date the patient was removed must be documented.
4.6.
Treatment Beyond Disease Progression
Subjects will be permitted to continue trial treatment beyond RECIST v1.1 defined PD as long as they 
meet the following criteria:  
•
Investigator-assessed clinical benefit and no rapid disease progression
•
Subject is tolerating study treatment
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases, impending vital organ compromise)
•
Subject provides written informed consent prior to receiving additional nivolumab and or 
ipilimumab treatment, using an informed consent form describing any reasonably foreseeable 
risks or discomforts, or other alternative treatment options. The decision to continue treatment 
beyond initial progression should be discussed with the PI.
Additionally, in cases where the majority of the disease is stable or responding, and progressing lesions 
can be controlled with local therapy (i.e. resection or radiotherapy), the patient may be continued on 
trial following local therapy.
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4.7.
Duration of Follow Up
Patients who discontinue trial therapy will be followed for survival after removal from study until death.
4.8.
General concomitant therapy and management of safety concerns
4.8.1. Concomitant therapy
Additional anti-tumor therapies are prohibited during study treatment. The use of corticosteroids or other 
immunosuppressive medications will not be allowed during study therapy (unless used to treat a drug 
related adverse event). Low-dose steroid use (≤2mg of dexamethasone or equivalent) as corticosteroid 
replacement therapy is allowed.
4.8.2. Management of Safety concerns
Measures will be taken to ensure the safety of patients participating in this trial, including the use of 
stringent inclusion and exclusion criteria (section 3.1 and 3.2) and close monitoring (as indicated below and 
in Sections 5 and 6). See Section 6 for complete details regarding safety reporting for this study.
4.8.3. Monitoring
Safety will be evaluated in this study through the monitoring of all serious and non-serious AEs, defined 
and graded according to NCI CTCAE v4.0. (see appendix 1). Patients will be assessed for safety (including 
laboratory values) according to Section 5 Patients will be followed for safety for 100 days following the last 
dose of study treatment.
General safety assessments will include serial interval histories, physical examinations, and specific 
laboratory studies, including serum chemistries and blood counts (see Section 5 for the list and timing 
of study assessments). All SAEs and protocol-defined events of special interest (see Section 6) will be reported 
in an expedited fashion (see Section 6.5). In addition, investigators will review and evaluate observed AEs 
on a regular basis.
Patients who have an ongoing study treatmentrelated adverse event upon study completion or at 
discontinuation from the study will be followed until the event has resolved to baseline grade, the event is 
assessed by the investigator as stable, new anti-cancer treatment is initiated, the patient is lost to follow-
up, the patient withdraws consent, or until  it has been  determined  that study treatment or participation 
is not the cause of the AE.
4.8.4. Management for Immuno-Oncology Agent AEs
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. Early recognition and management of AEs associated with immuno- oncology agents 
may mitigate severe toxicity. Please review the label/package insert for Management 
Algorithms developed to assist investigators in assessing and managing AEs.
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4.8.5. Treatment of Nivolumab or Ipilimumab Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, 
they are 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 within 24 hours to the PI 
and reported as an SAE if criteria are met. Infusion reactions should be graded according 
to NCI CTCAE (Version 4) guidelines.
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines, as appropriate:
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention 
not indicated)
Remain at bedside and monitor subject 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 or ipilimumab administrations.
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for ≤ 24 
hours)
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and treat the 
subject with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 
to 1000 mg; remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 
and/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 subject 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 subject until resolution of symptoms. The amount of study drug 
infused must be recorded.
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab or ipilimumab infusions. If 
necessary, corticosteroids (up to 25 mg of SoluCortef or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, 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)
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Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV infusion of normal 
saline and treat the subject as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of 
a 1:1000 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. Subject 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 subject until recovery of the 
symptoms.
In 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).
5.
STUDY ASSESSMENTS AND PROCEDURES
A  window  of  -2 / +3  days  can  be  applied  to  scheduled  visits  for  nivolumab  and  
ipilimumab administration if necessary for holidays, vacations, inclement weather, etc.
5.1.
Screening Period
The following procedures and tests will be completed during this period to determine eligibility.  All 
procedures to be completed within 28 days of first dose, except labs.  All labs should be collected 
within 14 days of first dose.
1) History and physical examination
2) Measurement of height, weight and vital signs (including blood pressure, heart rate, 
respiratory rate, oxygen saturation, and temperature).
3) Performance status evaluation
4) CBC with differential, serum chemistry (Na, K, Cl, CO2, BUN, creatinine, glucose, calcium), 
magnesium, phosphate, amylase, lipase, liver function tests (albumin, total protein, alkaline 
phosphatase, total bilirubin, ALT, AST), LDH, TSH (with reflex to free T3 and free T4)
5) Pregnancy test (serum or urine) for women of childbearing potential.  Sexually active women 
of childbearing potential must use an effective method of birth control during the course of 
the study, in a manner such that risk of failure is minimized.
6) Systemic tumor assessment with CT scan of the chest/abdomen/pelvis and CT or MRI Brain 
(MRI preferable).  MRI brain required only if known or suspected brain metastases. 
If eligible, a tumor biopsy and blood draw for research studies (approximately 2 tablespoons of 
blood) will be performed prior to initiation of therapy (see section 4.1.1).
5.2.
On-Study Visits
The day of the nivolumab infusion (every 2 weeks) and the day of the ipilimumab infusion (every 
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6 weeks):
1) History and physical examination
2) Measurement of height, weight and vital signs (including blood pressure, heart rate, 
respiratory rate, oxygen saturation, and temperature).
