Conditions: Non-small Cell Lung Cancer
Keywords: Non-Small Cell Lung Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
This research study is studying two immunotherapy drugs as a possible treatment for advanced non-small cell lung cancer (NSCLC).

The drugs involved in this study are:

* Ipilimumab
* Nivolumab

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of investigational drugs to learn whether the drugs work in treating a specific disease. "Investigational" means that the drugs are being studied.

The FDA (the U.S. Food and Drug Administration) has not approved ipilimumab for this specific disease but it has been approved for other uses, including for patients with advanced melanoma.

The FDA (the U.S. Food and Drug Administration) has approved nivolumab as a treatment option for this disease. However, nivolumab it is not approved in combination with ipilimumab to treat NSCLC.

Nivolumab and ipilimumab are both types of immunotherapy. Immunotherapy works by stimulating the body's own immune system to attack cancer cells. The combination of ipilimumab with nivolumab may or may not increase anti-cancer activity by further boosting the immune system.

In this research study, the investigators are investigating if the combination of ipilimumab and nivolumab is effective in treating advanced NSCLC. The investigators are also investigating whether there are certain DNA or protein markers in the blood or tumor tissue that may indicate whether the combination will work in future patients.

Arms:
arm 1: Nivolumab will be administered once every 2 weeks 1 mg/kg intravenously Ipilimumab will be administered once every 6 weeks 3 mg/kg intravenously

Interventions: intervention 1: Ipilimumab intervention 2: Nivolumab
Intervention descriptions: intervention 1: Ipilimumab is a type of immunotherapy. Immunotherapy works by stimulating the body's own immune system to attack cancer cells intervention 2: Nivolumab is a type of immunotherapy. Immunotherapy works by stimulating the body's own immune system to attack cancer cells

Protocol document:
Prot_SAP_000.pdf: 
 
 
NCI Protocol #: N/A 
 
DF/HCC Protocol #: 17-566 
 
TITLE:  Biomarkers of response to ipilimumab and nivolumab as first-line therapy for 
metastatic non-small cell lung cancer (NSCLC): an open-label, single arm phase 2 study 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute (DFCI) 
 
*Principal Investigator (PI): 
Mark Awad MD, PhD 
 
Lowe Center for Thoracic Oncology 
 
Dana-Farber Cancer Institute 
 
Mark_Awad@dfci.harvard.edu 
 
Statistician: 
 
Responsible Data Manager:  
Suzanne Dahlberg, PhD 
 
Bryan Marion  
Dana-Farber Cancer Institute  
Dana-Farber Cancer Institute 
Telephone: 617-632-5580 
 
Telephone: 617-632-3383 
Fax: 617-632-2444 
 
Fax: 617-632-6485 
dahlberg@jimmy.harvard.edu  
bryan_marion@dfci.harvard.edu 
 
Sasha Kravets, MA 
Dana-Farber Cancer Institute 
Telephone: 617-582-9118 
Sasha_Kravets@DFCI.HARVARD.EDU 
  
NCI-Supplied Agent: N/A 
Other Agent(s): Ipilimumab/YERVOY (Bristol-Myers Squibb); Nivolumab/OPDIVO (Bristol-
Myers Squibb) 
 
 
IND #: 135825 
IND Sponsor: Mark Awad MD, PhD / DFHCC Investigator 
 
Protocol Type / Version # / Version Date: Revised / Version 5 / 07 Mar 2018 
 


DFCI Protocol Number: 17-566 
Protocol Version Date: 07 Mar 2018 
 
2 
 
SCHEMA 
 
Informed consent 
and confirmation of 
trial eligibility 
Enroll 43 participants to 
receive treatment with 
ipilimumab and nivolumab, 
with 1 cycle defined as 6 weeks 
Pre-treatment 
biopsy 
On-treatment biopsy 
(4 weeks following C1D1) 
Patient treatment continues 
for a maximum of 24 
months or until disease 
progression, unacceptable 
toxicity, other factors 
rendering the patient 
unacceptable for further 
therapy, or withdrawal of 
consent. 
Post-treatment biopsy 
(Time of disease progression) 
≥ 15 responses 
(CR or PR) 
observed among 
first 43 subjects 
Trial expands to 
enroll an additional 
37 participants 
Trial discontinued 
< 15 responses 
(CR or PR) 
observed among 
first 43 subjects 


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Protocol Version Date: 07 Mar 2018 
 
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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Study Design ............................................................................................................6 
1.2 
Primary Objective ....................................................................................................6 
1.3 
Secondary Objectives...............................................................................................6 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Study Disease and Rationale ....................................................................................6 
2.2 
Ipilimumab (YERVOY)...........................................................................................7 
2.3 
Nivolumab (OPDIVO) ...........................................................................................12 
2.4 
Ipilimumab with Nivolumab ..................................................................................16 
2.5 
Correlative Studies Background ............................................................................19 
3. 
PARTICIPANT SELECTION ...........................................................................................20 
3.1 
Eligibility Criteria ..................................................................................................20 
3.2 
Exclusion Criteria ..................................................................................................21 
3.3 
Inclusion of Women and Minorities ......................................................................23 
4. 
REGISTRATION PROCEDURES ...................................................................................23 
4.1 
General Guidelines for DF/HCC Institutions ........................................................23 
4.2 
Registration Process for DF/HCC Institutions .......................................................23 
5. 
TREATMENT PLAN ........................................................................................................23 
5.1 
Treatment Regimen ................................................................................................23 
5.2 
Pre-Treatment Criteria ...........................................................................................24 
5.3 
Agent Administration.............................................................................................24 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................25 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .........................................26 
5.6 
Duration of Follow Up ...........................................................................................28 
5.7 
Criteria for Taking a Participant Off Study ...........................................................28 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................29 
6.1 
Toxicity Management ............................................................................................29 
6.2 
Dose Delays ...........................................................................................................41 
6.3 
Dose Reductions ....................................................................................................42 
6.4 
Overdose Management ..........................................................................................42 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................42 
7.1 
Expected Toxicities ................................................................................................42 
7.2 
Adverse Event Characteristics ...............................................................................43 
7.3 
Serious Adverse Events .........................................................................................46 
7.4 
Expedited Adverse Event Reporting ......................................................................47 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) ......................47 
7.6 
Expedited Reporting to Hospital Risk Management .............................................47 


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7.7 
Expedited Reporting to Bristol-Myers Squibb (BMS) ..........................................47 
7.8 
Routine Adverse Event Reporting .........................................................................49 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................49 
8.1 
Ipilimumab (Yervoy) .............................................................................................49 
8.2 
Nivolumab..............................................................................................................52 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................54 
9.1 
Archival Tumor Tissue Collection.........................................................................54 
9.2 
Collection of Fresh Tumor Tissue .........................................................................54 
9.3 
Plasma Cytokine Analysis .....................................................................................56 
9.4 
Peripheral Blood Mononuclear Cell Collection .....................................................56 
10. 
STUDY CALENDAR .......................................................................................................56 
11. 
MEASUREMENT OF EFFECT........................................................................................59 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................59 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................66 
12.1 
Data Reporting .......................................................................................................66 
12.2 
Data Safety Monitoring..........................................................................................66 
13. 
STATISTICAL CONSIDERATIONS...............................................................................67 
13.1 
Study Design/Endpoints.........................................................................................67 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................69 
13.3 
Reporting and Exclusions ......................................................................................70 
14. 
PUBLICATION PLAN .....................................................................................................70 
REFERENCES ..............................................................................................................................71 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................72 
 
 
LIST OF TABLES 
 
Table 1: Key T-cell Subsets following Ipilimumab Treatment .................................................... 11 
Table 2: Efficacy in Chemotherapy-Naive NSCLC Subjects Treated with Nivolumab and 
Ipilimumab .................................................................................................................................... 18 
Table 3: Regimen Description ...................................................................................................... 24 
Table 4: Gastrointestinal Adverse Event Management ................................................................ 29 
Table 5: Renal Adverse Event Management ................................................................................ 30 
Table 6: Pulmonary Adverse Event Management ........................................................................ 32 
Table 7: Hepatic Adverse Event Management ............................................................................. 33 
Table 8: Endocrinopathy Adverse Event Management ................................................................ 35 
Table 9: Skin Adverse Event Management .................................................................................. 37 
Table 10: Neurological Adverse Event Management ................................................................... 38 
Table 11: Pancreatic Adverse Event Management ....................................................................... 39 


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Table 12: Ocular Adverse Event Management ............................................................................. 40 
Table 13: Infusion-Related Reactions ........................................................................................... 40 
Table 14: Physical and Chemical Properties of Ipilimumab ........................................................ 50 
Table 15: Physical and Chemical Properties of Nivolumab ......................................................... 52 
Table 16: Study Calendar.............................................................................................................. 57 
Table 17: For Participants with Measurable Disease (i.e., Target Disease) ................................. 65 
Table 18: For Participants with Non-Measurable Disease (i.e., Non-Target Disease) ................. 65 
Table 19: Accrual Targets ............................................................................................................. 69 
 
 


DFCI Protocol Number: 17-566 
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1. OBJECTIVES 
 
 
1.1 
Study Design 
 
This is an open label phase II study evaluating potential immunologic biomarkers of response 
and resistance to first-line ipilimumab and nivolumab therapy in non-small cell lung cancer 
(NSCLC). The trial will employ a Simon 2-stage design, where 43 participants will be enrolled 
initially. If at least 15 radiological responses are observed among the first 43 participants, the 
trial will enroll an additional 37 subjects. 
 
1.2 
Primary Objective 
 
• Assess the overall response rate (ORR) of ipilimumab and nivolumab in NSCLC using 
RECIST 1.1 criteria. 
 
1.3 
Secondary Objectives 
 
• Evaluate immunologic correlates of response and primary resistance to ipilimumab and 
nivolumab therapy in NSCLC.  
• Evaluate immunologic correlates of acquired resistance to ipilimumab and nivolumab in 
NSCLC, with acquired resistance defined as participants who experience an objective 
radiologic response or stable disease per RECIST 1.1 criteria followed by disease 
progression.  
• Assess the progression-free survival (PFS) rate, duration of response (DoR), and overall 
survival (OS) of the combination utilizing RECIST 1.1 criteria. 
 
2. BACKGROUND 
 
2.1 
Study Disease and Rationale 
 
Lung cancer is the leading cause of cancer-related death worldwide in both men and women, and 
more people die from lung cancer than from colon, breast, and prostate cancer combined.  In the 
United States, there will be 222,500 new cases of lung cancer in 2017 (116,990 in men and 
105,510 in women), and an estimated 155,870 deaths from lung cancer (84,590 in men and 
71,280 in women)1. NSCLC accounts for 85-90% of lung cancer and is comprised of three main 
histologic subtypes:  adenocarcinoma (accounts for approximately 40% of lung cancers), 
squamous cell carcinoma (25-30%), and large cell (undifferentiated) carcinoma (10%). 
 
The current standard of care for first-line treatment of metastatic NSCLC lacking EGFR 
mutations or ALK rearrangements is the programmed death protein 1 (PD-1) inhibitor 
pembrolizumab for tumors with high programmed death-ligand 1 (PD-L1) expression, or 
cytotoxic chemotherapy with a platinum doublet for tumors with low or absent PD-L1 
expression, with an overall response rate (ORR) of 30-40%.  Treatment with CTLA-4 inhibitor 
ipilimumab and the PD-1 inhibitor nivolumab also appears to be a promising combination for the 
first-line treatment of NSCLC, with reported ORR of 30-40% and an acceptable toxicity profile2.   


DFCI Protocol Number: 17-566 
Protocol Version Date: 07 Mar 2018 
 
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There is a critical need to identify additional biomarkers of response, primary resistance, and 
acquired resistance to the combination of ipilimumab and nivolumab in NSCLC.  Among 
participants with NSCLCs with ≥ 50% PD-L1 expression, the response rate to pembrolizumab is 
only 45%, suggesting that there may be additional biomarkers that can distinguish responders 
from non-responders3.  In addition, while Rizvi and colleagues showed that a higher non-
synonymous mutation burden has been associated with increased objective responses, durable 
benefit, and progression-free survival (PFS) with PD-1 inhibition, some patients with high 
mutational load did not benefit from immunotherapy while other patients with low mutational 
load did benefit from immunotherapy4. This again suggests that there are other factors that 
contribute to response or resistance other than mutational load.   
 
We have developed a comprehensive flow cytometry platform to dissect the immune profile of 
tumor cells and immune cells in thoracic malignancies5,6.   Using this novel technique, we can 
identify immunologically “hot” and “cold” clusters of tumors and study expression of numerous 
immunologic markers (e.g. TIM3, LAG3, etc.) on individual immune cells.   
 
Furthermore, the laboratories of Dr. Roger Kamm (Massachusetts Institute of Technology) and 
Dr. David Barbie (DFCI) have developed a technique using a microfluidic system to support 
primary human tumor culture.  These tumor “spheroids” retain critical immune effector cells and 
allows for the ex vivo study of PD-1 and/or CTLA-4 inhibitor-induced immune responses7,8.  
 
2.2 
Ipilimumab (YERVOY) 
 
Ipilimumab (BMS-734016, MDX010, MDX-CTLA4) is a fully human monoclonal 
immunoglobulin (Ig) G1κ specific for human cytotoxic T-lymphocyte antigen 4 (CTLA-4, 
cluster of differentiation [CD] 152), which is expressed on a subset of activated T cells. CTLA-4 
is a negative regulator of T-cell activity. Ipilimumab is a monoclonal antibody (mAb) that binds 
to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of 
CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation 
and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also 
reduce T-regulatory cell (Treg) function, which may contribute to a general increase in T-cell 
responsiveness, including the anti-tumor response. 
 
Ipilimumab has been approved for use in over 47 countries including the United States (US, 
Mar-2011), the European Union (EU, Jul-2011), and Australia (Jul-2011). 
 
2.2.1 
Non-Clinical Summary 
 
Ipilimumab has specificity and a high affinity for human CTLA-4. The calculated dissociation 
constant value from an average of several studies was 5.25 nM. Binding of ipilimumab to 
purified, recombinant human CTLA-4 antigen was also demonstrated by enzyme-linked 
immunosorbent assay with half-maximal binding at 15 ng/mL, whereas saturation was observed 
at approximately 0.1 μg/mL. No cross-reactivity was observed against human CD28. Ipilimumab 
completely blocked binding of B7.1 and B7.2 to human CTLA-4 at concentrations higher than 6 
and 1 μg/mL, respectively. 
 


DFCI Protocol Number: 17-566 
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Please refer to the ipilimumab investigator’s brochure (IB) for further information on pre-clinical 
development. 
 