3) Performance status evaluation
4) Review concomitant medications
5) Adverse events assessment
6) CBC with differential, serum chemistry (Na, K, Cl, CO2, BUN, creatinine, glucose, calcium), 
magnesium, phosphate, liver function tests (albumin, total protein, alkaline phosphatase, 
total and, ALT, AST), LDH
7) Pregnancy test (serum or urine) for women of childbearing potential (every 6 weeks)
8) Administration of nivolumab and/or ipilimumab accordingly.
9) TSH with reflex free T4 and free T3 (every 6 weeks)
Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 
weeks, and thereafter every 12 weeks.
Tumor biopsies (excision, core or forceps) will be performed 9 to 10 weeks after initiating trial 
therapy after the 4th or 5th nivolumab infusion to allow for analysis of pharmacodynamics changes 
related to trial therapy (see Sections 4.1.1 and 7). Blood will be drawn for correlative studies the 
day of the first four nivolumab infusions, and the week after the 5th nivolumab infusion.
5.3.
Follow-up Visits
All patients who discontinue the study treatment will have a follow up visit at Day 28 ±7 days 
from the last study treatment.
1) History and physical examination
2) Measurement of height, weight and vital signs (including blood pressure, heart rate, 
respiratory rate, oxygen saturation, and temperature).
3) Performance status evaluation
4) Review concomitant medications
5) Adverse events assessment
6) CBC with differential, serum chemistry (Na, K, Cl, CO2, BUN, creatinine, glucose, calcium), 
magnesium, phosphate, liver function tests (albumin, total protein, alkaline phosphatase, 
total, ALT, AST), LDH, and TSH with reflex free T4 and free T3
7) Tumor assessment with CT scan of the chest/abdomen/pelvis and brain every 9 weeks (+/- 5 
days) until progression, withdrawal of consent, death, lost to follow-up, or start of a 
subsequent anti-cancer therapy
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All patients who discontinue early or who complete the study treatment period will be followed 
for survival. Survival follow-up information will be collected via telephone calls, patient medical 
records, and/ or clinic visits every 3 months +/- 14 days until death, loss to follow-up or study 
termination. All patients will be followed for survival unless the patient requests to be 
withdrawn from follow-up. If the patient withdraws from study treatment but not from follow- 
up, the study staff may use a public information source to obtain information about survival 
status.
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5.4.
STUDY CALENDAR
W (week)
Pre- 
Tx
W 
1
W 
2
W 
3
W 
4
W 
5
W 
6
W 
7
W 
8
W 
9
W 
10
W 
11
W 
12
W 
13
W 
14
W 
15
W 
16
W 17
& Q2W
End 
of Tx
Nivolumab
X
X
X
X
X
X
X
X
X
Ipilimumab
X
X
X
W 19
& Q6W
Informed Consent
X
Demographics
X
Medical History
X
Concurrent Meds
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
X
Vital Signs1
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
X
CBC w/diff, plts
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry2
X
X
X
X
X
X
X
X
X
X
X
TSH3
X
X
X
W 19
& Q6W
X
Amylase/ Lipase
X
X
B-HCG4
X
X
X
W 19
& Q6W
X
EKG
X
Adverse Event 
Evaluation
X
X
X
X
X
X
X
X
X
X
X
Trial Imaging
X
X
W 18
& Q12W
Tumor Biopsy
X
X
PD Blood Draw
X
X
X
X
X
X
X
1.
Includes blood pressure, heart rate, respiratory rate, oxygen saturation, and temperature
2.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium.
3.
Reflex to Free T3 and T4 is TSH abnormal
4.
Serum or urine pregnancy test (women of childbearing potential)
5.
All screening procedures except labs to occur within 28 days of first dose.  All labs to be collected within 14 days of first 
dose.
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6.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
6.1
Safety Analysis
Safety will be analyzed for patients treated in this study. All patients who receive any amount of 
study drug will be evaluable for toxicity.
At each visit, a brief focused history will be obtained and any indication of treatment- related toxicity 
will be evaluated by appropriate examination and/or laboratory/radiographic studies.
Safety analyses will include summaries of adverse event rates and changes in laboratory results, as 
well as number of CTCAE (v4.0) toxicity grades for both laboratory and non-laboratory data.
The evaluation period should extend from date of first treatment until 100 days from discontinuation 
of treatment, and until resolution from all acute toxicities associated with the drug administration.
6.2
Definition of Adverse Event Terms
Adverse Event: Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure 
regardless of whether it is considered related to the medical treatment or procedure (attribution of 
unrelated, unlikely, possible, probable, or definite). [NIH Guidelines, January 2001]
Serious Adverse Event (SAE): Any adverse drug experience occurring at any dose that results in any 
of the following outcomes:
1)
Death
2)
A life-threatening adverse drug experience
3)
In-patient hospitalization or prolongation of existing hospitalization
4)
Any persistent or significant disability/incapacity
5)
A congenital anomaly/birth defect
6)
Is a new cancer (that is not a condition of the study)
7)
Is associated with an overdose
8)
Is another important medical event
9)
Pregnancy
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. [Code of Federal Regulations Title 21].
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
“Serious” Versus “Severe” Adverse Events: There is a distinction between serious and severe AEs. 
Assessment of seriousness will be made solely by the serious criteria listed above.
Severity of AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events 
v4.0. Therefore, serious events will not be automatically considered severe. For example, a stroke 
that results in only a limited degree of disability may be considered a mild (not severe) stroke, but it 
would still meet serious criteria and thus, be captured as an SAE. Similarly, severe events may not 
always be serious. An example would be an episode of severe, transient nausea which persists for
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several hours. This would be classified as a “severe” episode of nausea, but if it did not require 
treatment, intervention, or somehow meet other serious criteria, it would not be considered an SAE.
Life-threatening Adverse Drug Experience: Any adverse drug experience that places the patient or 
subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred,
i.e. it does not include a reaction that, had it occurred in a more severe form, might have caused 
death. [21CFR312.32(a)]
Unexpected Adverse Drug Experience: Any adverse drug experience, the specificity or severity of 
which is not consistent with the current investigator brochure; or, if an investigator brochure is not 
required or available, the specificity or severity of which is not consistent with the risk information 
described in the general investigational plan. “Unexpected” as used in this definition, refers to an 
adverse drug experience that has not been previously observed rather than from the perspective of 
such experience not being anticipated from the pharmacological properties of the pharmaceutical 
product.
Laboratory test abnormalities: Laboratory abnormalities that constitute an adverse event in their 
own right (are considered clinically significant, induce clinical signs or symptoms, require 
concomitant therapy or require changes in study treatment), should be recorded. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for adverse events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. Please note that a dose hold or medication for a lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an adverse 
event and must be reported as such.
6.3.
Toxicity Grading
Toxicities will be graded according to the current version of the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0. The full text of the NCI CTCAE is available online at:  
http://ctep.cancer.gov/forms/CTCAEv4.pdf
If a certain event or symptom is not described in the CTCAE grades, use the following grading scale:
Mild
Awareness of event, but easily tolerated
Moderate
Discomfort enough to cause some interference with usual activity
Severe
Inability to carry out usual activity
Very Severe
Debilitating, significantly incapacitates patient despite symptomatic therapy
6.4.
Toxicity Attribution
Assessment of attribution is made by consideration of all clinically relevant data prior to, during, 
and after occurrence of the event, including diagnostic tests to assess the cause of the event.
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Clinically relevant data include, but are not limited to; underlying disease, past and present medical 
history (all concurrent non-malignant disease), concurrent medications, and timing between event 
and drug administration. The mechanism of action and prior toxicology of the study drug should be 
considered.
An adverse event is associated with the use of the drug when there is a reasonable possibility that 
the experience may have been caused by the drug. Potential attribution of an adverse event 
associated with trial therapy will be provided for all study drugs, nivolumab and/or ipilimumab.
Attribution Standards per NCI – CTEP:
Unrelated
The Adverse Event is clearly not related to the investigational agent (s) 
Unlikely
The Adverse Event is doubtfully related to the investigational agent(s) 
Possible
The Adverse Event may be related to the investigational agent(s) 
Probable
The Adverse Event is likely related to the investigational agent(s) 
Definite
The Adverse Event is clearly related to the investigational agent(s)
6.5.
Yale Principal Investigator Safety Reporting Requirements
6.5.1
Expedited Reporting of Unexpected SAEs
AEs classified as “serious” and “unexpected” that are possibly, probably, or definitely attributed to 
drug administration, or SAEs whose frequency exceeds expectations, require expeditious handling 
and reporting.
The PIs will promptly investigate all safety information related to an adverse experience. If the results 
of the PIs’ investigation show an adverse drug experience not initially determined to be reportable 
(based on whether the event is serious, unexpected, and associated with drug administration) is so 
reportable, the PIs will report such experience. Follow-up information to a safety report shall be 
submitted as soon as the relevant information is available.
6.5.2
Reporting to the Yale Human Investigation Committee
All SAEs, whether originating at Yale or a collaborating center, meeting the criteria for expedited 
reporting will be reported to the Yale University Human Investigation Committee (HIC) using HIC 
Form 710 FR 4: Unanticipated Problem Involving Risks to Subjects or Others (UPIRSOs), including 
Adverse Events (AEs) Reporting Form as per IRB Policy 710.
The HIC does not require reporting of any other Adverse Event type. A copy of the IRB Policy 710 
Reporting Unanticipated Problems Involving Risks to Subjects or Others, including Adverse Events 
is available at: 
http://www.yale.edu/hrpp/policies/documents/NewIRBPolicy710_UPIRSOSAE_4.3.2014_withfl 
owchart_vF.PDF
6.5.3
Reporting to the Food and Drug Administration
This study will be conducted under an IND (Investigational New Drug application) that will be held 
by the Principal Investigator, Dr. Scott Gettinger. The Principal Investigator will report in an 
expedited manner all SAEs meeting the criteria of “serious”, “unexpected” and “related to study 
treatment”. Written safety reports will use a MedWatch Form 3500A. A “fillable pdf” version with
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instructions   is   available   at:   http://www.fda.gov/medwatch/safety/FDA-3500A_Fillable_08-16- 
2006.pdf
There are two types of expedited safety reports to the FDA:
1.
7-Calendar-Day FDA Telephone or Fax Report: The sponsor-investigator will directly notify 
the FDA, within 7 calendar days after his initial receipt of the information, of any adverse event that 
is ALL of the following:

Death or immediately life-threatening

Unexpected

Associated with the use of nivolumab or ipilimumab
Notification to the FDA will be made directly to the new drug review division in the Center for Drug 
Evaluation and Research or in the product review division for the Center for Biologics Evaluation 
and Research, whichever was responsible for the review of the IND. [21CFR312.32(c)] A written 
report of the event is to follow within 15 calendar days.