2.2.2 
Clinical Studies 
 
Bristol-Myers Squibb (BMS) and Medarex, Inc. (MDX, acquired by BMS in Sep-2009) have co-
sponsored an extensive clinical development program for ipilimumab, encompassing more than 
19,500 subjects (total number of subjects enrolled in ipilimumab studies) in several cancer types 
in completed and ongoing studies, as well as a compassionate use program. The focus of the 
clinical program is in melanoma, prostate cancer, and lung cancer, with advanced melanoma 
being the most comprehensively studied indication. Ipilimumab is being investigated both as 
monotherapy and in combination with other modalities such as chemotherapy, radiation therapy, 
and other immunotherapies. 
 
Phase 3 programs are ongoing in melanoma, prostate cancer, and lung cancer. In melanoma, 2 
completed phase 3 studies have demonstrated a clinically meaningful and statistically significant 
survival benefit in pretreated advanced melanoma and previously untreated advanced melanoma, 
respectively. 
 
The safety profile of ipilimumab is generally consistent across these trials with a) the majority 
adverse events (AEs) being inflammatory in nature, which is consistent with the proposed 
mechanism of action of ipilimumab; b) the same types of such immune-mediated events in the 
gastrointestinal (GI) tract, skin, liver, and endocrine system being reported; and c) most of these 
events being manageable with immune suppressive therapies.  
 
In melanoma, 2 BMS-sponsored phase 3 studies are ongoing in subjects with high-risk stage III 
melanoma and pretreated and treatment-naïve advanced melanoma (3 mg/kg versus 10 mg/kg 
ipilimumab). 
 
The completed phase 3 study evaluated ipilimumab in subjects with metastatic castration-
resistant prostate cancer (mCRPC) who had progressed during or following treatment with 
docetaxel. Eligible subjects were randomized to a single dose of bone-directed radiotherapy 
(RT), followed by either ipilimumab 10 mg/kg or placebo (799 randomized: 399 ipilimumab, 
400 placebo). This study did not meet its primary endpoint of overall survival (OS). The hazard 
ratio (HR) of 0.85 (95% confidence interval [CI]: 0.72, 1.00) for survival favored ipilimumab but 
did not reach statistical significance with a P value of 0.053. Planned sensitivity analyses favored 
ipilimumab, where the greatest benefit appeared to be in subgroups defined by good prognostic 
features and low burden of disease. Additional evidence of ipilimumab activity observed in the 
study included a reduced risk of disease progression relative to placebo (HR = 0.70), superior 
clinical outcomes compared to placebo in tumor regression, and declines in prostate specific 
antigen (PSA). The safety profile in this study was consistent with the previously defined AE 
profile at the same dose. 
 
A second phase 3 study evaluated ipilimumab 10 mg/kg versus placebo in men with 
asymptomatic or minimally symptomatic, chemotherapy-naïve mCRPC with no visceral 
metastases. A total of 602 subjects were randomized in a 2:1 ratio (400 subjects to 10 mg/kg 


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ipilimumab and 202 subjects to placebo). Preliminary data indicate the study did not meet its 
primary endpoint based on intent-to-treat analysis. The HR of 1.11 (95.87% CI: 0.88, 1.39; P 
value = 0.3667) for OS did not favor ipilimumab. A longer median progression-free survival 
(PFS) interval was observed for the ipilimumab group than for the placebo group, which may be 
indicative of activity of ipilimumab in delaying disease progression. The safety profile in this 
study was generally consistent with the previously defined AE profile at the same dose. 
 
In addition, a completed, large phase 2 study has investigated the addition of ipilimumab to 
carboplatin and paclitaxel using 2 different schedules (concurrent and phased) in subjects with 
NSCLC or small cell lung cancer (SCLC, a secondary endpoint). Ipilimumab, given in 
combination with paclitaxel/carboplatin in a phased schedule improved immune-related 
progression-free survival (irPFS) compared to the control treatment, but no improvement was 
seen when ipilimumab was given in a concurrent schedule. Phased ipilimumab also improved 
PFS according to modified World Health Organization (mWHO) criteria and showed a trend for 
improved OS. 
 
The efficacy and safety of ipilimumab in a phased schedule with carboplatin/paclitaxel is also 
being investigated in a phase 3 study in subjects with advanced squamous NSCLC (CA184104). 
The efficacy and safety of ipilimumab in a phased schedule with etoposide/platinum in subjects 
with extensive stage disease SCLC is being investigated in a phase 3 study (CA184156). In 
Study CA184104, the last patient, last visit was achieved in June 2015, and database lock 
occurred on 01-Sep-2015. No final data are currently available, but preliminary data indicate that 
no new safety concerns were identified in the course of standard clinical safety monitoring of the 
study. In Study CA184156, preliminary data indicate the primary endpoint of prolonging 
survival was not achieved, but no new safety signals were identified. 
 
The unique immune-based mechanism of action is reflected in the clinical patterns of anti-cancer 
activity in some patients. Ipilimumab induces an immunologic response, and measurable clinical 
effects emerge after the immunological effects. Tumor infiltration with lymphocytes and the 
associated inflammation (documented by biopsy in some subjects) is likely the cornerstone of the 
effect of ipilimumab and can manifest in various patterns of clinical activity leading to tumor 
control. In some cases, inflammation may not be noted by radiological examination, and 
objective response is observed with the first tumor assessment in a manner seen in patients 
receiving other types of anti-cancer treatments. In other cases, response may be preceded by an 
apparent increase in initial tumor volume and/or the appearance of new lesions, which may be 
mistaken for tumor progression on radiological evaluations. Therefore, in patients who are not 
experiencing rapid clinical deterioration, confirmation of progression is recommended (at the 
investigator’s discretion) to better understand the prognosis, as well as to avoid unnecessarily 
initiating potentially toxic alternative therapies in subjects who might be benefiting from 
treatment. Immune-related response criteria were developed based on these observations to 
systematically categorize novel patterns of clinical activity and are currently being prospectively 
evaluated in clinical studies. 
 
In metastatic diseases, stabilization is more common than response, and in some instances is 
associated with a slow, steady decline in tumor burden over many months, sometimes improving 
to partial and/or complete responses (CRs). Thus, the immune-based mechanism of action of 


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ipilimumab results in durable disease control, sometimes with novel patterns of response, which 
contribute to its unique improvement in OS. 
 
The unique immune-based mechanism of action is also reflected in the safety profile. The most 
common treatment-related AEs are inflammatory in nature, consistent with the mechanism of 
action of the drug and generally medically manageable with topical and/or systemic 
immunosuppressants. Such immunological safety events are described as immune-related 
adverse events (irAEs) or immune-mediated adverse reactions (imARs). The irAEs are described 
as AEs of unknown etiology, which were consistent with an immune phenomenon and 
considered causally related to drug exposure by investigators. The irAEs primarily involve the 
GI tract and skin. Immune-related AEs in the liver were also observed, particularly in subjects 
receiving 10 mg/kg. Endocrinopathy and neuropathy were important irAEs that were observed 
less frequently. The imARs were adjudicated in a blinded fashion based on Sponsor-physician 
data review to exclude noninflammatory etiologies, such as infection or tumor progression, and 
to consider available evidence of inflammation, such as tumor biopsies or responsiveness to 
steroids, in an effort to determine whether specific AEs or abnormal hepatic laboratory values 
were likely to be immune mediated and associated with ipilimumab treatment. 
 
The early diagnosis of inflammatory events is important to initiate therapy and minimize 
complications. Inflammatory events are generally manageable using symptomatic or immuno-
suppressive therapy as recommended through detailed diagnosis and management guidelines.  
 
A program-wide independent Data Monitoring Committee (DMC) reviews data from the 
ipilimumab studies, allowing for an ongoing safety and benefit/risk assessment in subjects 
receiving ipilimumab. The DMC charter includes explicit stopping rules for some studies, 
allowing the DMC to recommend discontinuing further treatment across the ipilimumab 
program, if necessary. 
 
In summary, ipilimumab offers clinically meaningful and statistically significant survival benefit 
to patients with pretreated advanced melanoma (as 3 mg/kg monotherapy compared to the 
melanoma peptide vaccine gp100) and previously untreated advanced melanoma (at 10 mg/kg in 
combination with dacarbazine [DTIC] compared to DTIC alone) and evidence of clinical activity 
in randomized studies in other tumor types. These findings, together with evidence of a safety 
profile that is manageable with careful monitoring and appropriate intervention for treatment of 
immune-related toxicities, suggest an acceptable benefit to risk ratio. 
 
Please also refer to the IB for the most comprehensive clinical background information for 
ipilimumab. 
 
2.2.3 
Clinical Pharmacokinetics 
 
The pharmacokinetics (PK) of ipilimumab has been extensively studied in subjects with 
melanoma, at the 3 and 10 mg/kg doses administered as a 1.5-hour IV infusion. The PK of 
ipilimumab was characterized by population PK (PPK) analysis and determined to be linear and 
time invariant in the dose range of 0.3 to 10 mg/kg. The mean CL (±SD) value after IV 
administration of 10 mg/kg was 18.3 ± 5.88 mL/h, and the mean steady-state volume of 


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distribution (Vss) [±SD] value was 5.75 ± 1.69 L. 
 
2.2.4 
Pharmacodynamics 
 
CTLA-4 is a key regulator of T-cell activity. Ipilimumab is a CTLA-4 immune checkpoint 
inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, increasing the 
number of tumor reactive T-effector cells that mobilize to mount a direct T-cell immune attack 
against tumor cells. Preclinical data indicate that CTLA-4 blockade can also reduce Treg function, 
which may lead to an increase in anti-tumor immune response. Ipilimumab may selectively 
deplete Tregs at the tumor site, leading to an increase in the intratumoral T-effector/Treg cell ratio 
which drives tumor response leading to cell death9. 
 
2.2.4.1 
Ipilimumab Effect on Circulating T Cells 
 
CTLA-4 is a negative regulator of T-cell activation. By blocking CTLA-4, ipilimumab increases 
the percentage of peripheral activated T cells and central memory T cells. These changes are 
evidenced by Week 4 and generally remain sustained through Week 1. The sum of these changes 
in immune cell subsets may result in anti-tumor activity, as well as irAEs. 
 
Table 1: Key T-cell Subsets following Ipilimumab Treatment 
T-cell 
population 
Ipilimumab 
Dose (mg/kg) 
Fitted Mean Relative Frequency (%) Mean (95% CI) 
Baselinea 
Week 4b 
Week 12c 
Activated 
CD4+ / Total 
CD4+ 
3 
17.0 (13.4, 
20.6) 
25.2 (21.3, 
29.2) 
24.7 (21.0, 28.3) 
10 
14.9 (11.2, 
18.6) 
24.8 (20.8, 
28.8) 
24.7 (20.5, 29.0) 
Activated 
CD8+ / Total 
CD8+ 
3 
24.7 (18.9, 
30.5) 
31.1 (25.2, 
37.1) 
33.4 (27.5, 39.4) 
10 
22.5 (16.5, 
28.6) 
25.7 (19.6, 
31.9) 
27.6 (21.0, 34.2) 
Central 
Memory 
CD4+ / Total 
CD4+ 
10 
54.5 (52.4, 
56.7) 
59.6 (57.5, 
61.7) 
62.0 (59.9, 64.1) 
Central 
Memory 
CD8+ / Total 
CD8+ 
10 
37.4 (33.8, 
41.0) 
41.0 (37.5, 
44.6) 
45.3 (41.7, 48.9) 
a. Baseline is defined as the pre-dose measurement closest in time to first dose. 
b. Nominal Week 4 is defined as visits between study Days 8 and 42, inclusive. 
c. Nominal Week 12 is defined as visits between study Days 64 and 98, inclusive. 
Note: Means and 95% CI are estimates from extended linear models. 
 
2.2.4.2 
Ipilimumab Effect on Absolute Lymphocyte Count 
 
In clinical studies, ipilimumab increased absolute lymphocyte count (ALC) in peripheral blood. 


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In 214 subjects with advanced melanoma, ipilimumab increased ALC in a dose-dependent 
manner, with the largest increase observed at 10-mg/kg dose. 
 
In phase 3 studies in advanced melanoma, high baseline ALC was found to be significantly 
associated with longer OS regardless of treatment. However, subjects with low baseline ALC 
treated with ipilimumab demonstrated longer OS relative to subjects not treated with ipilimumab. 
 
2.2.5 
Clinical Efficacy 
 
Ipilimumab prolongs survival in subjects with pretreated and previously untreated advanced 
melanoma and has demonstrated anti-tumor activity in other malignancies, including lung, 
prostate cancer, and renal cell carcinoma. Please refer to the IB for detailed efficacy information 
regarding ipilimumab monotherapy. 
 
2.2.6 
Clinical Safety 
 
Blockade of CTLA-4 by ipilimumab leads to T-cell activation, with the potential for clinical 
inflammatory adverse events (AEs) primarily involving the skin (dermatitis/pruritus), GI tract 
(diarrhea/colitis), liver (hepatitis), endocrine glands (e.g., hypophysitis and adrenal or thyroid 
abnormalities), and other less frequent organs (e.g., uveitis/episcleritis). The majority of these 
inflammatory AEs initially manifested during treatment; however, a minority occurred weeks to 
months after discontinuation of ipilimumab. The majority of the inflammatory AEs are reversible 
with the guidance issued in Section 6. In rare cases, these inflammatory AEs may be fatal. 
 
Patients should be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy, and 
endocrinopathy, and clinical chemistries (including liver function, adrenocorticotropic hormone 
[ACTH] level, and thyroid function tests) should be evaluated. 
 
During evaluation of a suspected inflammatory AE, all efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes. Serological, immunological, 
imaging, and biopsy with histology (e.g., biopsy-proven lymphocytic) data should be used to 
support the diagnosis of an immune-mediated toxicity or support an alternative cause of the AE. 
In general, for severe inflammatory AEs, ipilimumab should be permanently discontinued, and 
systematic high-dose corticosteroid therapy should be initiated. For moderate immune-mediated 
AEs, ipilimumab should be held or delayed, and moderate-dose corticosteroids should be 
considered. 
 
Based on limited current clinical experience, corticosteroids do not appear to adversely affect the 
anti-tumor response. For example, disease control was maintained in subjects with objective 
responses who received corticosteroid administration for concomitant serious inflammatory AEs. 
 
2.3 
Nivolumab (OPDIVO) 
 
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody 
(HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the PD-1 cluster of differentiation 279 
(CD279) cell surface membrane receptor10. PD-1 is a negative regulatory molecule expressed by 
activated T and B lymphocytes. Binding of PD-1 to its ligands, PD-L1 and PD-L2, results in the 


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down-regulation of lymphocyte activation. Inhibition of the interaction between PD-1 and its 
ligands promotes immune responses and antigen-specific T-cell responses to both foreign 
antigens as well as self-antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) cells 
and is produced using standard mammalian cell cultivation and chromatographic purification 
technologies. The clinical study product is a sterile solution for parenteral administration. 
 