2.
15-Calendar-Day FDA Written Report: The sponsor-investigator will directly notify the FDA 
within 15 calendar days of any adverse event that is ALL of the following:

Serious (due to non-fatal and non-life threatening criteria)

Unexpected

Associated with the use of nivolumab or ipilimumab
Note: Serious Adverse Events which do not meet the criteria for expedited reporting will be 
reported to the FDA in the IND Annual Report.
6.5.4
Reporting to Bristol Myers Squibb
Investigators must report all SAEs to Bristol Myers Squibb within the timelines described below. The 
completed MedWatch/case report should be faxed and/or emailed immediately upon completion to 
BMS Drug Safety at:  
SAE Facsimile Number:  609-818-3804  
      
SAE Email Address:  Worldwide.Safety@BMS.com
Relevant follow-up information should be submitted to BMS Drug Safety as soon as it becomes 
available.
SAE reports whether related or unrelated to nivolumab or ipilimumab will be transmitted to BMS 
within 24 hours of the Awareness Date.
Additional reporting requirements to BMS include the following:
-
Any reports of pregnancy following the start of administration of nivolumab and 
within the follow-up period (for female patients within 5 months after the last 
dose of nivolumab or ipilimumab or the partner of a male patient within seven 
months of completing therapy) will be transmitted to BMS within 24 hours of the 
Awareness Date.
-
All non-serious nivolumab or ipilimumab AEs originating from the study will be 
forwarded to BMS quarterly
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Follow-Up Information
Additional information may be added to a previously submitted report by any of the following 
methods:
-
Adding to the original MedWatch 3500A report and submitting it as follow-up
-
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form
-
Summarizing new information and faxing it with a cover letter including patient 
identifiers (i.e., D.O.B. initial, patient number), protocol description and number, if 
assigned, brief AE description, and notation that additional or follow-up 
information is being submitted. (The patient identifiers are important so that the 
new information is added to the correct initial report.)
Occasionally BMS may contact the reporter for additional information, clarification, or current 
status of the patient for whom and AE was reported. Relevant follow-up information should be 
submitted to BMS Drug Safety as soon as it becomes available and/or upon request.
6.5.5.  Duration of Reporting of SAEs
From the administration of first treatment until 90 days (unless otherwise specified) subsequent to 
last treatment or withdrawal of subject, new onset adverse events will be captured. Follow-up and 
reporting of these events will follow the same procedure as for AEs observed during the study 
period. In addition, any unexpected Serious Adverse Event that occurs more than 90 days after drug 
administration but is possibly, probably or definitely attributed to drug administration will be 
recorded and reported.
6.6.
Yale Safety Reporting and Monitoring (DSMP)
The Yale Cancer Center (YCC) Data and Safety Monitoring Committee (DSMC) will provide the 
primary oversight of data and safety monitoring. The Yale DSMC will review and monitor 
compliance, toxicity and deviations from this study. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the Principal 
Investigator.
The DSMC will review this protocol bi-annually, at a minimum. Information to be provided to the 
committee includes: a study narrative by the PI, a summary DSMC report produced by OnCore 
(which includes participant accrual, response, trial status history, SAEs, adverse events, deviations 
and survival); audit results, and monitoring reports, as applicable. Other information (e.g., scans, 
laboratory values, etc.) will be provided upon request. Upon completing the review, the DSMC will 
approve whether the study should continue as planned, require modification/ amendment, or be 
placed on administrative hold with accrual temporarily suspended.
Trials being monitored by the YCC DSMC will remain under the YCC DSMC purview until a DSMC 
review has occurred that includes the research activity of the last subject who completed the 
intervention, or until the DSMC feels there are no patient safety concerns that require further 
monitoring. The DSMC will determine the length of continued DSMC review.
The DSMC has authority to intervene in the conduct of these studies as necessary to ensure the 
safety of the participants and to maintain the highest quality in the clinical research performed at 
YCC. The DSMC has the authority to require additional monitoring and/ or more frequent reporting 
on study progress and serious adverse events. 
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6.7.
Pregnancies
It is the responsibility of investigators or their designees to report any pregnancy or lactation in a 
subject (spontaneously reported to them), including the pregnancy of a male subject's female 
partner that occurs during the trial or within 120 days of completing the trial.
All subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and 
stillbirth must be reported as serious events (Important Medical Events). If the pregnancy continues 
to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to Yale IRB.
6.8.
Warnings and Precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochures. Additional safety information collected between IB updates will be communicated in the 
form of Investigator Notifications. This information will be included in the patient informed consent 
and should be discussed with the patient during the study as needed.
7.
CORRELATIVE/SPECIAL STUDIES
Correlative studies will be conducted on serial tumor biopsy and blood specimens. All patients will 
undergo a tumor biopsy prior to initiation of trial therapy, and after their 5th treatment with 
nivolumab (study week 10). Blood will be drawn prior to each tumor biopsy to allow additional 
correlative studies.
Tissue from Serial Tumor Biopsies:
a.
Multiplexed quantitative immunofluorescence will be used to evaluate multiple markers on 
tumor/ immune cells, including, but not limited to, PD-L1, PD-1, CK, CD4, CD8, CD20, Ki67, 
granzyme B, and IDO1.
b.
RNA, TCR and DNA sequencing (with neoantigen analysis)
c.
Additional studies, depending on tissue availability, may include: functional T cell studies 
(neoantigen stimulation assay, T cell culture) and generation of patient derived xenografts.
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Serial Blood Draws:
a.
Mass cytometer (CyTOF 2, DVS Sciences) will be used to comprehensively characterize 
phenotypic (CD45, CD3, CD8, CD4, CD33, CD11b, CD123, CD56, CD16, CD20, CD66b, CD68, 
TBET, GATA-3, FOXP-3, CD14, CCR7, CD45RA, γδTCR) and functional (KI-67, HLA-DR, CD25, 
PD-1, CD80, CD16, IFNg, TNFa, Granzyme B, Caspase 3, PARP) changes of blood cells in 
relation to changes in tumor tissue.
b.
Tetramer staining using neoantigenic peptides or ELISPOT (neoantigen stimulation assay).
8.
CRITERIA FOR RESPONSE
Anti-tumor activity: data on objective response, progression free survival, and duration of response 
will be listed for all patients in the study and summarized overall.
Objective response is defined as a complete or partial response, as determined by investigator 
assessment using RECIST v1.1 and irRC (see appendix 3 and 4) and confirmed by repeat assessments
≥4 weeks after initial documentation. Patients not meeting these criteria, including patients without 
any post baseline tumor assessment, will be considered non-responders in the analysis of objective 
response.
Duration of objective response will be analyzed for the subset of patients who achieved an objective 
response. Duration of response is defined as the time from the initial complete or partial response 
to the time of disease progression or death, whichever occurs first. If a patient does not experience 
death or disease progression before the end of the study, duration of response will be censored at 
the day of the last tumor assessment. If no tumor assessments were performed after the date of the 
first occurrence of a complete or partial response, duration of objective response will be censored 
at the date of the first occurrence of a complete or partial response plus 1 day.
Progression-free survival is defined as the time from the first day of nivolumab treatment until 
progression of disease using RECIST v1.1 and irRC (see appendix 3 and 4). If a patient has not 
experienced progressive disease or death, PFS will be censored at the day of the last tumor 
assessment. Patients with no post baseline tumor assessments will be censored at the date of first 
study treatment plus 1 day.
Overall survival is defined as the time from the first day of treatment until death from any cause. If a 
patient has not experienced death, OS will be censored at the day of last follow-up.     
9. STATISTICAL CONSIDERATIONS
This trial is designed to determine the objective response rate (ORR) using RECIST v1.1 and irRC to 
nivolumab and ipilimumab when administered in combination to patients with advanced NSCLC 
and primary resistance to PD-1 axis inhibitor therapy. Details on the response criteria and its 
duration are described in Section 8 of this protocol. For our primary endpoint we will employ a 
Simon two-stage design. This design is based on our intuition for a very low response rate and not 
on any specific experimental evidence. The study design will terminate early if there are no 
responses or prolonged stability (> 24 weeks) using irRC among the first 10 patients enrolled. 
Otherwise we will enroll a maximum of 40 and reject the null hypothesis if we observe 4 or more 
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positive responses. For a null hypothesis with a 5% ORR and alternative with a 19% ORR, this 
criterion has significance level 0.1 and power greater than 85%. The null and alternative hypothesis 
rates are not motivated by experimental evidence but rather, are examples of one pair of 
hypotheses that can be tested using this design.  
An operating characteristic of this design with other ORRs is plotted here:
We anticipate enrollment at a rate of at least 2 patients per month. Patients who drop out or leave 
the study before receiving any experimental treatment will be replaced.  Patients who leave the study 
after receiving any study treatment will be considered as treatment failures and not be replaced.
Our secondary analyses correlate ORR, time-to-event measures and correlative metrics listed in 
Section 7. Specifically, duration of response, progression-free survival (PFS) and overall survival (OS) 
will be estimated a l o n g  with the corresponding 95% CI, plotted using the Kaplan-Meier method. 
These plots will also be prepared separately by RECIST v 1.1 criteria and irRC and tested using the log-rank 
test.  Duration of response, OS, and PFS are defined in Section 8. 
Marker data and other metrics listed in Section 7 will be correlated to ORR and PFS using Cox 
proportional hazard regression methods. These values will be analyzed marginally using heatmaps 
and single linkage to identify any subpopulations.
The following analysis sets will be defined in this trial:

Full Analysis Set: All subjects who receive at least 1 dose of any trial treatment.

Completer Analysis Set: All subjects who complete the trial, all scheduled treatments, all 
biomarker assessments, and all tumor assessments.

Safety Analysis Set: All subjects who receive at least 1 dose of any trial treatment but 
subsequently drop out of the study for any reason.

Correlative Biomarker Set: All subjects who receive at least one dose of any trial treatment 
and have at least one set of correlative marker data listed in Section 7.
No formal statistical ORR analyses will be conducted on the 10 additional patients with acquired 
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resistance, though the finding of immune related response in 1 or more patients would be 
unexpected, and should prompt further study.
Demographics and baseline laboratory results will be summarized by cohort (primary and acquired 
resistance to anti-PD-1 axis therapy) and by all patients using descriptive statistics.