Nivolumab is approved for use in multiple countries including the United States 
(US, Dec-2014), the European Union (EU, Jun-2015), and Japan (Jul-2014). 
 
2.3.1 
Non-Clinical Summary 
 
Nivolumab has been shown to bind specifically to the human PD-1 receptor and not to related 
members of the CD28 family. Nivolumab inhibits the interaction of PD-1 with its ligands, PD-L1 
and PD-L2, resulting in enhanced T-cell proliferation and interferon-gamma (IFN-γ) release in 
vitro11. Nivolumab binds with high affinity to activated human T-cells expressing cell surface 
PD-1 and to cynomolgus monkey PD-1. In a mixed lymphocyte reaction (MLR), nivolumab 
promoted a reproducible concentration-dependent enhancement of IFN-γ release12.  
 
In intravenous (IV) repeat-dose toxicology studies in cynomolgus monkeys, nivolumab was well 
tolerated at doses up to 50 mg/kg, administered weekly for 5 weeks, and at doses up to 50 mg/kg, 
administered twice weekly for 27 doses. While nivolumab alone was well tolerated in 
cynomolgus monkeys, combination studies have highlighted the potential for enhanced toxicity 
when combined with other immunostimulatory agents. 
 
In addition, an enhanced pre- and postnatal development (ePPND) study in pregnant cynomolgus 
monkeys with nivolumab was conducted. Administration of nivolumab at up to 50 mg/kg 2QW 
was well tolerated by pregnant monkeys; however, nivolumab was determined to be a selective 
developmental toxicant when administered from the period of organogenesis to parturition at ≥ 
10 mg/kg (AUC(0-168 h) 117,000 μg•h/mL). Specifically, increased developmental mortality 
(including late gestational fetal losses and extreme prematurity with associated neonatal 
mortality) was noted in the absence of overt maternal toxicity. There were no nivolumab-related 
changes in surviving infants tested throughout the 6-month postnatal period. Although the cause 
of these pregnancy failures was undetermined, nivolumab-related effects on pregnancy 
maintenance are consistent with the established role of PD-L1 in maintaining fetomaternal 
tolerance in mice13. 
 
Please refer to the nivolumab IB for further information on pre-clinical development. 
 
2.3.2 
Clinical Studies 
 
The PK, clinical activity, and safety of nivolumab have been assessed in subjects with NSCLC, 
melanoma, clear-cell renal cell carcinoma (RCC), and classical Hodgkin Lymphoma (cHL) in 
addition to other tumor types. 
 
Nivolumab monotherapy is approved in multiple countries, including the US and EU, for 
unresectable or metastatic melanoma, previously treated metastatic NSCLC, and previously 
treated advanced RCC; it is also approved for the treatment of cHL in the US. In addition, 


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nivolumab has been approved for use in combination with ipilimumab for unresectable 
melanoma in multiple countries, including the US and EU. Nivolumab is being investigated both 
as monotherapy and in combination with chemotherapy, targeted therapies, and other 
immunotherapies. 
 
Please also refer to the IB for the most comprehensive clinical background information for 
nivolumab. 
 
2.3.3 
Clinical Pharmacokinetics 
 
The PK of nivolumab was studied in subjects over a dose range of 0.1 to 10 mg/kg administered 
as a single dose or as multiple doses of nivolumab every 2 or 3 weeks. The geometric mean (% 
CV%) clearance (CL) was 9.5 mL/h (49.7%), Vss was 8.0 L (30.4%), and geometric mean 
elimination half-life (t1/2) was 26.7 days (101%). Steady-state concentrations of nivolumab were 
reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation 
was approximately 3-fold. The exposure to nivolumab increased dose proportionally over the 
dose range of 0.1 to 10 mg/kg administered every 2 weeks. Additionally, nivolumab has a low 
potential for drug-drug interactions. The clearance of nivolumab increased with increasing body 
weight. The PPK analysis suggested that the following factors had no clinically important effect 
on the CL of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1. A PPK 
analysis suggested no difference in CL of nivolumab based on age, gender, race, solid tumor 
type, baseline tumor size, and hepatic impairment. 
 
Although ECOG status, baseline glomerular filtration rate (GFR), albumin, body weight, and 
mild hepatic impairment had an effect on nivolumab CL, the effect was not clinically 
meaningful. PPK analysis suggest that nivolumab CL in subjects with cHL was approximately 
32% lower relative to subjects with NSCLC; however, the lower CL in cHL subjects was not 
considered to be clinically relevant as nivolumab exposure was not a significant predictor for 
safety risks for these patients. When nivolumab is administered in combination with ipilimumab, 
the CL of nivolumab was increased by 24%, whereas there was no effect on the clearance of 
ipilimumab. Additionally, PPK and exposure response analyses have been performed to support 
use of 240 mg every 2 week (Q2W) dosing in addition to the 3 mg/kg Q2W regimen. A flat dose 
of nivolumab 240 mg Q2W was selected since it is identical to a dose of 3 mg/kg for subjects 
weighing 80 kg, the observed median body weight in nivolumab-treated cancer patients. Using a 
PPK model, the overall distributions of nivolumab exposures (Cavgss, Cminss, Cmaxss, and Cmin1) are 
comparable after treatment with either 3 mg/kg or 240 mg nivolumab. The predicted range of 
nivolumab exposures (median and 90% prediction intervals) resulting from a 240 mg flat dose 
across the 35 to 160 kg weight range is maintained well below the corresponding exposures 
observed with the well tolerated 10 mg/kg nivolumab Q2W dosage. 
 
2.3.4 
Pharmacodynamics 
 
The clinical PDs were assessed for nivolumab monotherapy and for nivolumab in combination 
with ipilimumab. 
 
The PD effects of nivolumab were studied by assessing receptor occupancy (RO), peripheral 
immune cell population modulation, systemic cytokine modulation, and change in absolute 


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15 
 
lymphocyte count (ALC) in two studies. Results were as follows: 
• Peripheral RO of PD-1 is saturated at doses ≥ 0.3 mg/kg dose levels as measured on 
CD3+ cells from frozen and fresh peripheral blood mononuclear cells (PBMCs). 
• Nivolumab treatment had no clinically meaningful changes in activated T-cells in 
peripheral blood; no dose response was evident. 
• Baseline measurements of select immune cell subsets were not associated with response 
to nivolumab. 
• Mean ALC measured over time did not change at any nivolumab dose nor was it 
associated with response to nivolumab. 
• Median percent increase from baseline to post-dose for CXCL9 and CXCL10 were 
consistent with demonstration of immunomodulatory activity of nivolumab on these 
chemokines. 
 
To understand if the effect of nivolumab in combination with ipilimumab was distinct from that 
of either nivolumab or ipilimumab monotherapy, changes in immunomodulatory PD biomarkers 
with combination nivolumab and ipilimumab treatment was assessed in one study. ALC, 
activated CD4+ and CD8+ T cells in the periphery, and levels of inflammatory cytokines were 
measured in blood and serum. Results were as follows: 
• No consistent rise in ALC was observed with combination nivolumab and ipilimumab 
therapy, similar to nivolumab monotherapy. 
• Increases in activated CD4+ and CD8+ T cells were observed with the combination 
regimen, consistent with the pharmacodynamic effects of ipilimumab alone and distinct 
from the effects of nivolumab alone. 
• Combination therapy resulted in increases in interferon-γ induced serum cytokines, such 
as MIG (CXCL9) and IP-10 (CXCL10), which are also increased with single agent 
nivolumab. 
 
2.3.5 
Clinical Efficacy 
 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy and in 
combination with ipilimumab in several tumor types, including NSCLC, melanoma, RCC, cHL, 
SCLC, gastric cancer, urothelial cancer, HCC, and CRC. In confirmatory trials, nivolumab as 
monotherapy demonstrated a statistically significant improvement in OS as compared with the 
current standard of care in subjects with advanced or metastatic NSCLC, unresectable or 
metastatic melanoma, advanced RCC, or SCCHN. Nivolumab in combination with ipilimumab 
improved PFS and ORR over ipilimumab alone in subjects with unresectable or metastatic 
melanoma. 
 
2.3.6 
Clinical Safety 
 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 12,300 treated subjects.  
 
For monotherapy, the safety profile is similar across tumor types. There is no pattern in the 
incidence, severity, or causality of AEs to nivolumab dose level. In Phase 3 controlled studies, 
the safety profile of nivolumab monotherapy is acceptable in the context of the observed clinical 


DFCI Protocol Number: 17-566 
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16 
 
efficacy, and manageable using established safety guidelines. Clinically relevant AEs typical of 
stimulation of the immune system were infrequent and manageable by delaying or stopping 
nivolumab treatment and timely immunosuppressive therapy or other supportive care. 
 
In several ongoing clinical trials, the safety of nivolumab in combination with other therapeutics 
such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies is being 
explored. Most studies are ongoing and, as such, the safety profile of nivolumab combinations 
continues to evolve. The most advanced combination under development is nivolumab with 
ipilimumab, which is approved in subjects with unresectable or metastatic melanoma, and being 
studied in multiple tumor types. Results to date suggest that the safety profile of nivolumab with 
ipilimumab combination therapy is consistent with the mechanisms of action of nivolumab and 
ipilimumab. The nature of the AEs is similar to that observed with either agent used as 
monotherapy; however, both frequency and severity of most AEs are increased with the 
combination. 
 
2.3.7 
Flat Dosing 
 
The safety and efficacy of 240 mg Q2W flat dose of nivolumab is expected to be similar to 3 
mg/kg Q2W dosing regimen. A flat dose of nivolumab 240 mg Q2W was selected since it is 
identical to a dose of 3 mg/kg for subjects weighing 80 kg, the observed median body weight in 
nivolumab treated cancer patients. Using a PPK model, the overall distributions of nivolumab 
exposures (Cavgss, Cminss, Cmaxss, and Cmin1) are comparable after treatment with either 3 mg/kg or 
240 mg nivolumab. The predicted range of nivolumab exposures (median and 90% prediction 
intervals) resulting from a 240 mg flat dose across the 35 to 160 kg weight range is maintained 
well below the corresponding exposures observed with the well tolerated 10 mg/kg nivolumab 
Q2W dosage. Across the various tumor types in the clinical program, nivolumab has been shown 
to be safe and well tolerated up to a dose level of 10 mg/kg, and the relationship between 
nivolumab exposure produced by 3 mg/kg and efficacy and safety has been found to be relatively 
flat. Given the similarity of nivolumab PK across tumor types and the similar exposures 
predicted following administration of 240 mg flat dose compared to 3 mg/kg Q2W regimen, it is 
expected that the safety and efficacy profile of 240 mg Q2W nivolumab will be similar to that of 
3 mg/kg nivolumab. Hence, a flat dose of 240 mg nivolumab is under investigation. 
 
In addition, nivolumab 480 mg administered once every 4 weeks (Q4W) is currently under 
investigation. The less frequent dosing regimen is designed to afford more convenience to the 
target patient populations. The nivolumab dose of 480 mg Q4W was selected based on clinical 
data and modeling and simulation approaches using PPK and exposure-response analyses of data 
from studies in multiple tumor types (melanoma, NSCLC, and RCC) to provide an 
approximately equivalent dose of nivolumab 3 mg/kg Q2W. Exposures following nivolumab 480 
mg Q4W regimen are predicted to be within the exposure ranges observed at doses up to 10 
mg/kg Q2W used in the nivolumab clinical program, and are not considered to put participants at 
increased risk. 
 
2.4 
Ipilimumab with Nivolumab 
 
2.4.1 
Clinical Pharmacokinetics 
 


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17 
 
The pharmacokinetics of nivolumab and ipilimumab were assessed using a PPK approach when 
nivolumab and ipilimumab were administered in combination. The %CV CL, Vss, and t1/2 of 
nivolumab were 10.0 mL/h (50.3%), 7.92 L (30.1%), and 24.8 days (94.3%), respectively. When 
ipilimumab 3 mg/kg (registrational dose) was administered in combination with nivolumab, the 
CL of nivolumab was increased by 24%, whereas there was no effect on the CL of ipilimumab. 
However, co-administration with ipilimumab 1 mg/kg did not appear to have an effect on 
nivolumab CL. This is unlikely to be clinically relevant given the observed efficacy with the 
nivolumab and ipilimumab combination regimen. 
 
When administered in combination, the CL of nivolumab increased by 42% in the presence of 
anti-nivolumab antibodies. There was no effect of anti-ipilimumab antibodies on the CL of 
ipilimumab. 
 
2.4.2 
Immunogenicity 
 
Of 394 patients who were treated with nivolumab in combination with ipilimumab and evaluable 
for the presence of anti-nivolumab antibodies, 149 patients (37.8%) tested positive for treatment-
emergent anti-nivolumab antibodies by an ECL assay and 18 patients (4.6%) had neutralizing 
antibodies against nivolumab. Of the 391 patients evaluable for the presence of anti-ipilimumab 
antibodies, 33 patients (8.4%) tested positive for treatment-emergent anti-ipilimumab antibodies 
by an ECL assay and 1 patient (0.3%) had neutralizing antibodies against ipilimumab. There was 
no evidence of increased incidence of infusion reactions/hypersensitivity reactions with 
antinivolumab antibody development. There was no evidence of altered toxicity profile 
associated with anti-product antibody development and there was no apparent casual effect of 
neutralizing antibodies on loss of efficacy. 
 
2.4.3 
Clinical Efficacy 
 
In trial CA209012 (NCT01454102; CheckMate 012), an ongoing multi-arm phase 1 safety study 
of nivolumab in chemotherapy-naive NSCLC subjects, 56 subjects were administered nivolumab 
in combination with chemotherapy (gemcitabine / cisplatin, pemetrexed / cisplatin, carboplatin / 
paclitaxel), 21 with nivolumab in combination with erlotinib, and 197 with nivolumab in 
combination with ipilimumab. 
 
A summary of ORR and PFS rate at 12 months for subjects treated with nivolumab plus 
ipilimumab is provided in the table below. The original nivolumab plus ipilimumab 
combinations using the same dosing regimens as in the melanoma studies (n = 49) were found to 
be non-tolerable for the NSCLC population, and these regimens were not pursued further. The 
results from newer combination dosing regimens (arms N, O, P, Q; n = 148) with lower and less 
frequent dosing of ipilimumab are presented below. The cohorts containing the approved dose of 
nivolumab (3 mg/kg) demonstrated improved ORR and PFS compared to the cohorts containing 
the lower dose of nivolumab (1 mg/kg). 
 