Safety analysis will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 by cohort (primary and acquired resistance to anti-PD-1 axis therapy) and by all 
patients.  All on-study AEs, drug-related AEs, SAEs and drug-related SAEs will be tabulated using 
worst grade per NCI CTCAE v 4.0 criteria by system organ class and preferred term. On-study lab 
parameters including hematology, coagulation, chemistry, liver function and renal function will be 
summarized using worst grade per NCI CTCAE v 4.0 criteria.
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Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus 
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Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in 
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Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of 
durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. 
Lancet Oncol 2016;17:299-308.
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17.
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. Proc Natl Acad Sci U S A 2010;107:4275-80.
18.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
19.
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clinical cancer research : an 
official journal of the American Association for Cancer Research 2009;15:7412-20.
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Appendix 1: NCI Common Terminology Criteria for Adverse Events (CTCAE)
Please use the following link to the NCI CTCAE website:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
Appendix 2: Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
Description
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework or 
office work
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities; up and about  50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair  50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair
5
Dead
Appendix 3: Response Evaluation Criteria in Solid Tumors (RECIST)
Modified Excerpt from Original Publication
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.118 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.
Measurability of Tumor at Baseline 
Definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable 
as follows:
a.
Measurable Tumor Lesions
Tumor Lesions. Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of:
-
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater 
than 5 mm)
-
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable)
-
20 mm by chest X-ray
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Malignant Lymph Nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be  15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement.
b.
Non-Measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm 
or pathological lymph nodes with  10 to  15 mm short axis), as well as truly
non-measurable lesions. Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.
c.
Special Considerations Regarding Lesion Measurability
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below.
Bone lesions:
-
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques 
can be used to confirm the presence or disappearance of bone lesions.
-
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT or 
MRI can be considered measurable lesions if the soft tissue component meets the 
definition of measurability described above.
-
Blastic bone lesions are non-measurable.
Cystic lesions:
-
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts.
-
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above. However, if non- 
cystic lesions are present in the same patient, these are preferred for selection as 
target lesions.
Lesions with prior local treatment:
-
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. For this study, such lesions will be considered 
measurable if they are clearly progressing and meet other RECIST 1.1 criteria.
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Target Lesions: Specifications by Methods of Measurements
a.
Measurement of Lesions
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.
b.
Method of Assessment
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during study. Imaging-based 
evaluation should always be the preferred option.
Clinical Lesions. Clinical lesions will only be considered measurable when they are 
superficial and  10 mm in diameter as assessed using calipers (e.g., skin nodules). For the 
case of skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is suggested.
Chest X-Ray. Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying  
new lesions. However, lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung.
CT, MRI. CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. MRI is also acceptable.
If prior to enrollment it is known that a patient is unable to undergo CT scans
with intravenous (IV) contrast due to allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the  
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease. For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to whether 
non-contrast CT or MRI (enhanced or non-enhanced) will be performed should also be 
based on the tumor type and the anatomic location of the disease and should be  
optimized to allow for comparison with the prior studies if possible. Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point  
forward. Care must be taken in measurement of target lesions on a different modality and 
interpretation of non-target disease or new lesions since the same lesion may appear to 
have a different size using a new modality.
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.
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Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology. The utilization of these 
techniques for objective tumor evaluation cannot generally be advised.
Tumor Response Evaluation
Assessment of Overall Tumor Burden and Measurable Disease
To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and to use this as a comparator for subsequent measurements. 
Measurable disease is defined by the presence of at least one measurable lesion, as 
detailed above.
Baseline Documentation of Target and Non-Target Lesions
When more than one measurable lesion is present at baseline, all lesions up to a maximum 
of five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured                  
at baseline. This means in instances where patients have only one or two organ sites 
involved, a maximum of two lesions (one site) and four lesions (two sites), respectively,  
will be recorded. Other lesions (albeit measurable) in those organs will be recorded as
non-measurable lesions (even if the size is  10 mm by CT scan).
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but additionally, should lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion does not lend itself to reproducible measurement, in which circumstance 
the next largest lesion that can be measured reproducibly should be selected.
Lymph nodes merit special mention since they are normal anatomical structures that may 
be visible by imaging even if not involved by tumor. As noted above, pathological nodes 
that are defined as measurable and may be identified as target lesions must meet the 
criterion of a short axis of  15 mm by CT scan. Only the short axis of these nodes will 
contribute to the baseline sum. The short axis of the node is the diameter normally used 
by radiologists to judge if a node is involved by solid tumor. Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or 
coronal). The smaller of these measures is the short axis. For example, an abdominal  
node that is reported as being 20 mm  30 mm has a short axis of 20 mm and qualifies as a 
malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis  10 mm but  15 mm) 
should be considered non-target lesions. Nodes that have a short axis  10 mm are 
considered non-pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters. If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added into 
the sum. The baseline sum of diameters will be used as a reference to further characterize 
any objective tumor regression in the measurable dimension of the disease.
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All other lesions (or sites of disease), including pathological lymph nodes,
should be identified as non-target lesions and should also be recorded at baseline.  
Measurements are not required and these lesions should be followed as “present,” 
“absent,” or in rare cases “unequivocal progression.”
In addition, it is possible to record multiple non-target lesions involving the same organ as 
a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph nodes” 
or “multiple liver metastases”).
Response Criteria
a.
Evaluation of Target Lesions
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions.
-
Complete response (CR): disappearance of all target lesions
Any pathological lymph nodes (whether target or non-target) must have reduction in short 
axis to  10 mm.
-
Partial response (PR): at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters
-
Progressive disease (PD): at least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (nadir), including baseline
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.
The appearance of one or more new lesions is also considered progression.
-
Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum on study
b.
Special Notes on the Assessment of Target Lesions
Lymph Nodes. Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to  10 mm on study. This means that when 
lymph nodes are included as target lesions, the sum of lesions may not be zero even if CR 
criteria are met since a normal lymph node is defined as having a short axis  10 mm.
Target Lesions That Become Too Small to Measure. While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes lesions 
or lymph nodes that are recorded as target lesions at baseline become so faint on CT scan 
that the radiologist may not feel comfortable assigning an exact measure and may report 
them as being too small to measure. When this occurs, it is important that a value be 
recorded on the CRF as follows:
-
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm.
-
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should be
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ticked. (Note: It is less likely that this rule will be used for lymph nodes since they 
usually have a definable size when normal and are frequently surrounded by fat such 
as in the retroperitoneum; however, if a lymph node is believed to be present and
is faintly seen but too small to measure, a default value of 5 mm should be assigned in 
this circumstance as well and BML should also be ticked.)
To reiterate, however, if the radiologist is able to provide an actual measure, that should  
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked.
Lesions That Split or Coalesce on Treatment. When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be maintained 
that would aid in obtaining maximal diameter measurements of each individual lesion. If 
the lesions have truly coalesced such that they are no longer separable, the vector of the 
longest diameter in this instance should be the maximal longest diameter for the  
coalesced lesion.
c.
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions. While some non-target lesions may actually be 
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol.
-
CR: disappearance of all non-target lesions and (if applicable) normalization of tumor 
marker level)
All lymph nodes must be non-pathological in size ( 10 mm short axis).
-
Non-CR/Non-PD: persistence of one or more non-target lesion(s) and/or (if applicable) 
maintenance of tumor marker level above the normal limits
-
PD: unequivocal progression of existing non-target lesions
The appearance of one or more new lesions is also considered progression.
d.
Special Notes on Assessment of Progression of Non-Target Disease
When the Patient Also Has Measurable Disease. In this setting, to achieve unequivocal 
progression on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease in a magnitude that, even in the presence of 
SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore be extremely rare.
When the Patient Has Only Non-Measurable Disease. This circumstance arises in some 
Phase III trials when it is not a criterion of study entry to have measurable disease. The 
same general concepts apply here as noted above; however, in this instance, there is no 
measurable disease assessment to factor into the interpretation of an increase in non- 
measurable disease burden. Because worsening in non-target disease cannot be easily
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quantified (by definition: if all lesions are truly non-measurable), a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase 
in overall disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease, 
that is, an increase in tumor burden representing an additional 73% increase in volume 
(which is equivalent to a 20% increase in diameter in a measurable lesion). Examples 
include an increase in a pleural effusion from “trace” to “large” or an increase in 
lymphangitic disease from localized to widespread or may be described in protocols as 
“sufficient to require a change in therapy.” If unequivocal progression is seen, the patient 
should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease 
makes it impossible to do so; therefore, the increase must be substantial.
e.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, that is, not attributable to differences in scanning technique, change in 
imaging modality, or findings thought to represent something other than tumor (for 
example, some “new” bone lesions may be simply healing or flare of preexisting lesions). 
This is particularly important when the patient’s baseline lesions show partial or complete 
response. For example, necrosis of a liver lesion may be reported on a CT scan report as a 
“new” cystic lesion, which it is not.
A lesion identified during the study in an anatomical location that was not scanned at  
baseline is considered a new lesion and will indicate disease progression.
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan.
Evaluation of Response
a.
Timepoint Response (Overall Response)
It is assumed that at each protocol-specified timepoint, a response assessment 
occurs. Table A3.1 provides a summary of the overall response status calculation 
at each timepoint for patients who have measurable disease at baseline.
When patients have non-measurable (therefore non-target) disease only, Table A3.2 is 
to be used.
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Table A3.1. Timepoint Response: Patients with Target Lesions (with or without Non- 
Target Lesions)
Target Lesions
Non-Target Lesions
New Lesions
Overall 
Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not 
all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CR  complete response; NE  not evaluable; PD  progressive disease; 
PR  partial response; SD  stable disease.
Table A3.2. Timepoint Response: Patients with Non-Target Lesions Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD a
Not all evaluated
No
NE
Unequivocal PD
Yes or no
PD
Any
Yes
PD
CR  complete response; NE  not evaluable; PD  progressive disease.
a   “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since 
stable disease is increasingly used as an endpoint for assessment of efficacy in some 
trials; thus, assigning “stable disease” when no lesions can be measured is not 
advised.
b.
Missing Assessments and Not-Evaluable Designation
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response. This would be most likely to happen 
in the case of PD. For example, if a patient had a baseline sum of 50 mm with three 
measured lesions and, during the study, only two lesions were assessed, but those gave a 
sum of 80 mm; the patient will have achieved PD status, regardless of the contribution of 
the missing lesion.
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If one or more target lesions were not assessed either because the scan was not done or 
the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not evaluable. 
Similarly, if one or more non-target lesions are not assessed, the response for non-target 
lesions should be “unable to assess” except where there is clear progression. Overall 
response would be “unable to assess” if either the target response or the non-target 
response is “unable to assess,” except where this is clear evidence of progression as this 
equates with the case being not evaluable at that timepoint.