The regimens for these cohorts were: 
• Arm N (n=31): nivolumab 1 mg/kg + ipilimumab 1 mg/kg every 3 weeks for 4 cycles, 
followed nivolumab 3 mg/kg every 2 weeks 


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• Arm O (n=40): nivolumab 1 mg/kg every 2 weeks + ipilimumab 1 mg/kg every 6 weeks 
• Arm P (n= 38): nivolumab 3 mg/kg every 2 weeks + ipilimumab 1 mg/kg every 12 weeks 
• Arm Q (n=39): nivolumab 3 mg/kg every 2 weeks + ipilimumab 1 mg/kg every 6 weeks 
 
Table 2: Efficacy in Chemotherapy-Naive NSCLC Subjects Treated with Nivolumab and 
Ipilimumab 
Treatment 
Group 
N 
Nivolumab 
(mg/kg) 
ORRa 
PFS at 12 
months 
Median OS 
 
 
 
n 
(%) 
95% 
CIb 
% 
95% 
CIc 
Months 
95% 
CIb 
Nivo 1 + Ipi 1 ×4 
(arm N) 
31 
1 
6 
(19) 
8, 38 
30 
14, 47 
NR 
11.5, 
NR 
Nivo 1 + Ipi 1 
(arm O) 
40 
1 
13 
(33) 
19, 49 
25 
12, 42 
NR 
11.0, 
NR 
Nivo 3 + Ipi 1 
q12w (arm P) 
38 
3 
18 
(47) 
31, 64 
48 
31, 63 
NR 
14.1, 
NR 
Nivo 3 + Ipi 1 
q6w (arm Q) 
39 
3 
15 
(39) 
23, 55 
35 
20, 50 
18.1 
13.3, 
18.1 
Database Lock Date 18-Feb-2016 
a. CR + PR; assessed according to RECIST v.1.1 
b. Based on Kaplan-Meier method 
c. Based on Greenwoods formula 
Abbreviations: CI = confidence interval; Ipi = ipilimumab; Nivo = nivolumab; NR: not 
reached; ORR = objective response rate; PFSR = progression-free survival rate; OS = overall 
survival 
 
2.4.4 
Clinical Safety 
 
The original nivolumab plus ipilimumab combinations using the same dosing regimens as in the 
melanoma studies were found to be non-tolerable for the NSCLC population, so 4 additional 
regimens were examined (arms N, O, P, Q), and the results from these newer cohorts are 
presented. The regimens for these cohorts were: 
• Arm N (n=31): nivolumab 1 mg/kg + ipilimumab 1 mg/kg every 3 weeks for 4 cycles, 
followed nivolumab 3 mg/kg every 2 weeks 
• Arm O (n=40): nivolumab 1 mg/kg every 2 weeks + ipilimumab 1 mg/kg every 6 weeks 
• Arm P (n= 38): nivolumab 3 mg/kg every 2 weeks + ipilimumab 1 mg/kg every 12 weeks 
• Arm Q (n=39): nivolumab 3 mg/kg every 2 weeks + ipilimumab 1 mg/kg every 6 
 
The most frequently reported drug-related adverse events (AEs) in the newer nivolumab plus 
ipilimumab cohorts were fatigue (29.0%), diarrhea (25.0%), pruritus (23.7%), and fatigue 
(23.1%) in arms N, O, P, Q, respectively. Drug-related serious adverse events (SAEs) reported in 
more than 2 subjects/cohort treated in the newer nivolumab plus ipilimumab cohorts were 
adrenal insufficiency, hypophysitis, pneumonitis, autoimmune hepatitis, diarrhea, colitis, and 
acute kidney injury. 
 
Drug-related AEs leading to discontinuation reported in more than 1 subject treated in the new 


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nivolumab plus ipilimumab arms included ALT increased, AST increased, colitis, myalgia, 
pneumonitis, rash, autoimmune hepatitis, infusion-related reaction, facial nerve disorder, 
esophagitis, and transaminases increased.  
 
Most deaths were due to disease progression. The only deaths reported due to study drug toxicity 
were in the nivolumab + ipilimumab original treatment groups (respiratory failure following 
Grade 3 colitis, pulmonary hemorrhage, and toxic epidermal necrolysis in a patient with history 
of ulcerative colitis). 
 
2.5 
Correlative Studies Background 
 
Baseline and on-treatment tumor biopsies will be evaluated for all participants, as well as an 
optional time of progression tumor biopsy. Biopsies are planned pre-treatment, approximately 4 
weeks post initiation of therapy, and at the time of disease progression. To perform 
immunoprofiling, tissue will be subjected to: 
 
• Flow cytometry.  This will assess for immune cell lineages (e.g. T cells, B cells, 
neutrophils, macrophages, dendritic cells, NK cells, etc.) as well as characterization of 
CD4+ and CD8+ T cells, including their differentiation status (e.g. FOXP3, CCR7, 
CD45RA, CD45RO), expression of activation markers (e.g. CD69, CD11a, CD38) and 
inhibitory receptors (e.g. PD-1, TIM-3, LAG-3, CTLA-4), and their proliferation (e.g. Ki-
67).  
 
If adequate tissue and resources are available, samples may also undergo: 
• Microfluidic culture.  Primary tumor spheroids in microfluidic culture will be exposed 
to CTLA-4 or PD-1 inhibitors and we will then observe whether engulfment of spheroids 
by macrophage-like cells occurs over time.  We will also perform cytokine profiling of 
conditioned media from these samples. 
• Ex vivo cytokine analysis. The cytokine release studies will study 15-20 different 
cytokines and their relationship with patient outcomes, with the overarching hypothesis 
that change in cytokines over time will be associated with outcome to therapy with 
immune checkpoint inhibition. 
 
Additional biomarkers may be analyzed as deemed appropriate at the time of analysis. 
Furthermore, tumor and germline whole exome sequencing (WES) as well as single cell RNA 
sequencing will be performed. To perform WES, nucleic acid (DNA and RNA) will be obtained 
from tumor cellular material using standard operating procedures. For clinical tumor specimens, 
a “high-coverage” sequencing approach will be utilized, which should yield an average coverage 
of 150-200 fold; paired normal DNA will be sequenced to a depth of approximately 80-100-fold. 
WES data will be analyzed for base mutations, small insertions/deletions, and copy number 
alterations. RNA sequencing will be done to examine gene expression changes and pathway 
adaptation on-treatment as compared to pre-treatment. 
 
Results from flow cytometry and cytokine analyses (if performed) will be compared to clinical 
outcomes. For the flow cytometric immunoprofiling on tumor and immune cells, t-distributed 
neighbor embedding (t-SNE) analyses will be performed, resulting in the identification of “hot” 


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and “cold” clusters5,6. Each of the immunologic markers/parameters will be analyzed 
individually and in compilation to form such clusters. We hypothesize that outcomes may vary 
according to the value of such markers and/or hot/cold cluster status. 
 
Peripheral blood mononuclear cells (PBMCs) as well as plasma will be collected from whole 
blood to assess immune cell populations and cytokines and other biomarkers of interest as 
appropriate. Surface staining with a panel of antibodies and intracytoplasmatic cytokine staining 
followed by flow cytometry will be performed on the PBMC samples.  Different T cell 
populations, their activation status, and the production of different cytokines as well as other 
immune cell populations including myeloid-derived suppressor cells (MDSCs) will be 
characterized. MDSCs are a heterogeneous group of immature cells which are greatly expanded 
in experimental models of cancer. Studies in humans have reported increased frequencies as well 
as immune-suppressive properties in some of the myeloid-derived subsets of MDSCs present in 
the peripheral blood of patients with various forms of cancer14,15. To further explore the 
relationship of immune cell populations and their potential correlation to clinical outcomes, 
peripheral blood levels will be serially collected from patients enrolled to the trial.   
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
 
3.1.1 Histologically confirmed stage IV NSCLC, with no prior systemic anti-cancer therapy of 
any kind (including EGFR and ALK inhibitors). Prior definitive chemoradiation for 
locally advanced disease is permitted as long as the last administration of chemotherapy 
or radiation (whichever was given last) occurred at least 6 months prior to enrollment. 
Prior adjuvant or neoadjuvant chemotherapy for early stage lung cancer is permitted if 
completed at least 6 months prior to initiating study treatment. 
 
3.1.2 Participants must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques 
or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam.  See Section 11 for 
the evaluation of measurable disease. 
Note: presence of measurable disease must be in at least one lesions that has not been 
previously irradiated.  
 
3.1.3 Age ≥ 18 years. 
 
3.1.4 ECOG performance status ≤ 1 (see Appendix A) 
 
3.1.5 Participants must have normal organ and marrow function as defined below: 
 
 
Absolute neutrophil count 
≥ 1,500/mcL 
 
Platelets 
≥ 100,000/mcL 
 
Total bilirubin 
≤ 1.5 × institutional upper limit of normal (ULN) 
 
AST(SGOT)/ALT(SGPT) 
≤ 2.5 × institutional ULN, OR 


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 
AST(SGOT)/ALT(SGPT) 
≤ 5 × institutional ULN if liver metastases are present 
 
Serum creatinine 
≤ 1.5 × institutional ULN, OR 
 
Creatinine clearance 
≥ 60 mL/min/1.73 m2 for participants with serum 
creatinine levels above 1.5 × institutional ULN. 
 
3.1.6 Ability to understand and the willingness to sign a written informed consent document. 
 
3.1.7 Participants must be able and willing to undergo a pre-treatment tumor tissue biopsy. 
Participants must also be willing to undergo an on-treatment tumor tissue biopsy if 
clinically feasible. 
 
3.1.8 Participants must have a tumor tissue sample available (formalin-fixed paraffin 
embedded [FFPE] tissue block or unstained slides); may be newly obtained or obtained 
within 6 months prior to enrollment (without systemic therapy given after the sample was 
obtained). Participants without sufficient archival tissue may be enrolled following 
successful completion of the pre-treatment tumor tissue biopsy. Tissue must be a core 
needle biopsy, excisional, or incisional biopsy. Fine needle aspirates (FNA) or malignant 
effusions are not adequate. Bone biopsies without a soft tissue component are not 
adequate. 
 
3.1.9 The effects of nivolumab and ipilimumab on the developing human fetus are unknown.  
For this reason, women of childbearing potential (WOCBP) must agree to follow 
instructions for acceptable contraception from the time of signing consent, and for 23 
weeks after their last dose of protocol-indicated treatment. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately.  Men treated or enrolled on this 
protocol who are not azoospermic who are sexually active with WOCBP must agree to 
follow instructions for acceptable contraception from the time of signing consent, and for 
31 weeks after their last dose of protocol-indicated treatment. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Participants with known EGFR mutations or ALK rearrangements. All subjects must have 
been tested for EGFR mutation and ALK rearrangement prior to study entry, unless they 
are known to have a KRAS mutation. 
Note: molecular testing is not required for squamous NSCLC.  
 
3.2.2 Participants who have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-
stimulation or checkpoint pathways. 
 
3.2.3 Participants who received prior non-CNS directed palliative radiation therapy within 7 
days of the date of study entry. 
 


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22 
 
3.2.4 Participants who are receiving any other investigational agents. 
 
3.2.5 Participants with known untreated brain metastases should be excluded from this clinical 
trial because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other 
adverse events. Subjects are eligible if CNS metastases are adequately treated and 
subjects are neurologically returned to baseline (except for residual signs or symptoms 
related to the CNS treatment) for at least 2 weeks prior to study entry.  Subjects must be 
either off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone 
(or equivalent) for at least 2 weeks prior to first study treatment. 
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ipilimumab or nivolumab. 
 
3.2.7 Participants with previous malignancies are excluded unless a complete remission was 
achieved at least 2 years prior to first treatment and no additional therapy is required or 
anticipated to be required during the study period as judged by the treating investigator. 
Exceptions include non-melanoma skin cancers, and in situ cancers of any type (e.g. 
bladder, gastric, colon, cervical/dysplasia, melanoma, or breast carcinoma in situ). 
 
3.2.8 Participants with any other active malignancy requiring concurrent intervention. 
 
3.2.9 Participants with an active, known, or suspected autoimmune disease. Subjects with type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions 
not expected to recur in the absence of an external trigger are permitted to enroll. 
 
3.2.10 Participants with a condition requiring systemic treatment with corticosteroids of > 10 
mg daily prednisone (or equivalent), or subjects requiring other immunosuppressive 
medications within 14 days of first treatment. Inhaled, topical, ophthalmologic, local 
steroid injections, and adrenal replacement steroid > 10 mg daily prednisone or 
equivalent are permitted in the absence of active autoimmune disease. 
 
3.2.11 Participants with interstitial lung disease that is symptomatic or may interfere with the 
detection or management of suspected drug-related pulmonary toxicity in the opinion of 
the treating investigator. 
 
3.2.12 Participants with a known history of testing positive for human immunodeficiency virus 
(HIV), or known acquired immunodeficiency syndrome (AIDS). 
 
3.2.13 Participants with known positive test for hepatitis B or C indicating acute or chronic 
infection. 
 
3.2.14 Participants with ≥ Grade 2 peripheral neuropathy. 
 


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3.2.15 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.16 Pregnant women are excluded from this study because ipilimumab and nivolumab are 
both agents with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with ipilimumab or nivolumab, breastfeeding should be discontinued if the 
mother is treated with ipilimumab or nivolumab. A negative serum pregnancy test is 
required prior to study entry. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
Nivolumab will be administered once every 2 weeks, on cycle days 1, 15, and 29. Ipilimumab 
will be administered once every 6 weeks, on cycle day 1. A treatment cycle is defined as 6 weeks 
or 42 days. Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications are described in 
Section 6.   
 


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Table 3: Regimen Description 
Agent 
Premedications 
DoseA 
RouteB 
Schedule Cycle 
Length 
Ipilimumab 
None 
1 mg/kg 
IV over 60 
minutes (± 5 
minute infusion 
window) 
Day 1 
42 
days 
(6 
weeks) 
Nivolumab 
None 
3 mg/kg 
IV over 60 
minutes (± 5 
minute infusion 
window) 
Days 1, 
15, 29 
A. Calculation of body surface area (BSA) should be performed per institutional 
standards of practice. Re-calculation of dosage for fluctuations in body weight should 
be made in accordance with institutional guidelines. 
B. On days where both nivolumab and ipilimumab will be administered, nivolumab 
should be administered first. The ipilimumab infusion will start at least 30 minutes 
after completion of the nivolumab infusion. 
 
5.2 
Pre-Treatment Criteria 
 
5.2.1 
Cycle 1, Day 1 
 
If screening laboratory values were completed ≤ 96 hours before Cycle 1 Day 1, laboratory tests 
do not need to be repeated on Cycle 1 Day 1 and the screening laboratory values may be used as 
the Cycle 1 Day 1 values.  
 
If screening laboratory values were completed > 96 hours prior to Cycle 1 Day 1, laboratory tests 
must be repeated on Cycle 1 Day 1. Laboratory values drawn on Cycle 1 Day 1 must re-meet 
eligibility criteria, exceptions to this are possible following discussion with the principal 
investigator. 
 
5.2.2 
Subsequent Cycles  
 
Management of specific toxicities considered at least possibly related to the study regimen is 
outlined in Section 6. 
 
5.3 
Agent Administration 
 
5.3.1 
Nivolumab 
 
Nivolumab will be administered as an IV infusion over approximately 60 minutes (± 5 minute 
infusion window). Nivolumab will be administered every 2 weeks, on cycle days 1, 15, and 29. 
On days where both nivolumab and ipilimumab will be administered, nivolumab should be 
administered first. The ipilimumab infusion will start at least 30 minutes after completion of the 
nivolumab infusion. 


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25 
 
 
5.3.2 
Ipilimumab 
 
Ipilimumab will be administered as an IV infusion over approximately 60 minutes (± 5 minute 
infusion window). Ipilimumab will be administered every 6 weeks, on cycle day 1. BSA for 
dosage calculations should be performed per institutional standards of practice. Re-calculation of 
dosage for fluctuations in body weight should be made in accordance with institutional 
guidelines. On days where both nivolumab and ipilimumab will be administered, nivolumab 
should be administered first. The ipilimumab infusion will start at least 30 minutes after 
completion of the nivolumab infusion. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
No investigational or commercial agents or therapies other than ipilimumab and nivolumab may 
be administered with the intent to treat the participant's malignancy, with the exception of 
palliative radiation therapy with the principal investigator’s agreement. As concurrent 
radiotherapy and nivolumab/ipilimumab have not been formally evaluated, in cases where 
palliative radiotherapy is required for a tumor lesion, then nivolumab/ipilimumab should be 
withheld for at least 1 week before, during, and 1 week after radiation. Bisphosphonate use is 
permitted. 
 
Investigators should use appropriate supportive medications to address toxicities that arise 
during the study, including but not limited to antiemetics, corticosteroids, and blood product 
transfusion.  
 
5.4.1 
Infusion-Related Reactions 
 
Infusion reactions, including high-grade hypersensitivity reactions, following administration of 
nivolumab or ipilimumab are uncommon. Participants should be monitored for fever, chills, 
rigors, itching, arthralgias, rash, hypertension, hypotension, bronchospasm, and dyspnea during 
and immediately after administration of the study agents.  
 
In the event of any ≥ Grade 3 infusion-related reaction, protocol therapy should be permanently 
discontinued. Emergency care should be implemented as clinically appropriate and per local 
institutional standards of practice. 
 
In the event of any Grade 1 infusion-related reaction, the patient should be monitored until 
recovery of symptoms to baseline. The following prophylactic premedications are recommended 
for future infusions:  diphenhydramine 25 – 50 mg (or equivalent) and/or acetaminophen 325 to 
1000 mg (or equivalent) at least 30 minutes before additional infusions. 
 
In the event of any Grade 2 infusion-related reaction, the infusion should be stopped. The patient 
may be medicated with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 – 
1000 mg PO (or equivalent). Corticosteroids or bronchodilators may also be administered as 
clinically appropriate. The patient should be monitored until symptoms have resolved to 
baseline. After resolution of symptoms, the infusion may be restarted at 50% of the original 
infusion rate. If no further complications ensue after 30 minutes, the rate may be increased to 


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100% of the original infusion rate. If symptoms recur, no further administration of nivolumab or 
ipilimumab should occur at that visit. Administer 50 mg IV diphenhydramine (or equivalent) and 
monitor patient until the symptoms resolve to baseline. 
 
For future infusions following a Grade 2 infusion-related reaction, the following prophylactic 
premedications are recommended: diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen 325 to 1000 mg (or equivalent), administered at least 30 minutes prior to the 
infusion. If necessary per the judgment of the treating investigator, corticosteroids (up to 25 mg 
SoluCortef or equivalent) may be used. 
 
5.4.2 
Drug-Drug Interaction Potential with Nivolumab 
 
Although monoclonal antibodies are not direct inhibitors/inducers of metabolizing enzymes, 
recent literature reports suggest that therapeutic proteins that are modulators of cytokines may 
indirectly affect expression of cytochrome (CYP) enzymes. The indirect drug-drug interaction 
potential of nivolumab was assessed using systemic cytokine modulation data for cytokines 
known to modulate CYP enzymes, at single and multiple doses of 0.3 to 10 mg/kg Q3 weeks. 
 
There were no meaningful changes in cytokines known to have indirect effects on CYP enzymes 
across all dose levels of nivolumab (0.3, 2 and 10 mg/kg) during the course of treatment. This 
lack of cytokine modulation suggests that nivolumab has no or low potential for modulating CYP 
enzymes, thereby indicating a low risk of therapeutic protein-drug interaction. 
 
Nivolumab is an IgG4 monoclonal antibody, which is eliminated by mechanisms similar to that 
of other antibodies, namely by non-specific catabolism (mainly by enzymes in the 
reticuloendothelial system). These enzymes are not known to be inhibited or induced by drugs, 
and therefore it is unlikely that other drugs will have an impact on the PK of nivolumab. 
 
5.4.3 
Drug-Drug Interaction Potential with Ipilimumab 
 
Ipilimumab is a human monoclonal antibody that is not metabolized by cytochrome P450 
enzymes (CYPs) or other drug metabolizing enzymes. 
 
A drug-interaction study of ipilimumab administered alone and in combination with 
chemotherapy (dacarbazine or paclitaxel/carboplatin) was conducted evaluating interaction with 
CYP isozymes (particularly CYP1A2, CYP2E1, CYP2C8, and CYP3A4) in patients with 
treatment-naive advanced melanoma. No clinically relevant pharmacokinetic drug-drug 
interaction was observed between ipilimumab and paclitaxel/carboplatin, dacarbazine or its 
metabolite, 5-aminoimidazole-4-carboxamide (AIC). 
 
The use of anticoagulants is known to increase the risk of gastrointestinal hemorrhage. Since 
gastrointestinal hemorrhage is an adverse reaction with ipilimumab, patients who require 
concomitant anticoagulant therapy should be monitored closely. 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 


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tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
a maximum of 24 months or until one of the following criteria applies: 
 
• 
Disease progression, unless the participant meets the requirements outlined in Section 
5.5.1. 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
The patient becomes pregnant or plans to become pregnant 
 
• 
Unacceptable adverse event(s) 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Mark Awad MD, PhD at telephone number 617-632-3468. 
 
5.5.1 
Treatment Beyond Disease Progression 
 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of progressive disease (PD)16. 
 
Subjects will be permitted to continue on nivolumab and ipilimumab for treatment beyond initial 
RECIST 1.1 defined PD as long as they meet all of the following criteria: 
1. Investigator-assessed clinical benefit and no rapid disease progression or threat to vital 
organs/critical anatomical sites requiring urgent alternative medical intervention (e.g. 
spinal cord compression) 
2. Subject is tolerating study treatment 
3. Subject has a stable performance status 
4. Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g. CNS metastases) 
5. Subject provides written informed consent prior to receiving additional nivolumab and 
ipilimumab treatment. 
 
The decision to continue treatment beyond initial investigator-assessed progression should be 


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discussed with the principal investigator and documented in the study records. A follow-up scan 
should be performed in six (6) weeks ± 7 days of original PD to determine whether there has 
been a decrease in the tumor size, or continued progression of disease. Subsequent scans should 
be performed as per protocol criteria. 
 
If the investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according to 
the Study Calendar located in Section 10. 
 
For the subjects who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden from time of initial PD. This includes an increase 
in the sum of diameters of all target lesions and/ or the diameters of new measurable lesions 
compared to the time of initial PD. Nivolumab and ipilimumab treatment should be discontinued 
permanently upon documentation of further progression. 
 
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 15 
mm). Any new lesion considered non-measurable at the time of initial progression may become 
measurable and therefore included in the tumor burden if the longest diameter increases to at 
least 10 mm (except for pathological lymph nodes which must have a short axis of at least 15 
mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm. 
 
5.6 
Duration of Follow Up 
 
Participants will be followed for a minimum of 90 days following their last dose of ipilimumab 
and 100 days following their last dose of nivolumab for serious adverse event (SAE) reporting. 
Participants removed from protocol therapy for unacceptable adverse event(s) will be followed at 
minimum until resolution or stabilization of the adverse event. Participants who are removed 
before documented disease progression should be followed for RECIST response criteria until 
disease progression or death. Following documentation of disease progression, participants will 
continue to be followed for a maximum of 3 years or until death for survival status only. 
 
5.7 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
• Completion of required 3 years follow-up  
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
The research team will update the relevant Off Study information in OnCore.  


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6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays will be made as indicated in the following tables. The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized for dose delays and dose modifications. A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
6.1 
Toxicity Management 
 
 
Table 4: Gastrointestinal Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat 
accordingly and continue protocol therapy. Opiates/narcotics may mask symptoms of 
perforation. Infliximab should not be used in cases of perforation or sepsis. 
Grade of 
Diarrhea / 
Colitis 
Management 
Follow-Up 
Grade 1 
Continue protocol therapy. 
 
Treat symptoms as clinically 
appropriate. 
 
Monitor patient closely for worsening 
symptoms. 
 
Educate patient to report worsening 
immediately. 
 
If worsens: 
Treat as Grade 2 or ≥ Grade 3. 
Grade 2 
Delay protocol therapy. 
 
Treat symptoms as clinically 
appropriate. 
If improves to Grade 1: 
 
Resume protocol therapy 
 
If persists > 5-7 days or recurs: 
 
Administer 0.5-1.0 mg/kg/day 
methylprednisolone or oral equivalent 
 
When symptoms improve to Grade 1, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume therapy per protocol. 
 
If worsens or persists > 3-5 days with oral 
steroids: 
 
Treat as ≥ Grade 3. 


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Table 4: Gastrointestinal Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat 
accordingly and continue protocol therapy. Opiates/narcotics may mask symptoms of 
perforation. Infliximab should not be used in cases of perforation or sepsis. 
Grade of 
Diarrhea / 
Colitis 
Management 
Follow-Up 
≥ Grade 3 
Permanently discontinue 
protocol therapy 
 
Administer 1.0 to 2.0 
mg/kg/day 
methylprednisolone IV or IV 
equivalent 
 
Add prophylactic antibiotics 
for opportunistic infections 
 
Consider lower endoscopy as 
clinically appropriate 
If improves: 
 
Continue steroids until grade 1, then taper over 
at least 1 month 
 
If persists > 3-5 days, or recurs after 
improvement: 
 
Add infliximab 5 mg/kg (if no 
contraindication) 
 
Note: Infliximab should not be used in cases 
of perforation or sepsis 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids. 
 
 
Table 5: Renal Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue protocol therapy. 
Grade of 
Creatinine 
Elevation 
Management 
Follow-Up 
Grade 1 
Continue protocol therapy. 
 
Monitor creatinine weekly. 
If returns to baseline: 
 
Resume routine creatinine monitoring 
per protocol 
 
If worsens: 
 
Treat as Grade 2-3 or 4 


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Table 5: Renal Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue protocol therapy. 
Grade of 
Creatinine 
Elevation 
Management 
Follow-Up 
Grade 2 – 3 
Delay protocol therapy 
 
Monitor creatinine every 2-3 days 
 
Administer 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent 
 
Consider renal biopsy with 
nephrology consult as clinically 
appropriate 
If returns to Grade 1: 
 
Taper steroids over at least 1 month, 
consider prophylactic 
antibiotics for opportunistic infections, 
and resume protocol therapy and 
routine creatinine monitoring per 
protocol 
 
If elevations persist > 7 days or 
worsens: 
 
Treat as Grade 4 
Grade 4 
Permanently discontinue protocol 
therapy 
 
Monitor creatinine daily 
 
Administer 1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
 
Consult nephrologist and 
consider renal biopsy as clinically 
appropriate 
If returns to Grade 1: 
 
Taper steroids over at least 1 month 
and add prophylactic antibiotics for 
opportunistic infections 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids. 
 
 


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Table 6: Pulmonary Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue protocol therapy. Evaluate with imaging and pulmonary consultation as clinically 
appropriate. 
Grade of 
Pneumonitis 
Management 
Follow-Up 
Grade 1 
Consider delay of protocol 
therapy 
 
Monitor for symptoms 
every 2-3 days 
 
Consider Pulmonary and ID 
consults 
Re-image at least every 3 weeks 
 
If worsens: 
 
Treat as Grade 2 or ≥ Grade 3. 
Grade 2 
Delay protocol therapy 
 
Obtain Pulmonary and ID 
consults as clinically 
appropriate 
 
Monitor symptoms daily, 
consider hospitalization 
 
Administer 1.0 mg/kg/day 
methylprednisolone 
IV or oral equivalent 
 
Consider bronchoscopy, 
lung 
biopsy as clinically 
appropriate 
Re-image every 1-3 days 
 
If improves: 
 
When symptoms return to near baseline, taper 
steroids over at least 1 month and then 
resume protocol therapy and consider 
prophylactic antibiotics 
 
If not improving after 2 weeks or 
worsening: 
 
Treat as ≥ Grade 3. 


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Table 6: Pulmonary Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue protocol therapy. Evaluate with imaging and pulmonary consultation as clinically 
appropriate. 
Grade of 
Pneumonitis 
Management 
Follow-Up 
≥ Grade 3 
Permanently discontinue 
protocol therapy 
 
Hospitalize as clinically 
indicated 
 
Obtain pulmonary and ID 
consults as appropriate 
 
Administer 2-4 mg/kg/day 
methylprednisolone IV or 
IV 
equivalent 
 
Add prophylactic antibiotics 
for opportunistic infections 
 
Consider bronchoscopy, 
lung biopsy 
If improves to baseline: 
 
Taper steroids over at least 6 weeks. 
 
If not improving after 48 hours or 
worsening: 
 
Add additional immunosuppression. 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids. 
 
 
Table 7: Hepatic Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue protocol therapy. Consider imaging for obstruction. 
Grade of 
Liver Test 
Elevation 
Management 
Follow-Up 
Grade 1 
Continue protocol 
therapy 
Continue LFT monitoring per protocol 
 
If worsens: 
 
Treat as Grade 2 or ≥ Grade 3. 