Table A3.3. Best Overall Response When Confirmation Is Required
Overall Response at 
First Timepoint
Overall Response at 
Subsequent Timepoint
Best Overall Response
CR
CR
CR
CR
PR
SD, PD, or PR a
CR
SD
SD, provided minimum 
duration for SD was met; 
otherwise, PD
CR
PD
SD, provided minimum 
duration for SD was met; 
otherwise, PD
CR
NE
SD, provided minimum 
duration for SD was met; 
otherwise, NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD, provided minimum 
duration for SD was met; 
otherwise, PD
PR
NE
SD, provided minimum 
duration for SD was met; 
otherwise, NE
NE
NE
NE
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial 
response; SD  stable disease.
a   If a CR is truly met at the first timepoint, any disease seen at a subsequent  
timepoint, even disease meeting PR criteria relative to baseline, qualifies as PD at 
that point (since disease must have reappeared after CR). Best response would 
depend on whether the minimum duration for SD was met. However, sometimes CR 
may be claimed when subsequent scans suggest small lesions were likely still  
present and in fact the patient had PR, not CR, at the first timepoint. Under these 
circumstances, the original CR should be changed to PR and the best response is PR.
c.
Special Notes on Response Assessment
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size ( 10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to
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overstate progression should it be based on increase in size of the nodes. As noted earlier, 
this means that patients with CR may not have a total sum of “zero” on the CRF.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document objective 
progression even after discontinuation of treatment. Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy. The  
objective response status of such patients is to be determined by evaluation of target and 
non-target disease as shown in Tables A3.1-A3.3.
For equivocal findings of progression (e.g., very small and uncertain new lesions; 
cystic changes or necrosis in existing lesions), treatment may continue until the next 
scheduled assessment. If at the next scheduled assessment progression is confirmed, 
the date of progression should be the earlier date when progression was suspected.
In studies for which patients with advanced disease are eligible (i.e., primary disease still or  
partially present), the primary tumor should also be captured as a target or non-target  
lesion, as appropriate. This is to avoid an incorrect assessment of complete response if the  
primary tumor is still present but not evaluated as a target or non-target lesion
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Appendix 4: Immune-Related Response Criteria 
INTRODUCTION
Increasing clinical experience indicates that traditional response criteria (e.g., Response 
Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] and World Health 
Organization [WHO]) may not be sufficient to characterize fully activity in the new era of 
target therapies and/or biologics. In studies with cytokines, cancer vaccines,
and monoclonal antibodies, complete response, partial response, or stable disease has 
been shown to occur after an increase in tumor burden as characterized by progressive 
disease by traditional response criteria. Therefore, conventional response criteria may not 
adequately assess the activity of immunotherapeutic agents because progressive disease 
(by initial radiographic evaluation) does not necessarily reflect therapeutic failure.
Long-term effect on the target disease must also be captured. The immune-related 
response criteria19 (irRC) are criteria that attempt to do that by enhancing characterization 
of new response patterns that have been observed with immunotherapeutic agents
(i.e., ipilimumab). (Note: The irRC only index and measurable new lesions are taken 
into account.)
GLOSSARY
Term
Definition
SPD
sum of the products of the two largest perpendicular diameters
Tumor burden
SPDindex lesions  SPDnew, measurable lesions
Nadir
minimally recorded tumor burden
irCR
immune-related complete response
irPD
immune-related progressive disease
irPR
immune-related partial response
irSD
immune-related stable disease
irBOR
immune-related best overall response
BASELINE ASSESSMENT USING irRC
Step 1. Identify the index lesions (five lesions per organ, up to ten visceral lesions and 
five cutaneous lesions).
Step 2. Calculate the SPD of all of these index lesions:
SPD  
i
(Largest diameter of lesion i)  (Second largest diameter of lesion i).
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POST-BASELINE ASSESSMENTS USING irRC
Step 1. Calculate the SPD of the index lesions.
Step 2. Identify new, measurable lesions ( 5  5 mm; up to five new lesions per organ: 
five new cutaneous lesions and ten visceral lesions).
Step 3. Calculate the SPD of the new, measurable lesions. 
Step 4. Calculate the tumor burden:
Tumor burden  SPDindex lesions  SPDnew, measurable lesions
Step 5. Calculate the change in tumor burden relative to baseline and the change in tumor 
burden relative to nadir.
Step 6. Derive the overall response using the table below.
Overall Response
Criterion
irCR
Complete disappearance of all lesions (whether measurable or not, 
and no new lesions) confirmed by a repeat, consecutive assessment
 4 weeks from the date first documented
irPR
Decrease in tumor burden  50% relative to baseline confirmed by a 
consecutive assessment  4 weeks from the date first documented
irSD
Criteria for irCR, irPR, and irPD are not met; does not require 
confirmation
irPD
Increase in tumor burden  25% relative to nadir confirmed by a 
consecutive assessment  4 weeks from the date first documented
irCR  immune-related complete response; irPD  immune-related progressive disease; 
irPR  immune-related partial response; irSD  immune-related stable disease.
DETERMINATION OF irBOR
Once a patient has completed all tumor assessments, his/her irBOR may be determined:
Condition
irBOR
At least one irCR
irCR
At least one irPR and no irCR
irPR
At least one irSD and no irCR and no irPR
irSD
At least one irPD and no irCR, no irPR, and no irSD
irPD
irBOR  immune-related best overall response; irCR  immune-related complete 
response; irPD  immune-related progressive disease; irPR  immune-related partial 
response; irSD  immune-related stable disease.
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