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Table 7: Hepatic Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue protocol therapy. Consider imaging for obstruction. 
Grade of 
Liver Test 
Elevation 
Management 
Follow-Up 
Grade 2 
Delay protocol therapy 
 
Increase frequency of 
monitoring to every 3 
days 
If returns to baseline: 
 
Resume routine monitoring, resume protocol 
therapy  
 
If elevations persist > 5-7 days or worsen: 
 
Administer 0.5-1 mg/kg/day methylprednisolone or 
oral equivalent and when LFT returns to grade 1 or 
baseline, taper steroids over at least 1 month, 
consider prophylactic antibiotics for opportunistic 
infections, and resume protocol therapy 
≥ Grade 3 
Permanently discontinue 
protocol therapyA 
 
Increase frequency of 
monitoring to every 1-2 
days 
 
Administer 1.0 to 2.0 
mg/kg/day 
methylprednisolone IV 
or IV 
equivalentB 
 
Add prophylactic 
antibiotics for 
opportunistic infections 
 
Consult 
gastroenterologist as 
clinically appropriate 
If returns to grade 2: 
 
Taper steroids over at least 1 month 
 
If does not improve in >3-5 days, worsens or 
rebounds: 
 
Add mycophenolate mofetil 1 g BID 
 
If no response within an additional 3-5 days, 
consider other immunosuppressants per local 
guidelines 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids. 
A. Protocol therapy may be delayed rather than discontinued if AST/ALT ≤ 8 × 
institutional ULN or total bilirubin ≤ 5 × institutional ULN. 
B. The recommended starting dose for Grade 4 hepatitis is 2 mg/kg/day 
methylprednisolone IV. 


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Table 8: Endocrinopathy Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue protocol therapy. Consider visual field testing, endocrinology consultation, and 
imaging. 
Event 
Management 
Follow-Up 
Asymptomatic TSH 
Elevation 
Continue protocol therapy. 
 
If TSH < 0.5 × lower limit of normal 
(LLN), or TSH > 2 × ULN, or 
consistently out of range in 2 
subsequent measurements: include free 
T4 at subsequent cycles as clinically 
indicated; consider endocrinology 
consult. 
 
Symptomatic 
Endocrinopathy 
 
Evaluate endocrine function 
 
Consider pituitary scan 
 
Symptomatic with abnormal 
lab/pituitary scan: 
 
Delay protocol therapy 
 
Administer 1-2 mg/kg/day 
methylprednisolone IV or PO 
equivalent 
 
Initiate appropriate hormone therapy 
 
No abnormal lab/pituitary MRI scan 
but symptoms persist: 
 
Repeat labs in 1-3 weeks / MRI in 1 
month 
If improves (with or 
without 
hormone replacement): 
 
Taper steroids over at 
least 1 month and 
consider prophylactic 
antibiotics for 
opportunistic infections 
 
Resume protocol therapy 
 
Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid 
component 


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Table 8: Endocrinopathy Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue protocol therapy. Consider visual field testing, endocrinology consultation, and 
imaging. 
Event 
Management 
Follow-Up 
Suspicion of adrenal 
crisis (e.g. severe 
dehydration, 
hypotension, shock out 
of proportion to current 
illness) 
Permanently discontinue protocol 
therapy 
 
Rule out sepsis 
 
Stress dose of IV steroids with 
mineralocorticoid activity 
 
Administer IV fluids 
 
Consult endocrinologist as clinically 
appropriate 
 
If adrenal crisis ruled out, then treat as 
above for symptomatic endocrinopathy 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids. 
 
 


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Table 9: Skin Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue protocol therapy. 
Grade 
of 
RashA 
Management 
Follow-Up 
Grade 1 
– 2 
Continue protocol therapy. 
 
Administer symptomatic 
therapy (e.g. antihistamines, 
topical steroids) 
If persists > 1-2 weeks or recurs: 
 
Consider skin biopsy 
 
Delay protocol therapy 
 
Consider 0.5-1.0 mg/kg/day methylprednisolone IV 
or oral equivalent. Once improving, taper steroids 
over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume 
protocol therapy 
 
If worsens: 
 
Treat as Grade 3-4 
Grade 3 
– 4 
Delay or discontinue 
protocol therapy 
 
Consider skin biopsy 
 
Dermatology consult as 
clinically appropriate 
 
Administer 1.0-2.0 
mg/kg/day IV 
methylprednisolone 
IV or IV equivalent 
If returns to Grade 1: 
 
Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic infections. 
 
Resume protocol therapy if appropriate. 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids. 
 
A. If Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) is 
suspected, withhold protocol therapy and refer patient for specialized care for 
assessment and treatment. If SJS or TEN is diagnosed, permanently discontinue 
protocol therapy. 
 
 


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Table 10: Neurological Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue protocol therapy. 
Grade of 
Neurological 
Toxicity 
Management 
Follow-Up 
Grade 1 
Continue protocol therapy. 
Continue to monitor the patient. 
 
If worsens: 
 
Treat as Grade 2 or ≥ Grade 3. 
Grade 2 
Delay protocol therapy 
 
Treat symptoms per local 
guidelines 
 
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent 
If improves to baseline: 
 
Resume protocol therapy. 
 
If worsens: 
 
Treat as ≥ Grade 3. 
≥ Grade 3 
Permanently discontinue 
protocol therapy 
 
Obtain neurology consult as 
clinically appropriate 
 
Treat symptoms per local 
guidelines 
 
Administer 1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
 
Add prophylactic antibiotics for 
opportunistic infections 
If returns to Grade 2: 
 
Taper steroids over at least 1 month. 
 
If worsens or atypical 
presentation: 
 
Consider IVIG or other 
immunosuppressive therapies per 
local guidelines. 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids. 
 
 


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Table 11: Pancreatic Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue protocol therapy. 
Grade of Amylase or Lipase 
Elevation, Pancreatitis 
ManagementB 
Follow-Up 
Asymptomatic Grade 1A 
Continue protocol therapy. 
 
Monitor amylase and lipase 
weekly until resolution to 
baseline. 
 
 
Resume routine protocol 
monitoring. 
 
If worsens: 
 
Treat as Grade 2-3 or 4. 
Asymptomatic Grade 2-3A 
Delay protocol therapy. 
 
Monitor amylase and lipase 
weekly until resolution to 
baseline. 
If improves to baseline: 
 
Resume protocol therapy 
and routine protocol 
monitoring. 
 
If worsens: 
 
Treat as Grade 4. 
Asymptomatic Grade 4A 
Permanently discontinue 
protocol therapy. 
 
Monitor amylase and lipase 
weekly until resolution. 
  
Monitor patient until 
resolution to baseline. 
Any Symptomatic Elevations 
in Amylase/Lipase, Pancreatitis 
Permanently discontinue 
protocol therapy. 
 
Consider GI consult as 
clinically appropriate. 
 
Administer supportive care. 
Monitor patient until 
resolution to baseline. 
A. Patients should be monitored for signs/symptoms consistent with pancreatitis, 
including abdominal pain and vomiting. 
B. Corticosteroids do not seem to alter the natural course of amylase/lipase elevations. 
 
 


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Table 12: Ocular Adverse Event Management 
Note: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue protocol therapy. Work-up for ocular adverse events should also consider pituitary 
inflammation as a potential cause. 
Event 
Grade 
ManagementA 
Follow-Up 
Grade 1 
Continue protocol therapy. 
 
Monitor patient for worsening 
symptoms. 
 
Consider ophthalmologist consult as 
clinically appropriate. 
 
Administer topical corticosteroids as 
clinically indicated. 
If worsens: 
 
Treat as Grade 2 or ≥ Grade 3. 
Grade 2 
Delay protocol therapy. 
 
Obtain ophthalmologist consult. 
 
Administer topical corticosteroids as 
clinically indicated. 
If improves to baseline: 
 
Resume protocol therapy. 
 
If worsens: 
 
Treat as ≥ Grade 3. 
≥ Grade 3 
Permanently discontinue protocol 
therapy. 
 
Obtain ophthalmologist consult. 
 
Administer systemic corticosteroids as 
clinically indicated. 
Monitor patient until resolution to 
baseline. 
 
Taper systemic corticosteroids as 
clinically appropriate. 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. 
prednisone) at start of tapering or earlier, once sustained clinical improvement is observed. 
Lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids. 
 
 
Table 13: Infusion-Related Reactions 
Event 
Grade 
Management 
Follow-Up 
Grade 1 
 
Monitor patient until recovery of symptoms to 
baseline. 
Prophylactic premedications are 
recommended for future infusions:  
diphenhydramine 25 – 50 mg (or 
equivalent) and/or acetaminophen 
325 to 1000 mg (or equivalent) at 
least 30 minutes before additional 
infusions. 


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Table 13: Infusion-Related Reactions 
Event 
Grade 
Management 
Follow-Up 
Grade 2 
 
Stop infusion. 
 
Administer diphenhydramine 50 mg IV (or 
equivalent) and/or acetaminophen 325 – 1000 
mg PO (or equivalent).  
 
Corticosteroids or bronchodilators may also 
be administered as clinically appropriate.  
 
Monitor patient until symptoms have resolved 
to baseline.  
 
After resolution of symptoms, the infusion 
may be restarted at 50% of the original 
infusion rate. If no further complications 
ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion 
rate. If symptoms recur, no further 
administration of nivolumab or ipilimumab 
should occur at that visit. Administer 50 mg 
IV diphenhydramine (or equivalent) and 
monitor patient until the symptoms resolve to 
baseline. 
Prophylactic premedications are 
recommended for future infusions: 
diphenhydramine 50 mg (or 
equivalent) and/or acetaminophen 
325 to 1000 mg (or equivalent), 
administered at least 30 minutes 
prior to the infusion.  
 
If necessary per the judgment of 
the treating investigator, 
corticosteroids (up to 25 mg 
SoluCortef or equivalent) may be 
used as well. 
≥ Grade 
3 
Permanently discontinue protocol therapy. 
 
Emergency care should be implemented as 
clinically appropriate and per local 
institutional standards of practice. 
Monitor patient until resolution to 
baseline. 
 
6.2 
Dose Delays 
 
Dosing of ipilimumab or nivolumab may be held at the treating investigator’s discretion for any 
toxicity of any grade. Additionally, holding of the study agents may be required as indicated in 
the tables in Section 6.1.  
 
A treatment delay of up to six weeks for nivolumab and up to 12 weeks for ipilimumab is 
allowable. Participants requiring a longer hold should be removed from protocol therapy. 
Exceptions for participants exhibiting clinical benefit may be possible with approval from the 
principal investigator. 
 
If study agent dosing is held due to toxicity, the counting of cycle days and assessment schedule 
will continue without interruption. For example, a participant who does not receive their Cycle 3 


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Day 15 dose of nivolumab due to toxicity will proceed with their next regularly scheduled clinic 
visit (Cycle 3 Day 29) as previously planned. Additional interim clinic visits may be scheduled 
to manage toxicity, however the cycle will not restart due to dosing delays due to adverse events 
and the assessment schedule (including tumor imaging evaluations) will continue as originally 
planned. 
 
6.3 
Dose Reductions 
 
There will be no dose reductions for nivolumab or ipilimumab allowed. Participants who cannot 
tolerate the assigned doses of nivolumab or ipilimumab should be removed from protocol 
therapy. 
 
6.4 
Overdose Management 
 
There is no available information concerning overdose with nivolumab or ipilimumab. In case of 
overdose, patients must be closely monitored for signs or symptoms of adverse reactions and 
appropriate symptomatic treatment instituted. There are no specific antidotes. 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2 and Section 7.3) will determine whether the event requires expedited 
reporting in addition to routine reporting. 
 
7.1 
Expected Toxicities 
 
7.1.1 
Adverse Events List 
 
In addition to the list below, please also refer to the investigator’s brochure (IB) for both 
nivolumab and ipilimumab for comprehensive adverse event information. 
 
7.1.1.1 
Adverse Event List for Nivolumab combined with Ipilimumab 
 
Common adverse events associated with combination treatment include: 
• Fatigue 
• Fever 
• Chills 
• Flu-like symptoms 
• Infusion-related reactions 
• Headache 
• Dizziness 
• Hyperthyroidism or hypothyroidism 
• Cough 
• Dyspnea 


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• Pneumonitis 
• Hypotension 
• Dry mouth 
• Anorexia 
• Diarrhea 
• Nausea 
• Vomiting 
• Dehydration 
• Abdominal pain 
• Colitis 
• Elevated liver transaminases 
• Elevated lipase and/or amylase 
• Rash 
• Pruritus 
• Vitiligo 
• Joint pain or stiffness 
• Muscle soreness, weakness, stiffness, or spasms 
 
7.2 
Adverse Event Characteristics 
 
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a clinical investigation participant administered study drug. It 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of investigational product, whether or not considered related 
to the investigational product. 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
 
The causal relationship to study drug is determined by the treating investigator and should be 
used to assess all adverse events (AE). The casual relationship can be one of the following: 
 
• Related: There is a reasonable causal relationship between study drug administration and 
the AE.  


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• Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
 
7.2.1 
NON-SERIOUS ADVERSE EVENTS 
 
Non-serious adverse events are to be provided to BMS in aggregate via a final study report as 
specified in the research agreement or, if a regulatory requirement [e.g. IND US trial] as part of 
an annual reporting requirement.  
 
A non-serious adverse event is an AE not classified as serious (see Section 7.3 below).  
 
7.2.2 
Non-serious Adverse Event Collection and Reporting 
 
The collection of non-serious AE information should begin at initiation of study drug. All non-
serious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 30 days following the last dose 
of study treatment.  
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. 
 
7.2.3 
Laboratory Test Abnormalities 
 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs (see Section 7.3 below) should be documented and 
reported as such. 
 
The following laboratory abnormalities should be documented and reported appropriately: 
• Any laboratory test result that is clinically significant or meets the definition of an SAE 
(located in Section 7.3). 
• Any laboratory abnormality that required the participant to have study drug discontinued 
or interrupted. 
• Any laboratory abnormality that required the subject to receive specific corrective 
therapy.  
 
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (e.g., anemia versus low hemoglobin value). 
 


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7.2.4 
Potential Drug Induced Liver Injury (DILI) 
 
Wherever possible, timely confirmation of initial liver related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs (see Section 7.3). 
 
Potential drug induced liver injury is defined as:  
• AT (ALT or AST) elevation > 3 × ULN, 
AND 
• Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
• No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic. 
 
For protocols involving participants with known abnormalities at baseline, or with other clinical 
confounders, the clinical team should establish and document an agreed upon definition for 
events considered to be potential DILI cases. Wherever possible, timely confirmation of initial 
liver related laboratory abnormalities should occur prior to the reporting of a potential DILI 
event. All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs 
(see Section 7.3). 
 
7.2.5 
Pregnancy 
 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 5 half-lives after product administration, the investigational 
product will be permanently discontinued in an appropriate manner (e.g., dose tapering if 
necessary for participant).  
 
The investigator must immediately notify Worldwide.Safety@bms.com of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures.  
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form (provided upon request from BMS). 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In 
order for the principal investigator or designee to collect any pregnancy surveillance information 
from the female partner, the female partner must sign an informed consent form for disclosure of 
this information. 


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46 
 
 
7.2.6 
Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
 
7.2.7 
Other Safety Considerations 
 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non-serious or serious AE, 
as appropriate, and reported accordingly. 
 
7.3 
Serious Adverse Events 
 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:  
 
• Results in death 
• Is life-threatening (defined as an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect  
• Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [e.g., 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.)  
• Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE.  
 
Although pregnancy, overdose, potential drug-induced liver injury (DILI) and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
 
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
 
NOTE: The following hospitalizations are not considered SAEs:  
• A visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 


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• Elective surgery, planned prior to signing consent 
• Admissions as per protocol for a planned medical/surgical procedure 
• Routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy) 
• Medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases. 
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
• Admission for administration of anti-cancer therapy in the absence of any other SAEs  
 
7.4 
 Expedited Adverse Event Reporting  
 
7.4.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 90 days of the last 
dose of ipilimumab or 100 days of the last dose of nivolumab on the local institutional 
SAE form.  
 
7.5 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.6 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.7 
Expedited Reporting to Bristol-Myers Squibb (BMS) 
 
All SAEs that occur following the subject’s written consent to participate in the study through 90 
days of discontinuation of dosing of ipilimumab and 100 days of discontinuation of nivolumab 
must be reported to BMS Worldwide Safety. If applicable, SAEs must be collected that relate to 
any later protocol-specified procedure (e.g., a follow-up biopsy). 
 
The BMS SAE form should be used to report SAEs. The BMS protocol ID number must be 
included on the form that is submitted by the Investigator. 
 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, are collected, including those thought to be associated with protocol-
specified procedures. The investigator should report any SAE occurring after these time periods 
that is believed to be related to study drug or protocol-specified procedure. For drugs with 
potential for delayed SAEs (e.g., delayed excretion of the parent or active metabolites), a longer 
follow-up period may be warranted to allow collection of these SAEs, laboratory tests, and other 


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assessments. 
 
For studies with long-term follow-up periods in which safety data are being reported, include the 
timing of SAE collection. 
 
The Principal Investigator will reconcile the clinical database SAE cases transmitted to BMS 
Global Pharmacovigilance (Worldwide.Safety@bms.com). Frequency of reconciliation should 
be every 3 months and prior to the database lock or final data summary. BMS GPV&E will 
email, upon request from the Investigator, the GPV&E reconciliation report. Requests for 
reconciliation should be sent to aepbusinessprocess@bms.com. The data elements listed on the 
GPV&E reconciliation report will be used for case identification purposes. If the Investigator 
determines a case was not transmitted to BMS GPV&E, the case should be sent immediately to 
BMS. 
 
In accordance with local regulations, BMS will notify investigators of all reported SAEs that are 
suspected (related to the investigational product) and unexpected (i.e., not previously described 
in the IB). In the European Union (EU), an event meeting these criteria is termed a Suspected, 
Unexpected Serious Adverse Reaction (SUSAR). Investigator notification of these events will be 
in the form of an expedited safety report (ESR).  
• Other important findings which may be reported by BMS as an ESR include: increased 
frequency of a clinically significant expected SAE, an SAE considered associated with 
study procedures that could modify the conduct of the study, lack of efficacy that poses 
significant hazard to study subjects, clinically significant safety finding from a non-
clinical (e.g., animal) study, important safety recommendations from a study data 
monitoring committee, or sponsor decision to end or temporarily halt a clinical study for 
safety reasons. 
• Upon receiving an ESR from BMS, the investigator must review and retain the ESR with 
the IB. Where required by local regulations or when there is a central IRB/IEC for the 
study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and 
IRB/IEC will determine if the informed consent requires revision. The investigator 
should also comply with the IRB/IEC procedures for reporting any other safety 
information.  
• In addition, suspected serious adverse reactions (whether expected or unexpected) shall 
be reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate reports). 
 
SAEs (whether related or not related to study drug) and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies must be 
reported on a Pregnancy Surveillance Form. 
 
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Facsimile Number: 609-818-3804 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.)  
 


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If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.  
 
All SAEs should be followed to resolution or stabilization. 
 
For studies conducted under an Investigator IND in the US, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as possible 
and no later than 7 days (for a death or life-threatening event) or 15 days (for all other SAEs) 
after the investigator’s or institution’s initial receipt of the information. BMS will be provided 
with a simultaneous copy of all adverse events filed with the FDA.  
 
SAEs should be reported on MedWatch Form 3500A. 
 
An SAE report should be completed for any event where doubt exists regarding its seriousness.  
 
For studies with long-term follow-up periods in which safety data are being reported, include the 
timing of SAE collection in the protocol. 
 
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow up 
SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS using the 
same procedure used for transmitting the initial SAE report. All SAEs should be followed to 
resolution or stabilization.  
 
7.8 
 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1. 
 
8.1 
Ipilimumab (Yervoy) 
 
8.1.1 
Description 
 
Ipilimumab (BMS-734016, MDX-010) is a fully human IgG1κ consisting of 4 


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polypeptide chains; 2 identical heavy chains primarily consisting of 447 amino acids each 
with 2 identical kappa light chains consisting of 215 amino acids each linked through 
inter-chain disulfide bonds. 
 
Table 14: Physical and Chemical Properties of Ipilimumab 
Other Names 
BMS-734016, MDX-010, YERVOY 
Molecular 
Weight 
147,991 daltons 
Appearance 
Clear to slightly opalescent, colorless to pale yellow liquid, may 
contain particles 
Solution pH 
7.0 
pI 
The isoelectric focusing analysis generates a banding pattern in the pI 
range of 8.5 to 8.8, with the major isoform at an approximate pI of 8.7 
 
8.1.2 
Form 
 
Ipilimumab injection, 200 mg/40 mL (5 mg/mL), is formulated as a clear to slightly 
opalescent, colorless to pale yellow, sterile, nonpyrogenic, single-use, isotonic aqueous 
solution that may contain particles. Ipilimumab injection, 50 mg/10 mL and 200 mg/40 
mL, is supplied in 10-cc or 50-cc Type I flint glass vials, respectively, stoppered with 
gray butyl stoppers and sealed with aluminum seals. The drug product is formulated at a 
concentration of 5 mg/mL at a pH of 7.0.  
 
8.1.3 
Storage and Stability 
 
Ipilimumab Injection, 200 mg/40 mL (5 mg/mL), must be stored refrigerated (2°C to 
8°C) and protected from light. Ipilimumab injection must not be frozen. 
 
Partially used vials or empty vials of ipilimumab injection should be discarded at the site 
according to appropriate drug disposal procedures. 
 
Ipilimumab injection may be stored undiluted (5 mg/mL) or following dilution in 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose Injection in PVC, non-PVC/non-DEHP 
or glass containers for up to 24 hours (at 2°C to 8°C) or room temperature/room light. 
 
8.1.4 
Compatibility 
 
Ipilimumab injection may be diluted in 0.9% Sodium Chloride Injection, United States 
Pharmacopeia (USP) or 5% Dextrose Injection. . 
 
8.1.5 
Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment.  
 


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51 
 
8.1.6 
Availability 
 
Ipilimumab will be supplied as an investigational agent by Bristol-Myers Squibb (BMS). 
 
8.1.7 
Preparation 
 
Ipilimumab injection (5 mg/mL) can be used for intravenous (IV) administration after 
transferring to a polyvinyl chloride (PVC), non-PVC/non-di-(2-ethylhexyl)phthalate 
(DEHP), or glass container and is stable for 24 hours at 2°C to 8ºC or room 
temperature/room light (RT/RL). Ipilimumab injection may be diluted in 0.9% Sodium 
Chloride Injection, United States Pharmacopeia (USP) or 5% Dextrose Injection. 
Preparation will follow institutional standard. The product may be infused using a 
volumetric pump at the protocol-specific dose(s) and rate(s) through a infusion set with 
an inline, sterile, nonpyrogenic, low-protein-binding filter (pore size of 0.2 to 1.2 
micrometer).  
 
Ipilimumab injection must not be administered as an IV push or bolus injection. Care 
must be taken to assure sterility of the prepared solutions since the drug product does not 
contain any antimicrobial preservatives or bacteriostatic agents. 
 
8.1.8 
Administration 
 
Ipilimumab will be administered as an IV infusion over approximately 60 minutes (± 5 
minute infusion window). Ipilimumab will be administered every 6 weeks, on cycle day 
1. Calculation of BSA should be done per institutional standards of practice. Re-
calculation of dosage for fluctuations in body weight should be made in accordance with 
institutional guidelines. On days where both nivolumab and ipilimumab will be 
administered, nivolumab should be administered first. The ipilimumab infusion will start 
at least 30 minutes after completion of the nivolumab infusion. 
 
8.1.9 
Ordering 
 
Ipilimumab will be ordered by site pharmacy personnel from BMS. 
 
8.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.1.11 Destruction and Return 
 
Expired or unused supplies of ipilimumab should be destroyed according to institutional 
policies. Destruction will be documented in the Drug Accountability Record Form. 
 


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8.2 
Nivolumab 
 
8.2.1 
Description 
 
Nivolumab, also referred to as BMS-936558-01, BMS-936558, or Opdivo, is a soluble 
protein consisting of 4 polypeptide chains, which include 2 identical heavy chains and 2 
identical light chains. 
 
Table 15: Physical and Chemical Properties of Nivolumab 
Other Names 
Nivolumab, BMS-936558, MDX1106, ONO-4538, BMS-936558-
01 
Molecular 
Weight 
146,221 daltons (143,619.17 daltons, protein portion) 
Appearance 
Clear to opalescent, colorless to pale yellow liquid, light (few) 
particulates may 
be present 
Solution pH 
5.5 to 6.5 
 
 
8.2.2 
Form 
 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is a clear to opalescent, colorless to 
pale yellow liquid, which may contain light (few) particulates. The drug product is a 
sterile, non-pyrogenic, single-use, isotonic aqueous solution formulated at 10 mg/mL in 
sodium citrate, sodium chloride, mannitol, diethylenetriaminepentacetic acid (pentetic 
acid), and polysorbate 80 (TweenTM 80), pH 6.0 and includes an overfill to account for 
vial, needle, and syringe holdup. It is supplied in 10-cc Type I flint glass vials, stoppered 
with butyl rubber stoppers and sealed with aluminum seals. The only difference between 
the two drug product presentations is the vial fill volume. 
 
8.2.3 
Storage and Stability 
 
8.2.3.1 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL)  
 
Vials of nivolumab injection must be stored at 2°C to 8°C (36°F to 46°F) and protected 
from light and freezing. 
 
8.2.3.2 
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Container 
 
The administration of nivolumab infusion must be completed within 24 hours of 
preparation. If not used immediately, the infusion solution may be stored under 
refrigeration conditions (2°C to 8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 
8 hours of the total 24 hours can be at room temperature (20°C to 25°C, 68°F to 77°F) 
and room light. The maximum of 8 hours under room temperature and room light 
conditions includes the product administration period. 
 


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8.2.4 
Compatibility 
 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin 
containers and infusion sets, and glass bottles. 
 
8.2.5 
Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment.  
 
8.2.6 
Availability 
 
Nivolumab will be supplied as an investigational agent by Bristol-Myers Squibb (BMS). 
 
8.2.7 
Preparation 
 
Nivolumab injection is to be administered as an IV infusion through a 0.2-micron to 1.2-
micron pore size, low-protein binding (polyethersulfone membrane) in-line filter at the 
protocol-specified doses and infusion times. It is not to be administered as an IV push or 
bolus injection.  
 
When the dose is based on patient weight (ie mg/kg), nivolumab injection can be infused 
undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP to protein concentrations as low as 0.35 mg/mL. When the dose 
is fixed (e.g. 240 mg, 360 mg, or 480mg flat dose), nivolumab injection can be infused 
undiluted or diluted so as not to exceed a total infusion volume of 120 mL. During drug 
product preparation and handling, vigorous mixing or shaking is to be avoided. Care must 
be taken to assure sterility of the prepared solution as the product does not contain any 
antimicrobial preservative or bacteriostatic agent.  
 
8.2.8 
Administration 
 
Nivolumab will be administered as an IV infusion over approximately 60 minutes (± 5 
minute infusion window). Nivolumab will be administered every 2 weeks, on cycle days 
1, 15, and 29. On days where both nivolumab and ipilimumab will be administered, 
nivolumab should be administered first. The ipilimumab infusion will start at least 30 
minutes after completion of the nivolumab infusion. 
 
8.2.9 
Ordering 
 
Nivolumab will be ordered by site pharmacy personnel from BMS. 
 
8.2.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 


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Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.2.11 Destruction and Return 
 
Expired or unused supplies of nivolumab should be destroyed according to institutional 
policies. Destruction will be documented in the Drug Accountability Record Form. 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Archival Tumor Tissue Collection 
 
Archival tissue obtained from a core needle biopsy, excisional, or incisional biopsy is required 
for enrollment to the trial. Archival tissue may be either a FFPE block or unstained slides, and 
must have been obtained from a biopsy procedure performed within 6 months prior to 
enrollment. Participants without sufficient archival tissue may be enrolled following successful 
completion of the pre-treatment tumor tissue biopsy. 
 
Archival tissue will be submitted for whole exome sequencing (WES). Please refer to the 
separate laboratory manual for specific sample collection and handling details. 
 
A germline blood sample will be obtained from participants during screening (any time prior to 
cycle 1 day 1) for WES analysis. The germline blood sample should be sent for analysis at 
the same time as the archival tissue sample. 
 
9.2 
Collection of Fresh Tumor Tissue 
 
Fresh tumor tissue biopsies will be obtained from patients enrolling to the trial at the following 
times: 
 
• Baseline - any time following signing of the informed consent form but prior to cycle 1 
day 1 
• On-treatment - between cycle 1 day 22 and cycle 1 day 36 
• Optionally at the time of disease progression per RECIST 1.1 criteria - time of 
progression biopsies should be obtained prior to the initiation of another cancer 
treatment. In the event that it is not possible to perform the biopsy before another 
treatment is begun, biopsies can be obtained up to 30 days after the date at which disease 
progression was determined. 
 
The pre-treatment biopsy is mandatory for all participants for enrollment to the trial. The on-
treatment biopsy is mandatory unless it would pose a significant medical risk to the participant as 
judged by the treating investigator and clinician performing the procedure. Time of progression 
biopsy is optional for participants when clinically feasible. Additionally, if clinically feasible 
participants may undergo fluid collection procedures (e.g. pleural effusion drainage) in addition 
to tumor tissue biopsy collection. If the participant undergoes a surgical resection for standard of 


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care needs at any point during the trial, the resected tissue may also be collected for analysis as 
clinically appropriate. Please refer to the laboratory manual for specific collection and handling 
guidelines. 
 
 
9.2.1 
Pre-Treatment Specimens 
 
Biopsy specimens obtained pre-treatment will be sent for single cell RNA sequencing, 
immunoprofiling via flow cytometry, multiplexed immunofluorescence and 
immunohistochemistry (IHC), and if adequate specimens are collected cytokine 
analysis/microfluidic culture. Please refer to the separate laboratory manual for specific 
collection and handling instructions.  
 
In the event sufficient archival tissue is not available, WES will be performed on the pre-
treatment biopsy sample in addition to the above testing. In this case, the germline blood sample 
obtained from participants during screening (any time prior to cycle 1 day 1) for WES should be 
sent for analysis at the same time as the pre-treatment tissue sample. Please refer to the 
laboratory manual for more detail. 
 
9.2.2 
On-Treatment Specimens 
 
Biopsy specimens obtained on-treatment will be sent for single cell RNA sequencing 
immunoprofiling via flow cytometry, , multiplexed immunofluorescence and IHC, and if 
adequate specimens are collected cytokine analysis/microfluidic culture. Please refer to the 
laboratory manual for specific collection and handling instructions.  
 
9.2.3 
Time of Progression Specimens 
 
Biopsy specimens obtained at the time of disease progression will be sent for WES, single cell 
RNA sequencing, immunoprofiling via flow cytometry, and multiplexed immunofluorescence 
and IHC. Please refer to the laboratory manual for specific collection and handling instructions.  
 
9.2.4 
Prioritization of Analyses 
 
In the event that insufficient tumor tissue is obtained (e.g. the collected tumor tissue is scant, or 
the participant did not tolerate the biopsy procedure and it was aborted prior to collection of all 
of the core samples), priority of analyses will be as follows: 
 
1. Performance of single cell RNA sequencing 
2. Performance of immune profiling via flow cytometry 
3. Performance of WES (applicable only to pre-treatment and time of progression 
samples) 
4. Performance of multiplexed immunofluorescence and IHC 
5. Performance of cytokine analysis/microfluidic culture 
 
Collection of insufficient tumor tissue for analysis will not be considered a protocol violation.  
 


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9.3 
Plasma Cytokine Analysis 
 
Blood for performance of cytokine analysis will be collected from participants at the following 
time points: 
• Baseline, to be collected any time prior to administration of the study drugs 
• On day 1 of each subsequent cycle prior to administration of the study drugs 
• At the off treatment visit 
 
 
9.4 
Peripheral Blood Mononuclear Cell Collection 
 
Peripheral blood mononuclear cells (PBMCs) will be collected to examine T-cell responses in 
blood. Collection will occur at the following time points: 
• Baseline, to be collected any time prior to administration of the study drugs 
• On Cycle 2 Day 1 any time prior to administration of the study drugs 
• At the off treatment visit 
 
A total of 60 mL of blood will be collected at each time point. Please refer to the separate 
laboratory manual for specific collection and handling instructions. 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to the start of protocol therapy. 
The informed consent and baseline tumor imaging may be obtained up to 28 days prior to the 
start of protocol therapy.  In the event that the participant’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. 
 
Assessments must be performed prior to administration of any study agent. 
 


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Table 16: Study Calendar 
 
Pre- 
Study 
Cycle 1 Day 1 
Cycle 1 Day 15A 
Cycle 1 Day 29A 
Cycle 2+ Day 1B 
Cycle 2+ Day 15A 
Cycle 2+ Day 29A 
Off 
TreatmentC 
Long-
term 
Follow 
UpD 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signsE 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG 
Performance 
Status 
X 
X 
 
 
X 
 
 
X 
 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistryF 
X 
X 
X 
X 
X 
X 
X 
X 
 
TSH 
X 
 
 
 
X 
 
 
 
 
ACTH 
X 
 
 
 
X 
 
 
 
 
Amylase and 
Lipase 
X 
 
 
 
X 
 
 
 
 
Adverse event 
evaluation 
X 
X--------------------------------------------------------------------------------X 
X 
 
Radiologic 
evaluation 
X 
CT or MRI imaging of any disease-involved site. Imaging evaluations to be obtained at baseline and then every 6 weeks × 6 cycles (-3 
day/+7 day scheduling window). Brain MRI is required for all patients at baseline, and every 12 weeks on study for patients with CNS 
disease. At the completion of 6 cycles of therapy, at the treating investigator’s discretion, imaging may be moved to every 12 weeks (-14 
day/+7 day scheduling window). Participants who discontinue treatment prior to documented disease progression should continue to be 
followed for radiologic response every 12 weeks until documented disease progression or death.  
X 
X 
Serum β-HCGG 
X 
 
 
 
 
 
 
 
 
Nivolumab 
InfusionH 
 
X 
X 
X 
X 
X 
X 
 
 
Ipilimumab 
InfusionH 
 
X 
 
 
X 
 
 
 
 


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58 
 
Table 16: Study Calendar 
 
Pre- 
Study 
Cycle 1 Day 1 
Cycle 1 Day 15A 
Cycle 1 Day 29A 
Cycle 2+ Day 1B 
Cycle 2+ Day 15A 
Cycle 2+ Day 29A 
Off 
TreatmentC 
Long-
term 
Follow 
UpD 
Fresh Tumor 
Tissue BiopsyI 
X 
 
 
XI 
 
 
 
X 
 
Archival Tumor 
Tissue Collection 
X 
 
 
 
 
 
 
 
 
Plasma Collection 
X 
 
 
 
X 
 
 
X 
 
PBMC CollectionJ 
X 
 
 
 
X 
 
 
X 
 
Telephone or Care 
Provider Contact 
 
 
 
 
 
 
 
 
X 
A. 
A ± 3 day scheduling window exists for this visit to accommodate vacations, holidays, adverse weather, or other scheduling difficulties. 
B. 
The start of a subsequent cycle may be delayed by 7 days (+7 day window) to accommodate vacations, holidays, adverse weather, or other scheduling difficulties. The start of a 
subsequent cycle may also be moved up by 3 days (-3 day window) for scheduling issues. 
C. 
Off-treatment evaluation. Note: follow up visits or other contact is required in order to identify SAEs during the 90 days following the last dose of ipilimumab and 100 days 
following the last dose of nivolumab. Participants removed from therapy due to adverse events must be followed at minimum until resolution or stabilization of the adverse event. 
Please refer to Section 5.6 for more detail. 
D. 
Long-term follow up evaluation via telephone or care provider contact is required for survival status only for 3 years following documentation of disease progression, or until death. 
Contact to be performed every 3 months following the last dose of study treatment (± 1 month window). 
E. 
Vital signs to include heart rate, blood pressure, temperature, and respiratory rate. 
F. 
Serum chemistry to include sodium, potassium, chloride, CO2, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline phosphatase, total bilirubin, SGOT 
[AST], and SGPT [ALT]. Other tests may be ordered as clinically indicated. 
G. 
Serum pregnancy test only required for women of childbearing potential. Childbearing potential defined as any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive months; or 
women with a documented plasma follicle-stimulating hormone level >35µlU/mL). 
H. 
Nivolumab and ipilimumab infusions to be administered as described in Section 5. 
I. 
Fresh tumor tissue biopsy as described in Section 9. Biopsy required at baseline prior to the administration of any study agents, and again on Cycle 1 Day 29 (± 7 day scheduling 
window). An optional biopsy at the time of disease progression will also be offered to all participants. Note that a germline blood sample is required with the pre-treatment tumor 
biopsy as described in Section 9. 
J. 
PBMC collection to occur at baseline (any time prior to the first study drug administration), on Cycle 2 Day 1, and at the off treatment visit as described in Section 9. 
 
 
 


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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 6 weeks for 
the first 6 cycles of therapy. Following completion of 6 cycles, imaging may be performed every 
12 weeks at the discretion of the treating investigator.  In addition to a baseline scan, 
confirmatory scans should also be obtained not less than 4 weeks following initial documentation 
of objective response. Participants who discontinue treatment prior to documented disease 
progression should continue to be followed for RECIST response evaluation until progression. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
Unevaluable patients will be included in the analysis of response as non-responders 
assuming they were eligible and received study drug. 
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area are not considered 
measurable unless there has been demonstrated growth in the lesion. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 


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thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 


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The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 


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biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
MIBG (meta-iodobenzylguanidine).The following is recommended, to assure high 
quality images are obtained.  
Patient preparation: Iodides, usually SSKI (saturated solution of potassium iodide), 
are administered to reduce thyroidal accumulation of free radioiodine, preferably 
beginning the day prior to injection and continuing for 3 additional days (4 days 
total). For infants and children, one drop t.i.d. is sufficient, for adolescents 2 drops 
t.i.d., and for adults 3 drops t.i.d. Participants and/or parents are asked about exposure 
to potential interfering agents. If none is noted, an indwelling intravenous line is 
established. The dose of MIBG is administered by slow intravenous injection over 90 
seconds.  
Images from the head to the distal lower extremities should be obtained.  
I-123MIBG scintigraphy is performed to obtain both planar and tomographic images.  
Planar: Anterior and posterior views from the top of the head to the proximal lower 
extremities are obtained for 10 minutes at 24 hours and occasionally at 48 hours 
following injection of 10 mCi/1.7 square meters of body surface area (~150 μCi/kg, 
maximum 10 mCi). Anterior views of the distal lower extremities are adequate. A 
large field of view dual head gamma camera with low energy collimators is preferred.  
 
SPECT: Most participants receiving I-123 MIBG also undergo SPECT at 24 hours, 
using a single or multi-headed camera with a low energy collimator. The camera is 
rotated through 360 degrees, 120 projections at 25 seconds per stop. Data are 
reconstructed using filtered back projections with a Butterworth filter and a cut off 


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63 
 
frequency of 0.2-0.5. SPECT/CT may be performed at institutions with this capacity. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
from CT, MRI may be used instead of CT in selected instances.  
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
11.1.3.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  


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the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.3.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.3.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
11.1.3.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 


DFCI Protocol Number: 17-566 
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65 
 
 
 
 
Table 17: For Participants with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants 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 the 
objective progression even after discontinuation of treatment. 
 
 
Table 18: For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 


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for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.  
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
 
11.1.5 Response Review 
 
Imaging will be reviewed at the Tumor Imaging Metrics Core (TIMC). 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality in accordance with DF/HCC SOPs. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data 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 Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 


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unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is an open label phase II study evaluating potential immunologic biomarkers of response 
and resistance to first-line ipilimumab and nivolumab therapy in non-small cell lung cancer 
(NSCLC). The primary objective of the trial is to determine whether combination therapy with 
ipilimumab and nivolumab confers a promising best overall objective response rate per RECIST 
1.1 in this patient population. Secondary objectives include estimation of progression-free 
survival, overall survival, and toxicity. 
 
13.1.1 Study Endpoints 
Best objective response will be evaluated via RECIST1.1 criteria. Progression-free 
survival (PFS) is defined as the time from registration to documented disease progression 
or death from any cause, whichever occurs first. Patients who have not experienced an 
event of interest by the time of analysis will be censored at the date they are last known to 
be alive and progression-free. Overall survival is defined as the time from registration to 
death from any cause, and patients who are thought to be alive at the time of final 
analysis will be censored at the last date of contact. Duration of response is defined as the 
time from tumor response to documented disease progression or death from any cause, 
whichever occurs first. Patients who have not experienced an event of interest by the time 
of analysis will be censored at the date they are last known to be alive and progression-
free. Toxicity will be determined using the CTCAE version 4.0 criteria.  
 
13.1.2 Sample Size Considerations 
 
The primary comparison will include all eligible and treated patients, of whom 80 will be 
accrued. Whereas traditional chemotherapy confers a response rate (CR + PR) of roughly 30%, 
the goal of this trial is to target a response rate of 44%, which will be taken as evidence of 
activity of combination therapy with ipilimumab and nivolumab. We will employ a Simon two 
stage design for this trial. In the first stage, a total of 43 eligible and treated patients will be 
enrolled. Accrual will proceed to the second stage if at least 15 patients achieve a CR or PR 
among those first 43 patients. In the second stage, an additional 37 patients will be enrolled. If at 
least 29 responses are observed among all 80 patients enrolled, then the combination of 
ipilimumab and nivolumab will be deemed worthy of additional study. This trial has 88% power 
against the null hypothesis while testing at the one-sided level of 0.109, and the probability that 
the study stops early under the null is 0.71. 
 
We note that per RECIST 1.1, these responses must be confirmed with a second scan after the 


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initial response is determined. We also note that patients who are deemed unevaluable for 
response will not be replaced, and will be included as non-responders in the assessment of the 
best objective response rate. 
 
 
13.1.3 Statistical Analysis Plan  
 
The primary and some secondary analyses will include all eligible and treated patients. 
Exceptions to this include: analysis of toxicity data, which will include all patients who received 
study drug regardless of eligibility. 
 
Time-to-event data, such as PFS and OS, will be estimated using the Kaplan-Meier method, and 
Cox proportional hazards models will be used to estimate hazard ratios. Comparisons of groups 
will be made using the logrank test and Cox modeling. 
 
Categorical data, such as response rates (CR+PR) and toxicity, will be compared using Fisher’s 
exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling 
will be used to adjust for the effect of any covariates that are associated with these categorical 
outcomes. Though none are currently planned, any continuous outcomes will be analyzed using 
Wilcoxon rank sum test, and multivariable linear regression models may be used to adjust for 
multiple associations with outcome.  
 
Modeling procedures will implement backward selection; variables significant at the 0.10 level 
in the univariate setting will be chosen for inclusion in an initial full model, and at each step the 
least significant variable will be removed from the model. Only those covariates with p<0.05 will 
remain in any final models, unless there are factors identified by the study team as crucial to 
model interpretation.  
 
Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% 
confidence intervals. The method of Atkinson and Brown will be used for the estimation of the 
confidence interval for response. 
 
In the event that there are missing data, no imputation of the missing data will be conducted. We 
will assume that data are missing at random and will conduct all analyses as originally planned 
because we do not anticipate an excess of missing data. 
  
Subset analyses of all variables, including correlatives, are considered to be exploratory in 
nature. 
 
13.1.4 Correlative Analysis 
 
The correlative studies planned for this trial include evaluation of flow cytometry, RNA seq, and 
cytokine release data with outcomes on this trial. Biopsies are planned pre-treatment, 4 weeks 
post initiation of therapy, and at the time of disease progression.  
 
For the flow cytometric immunoprofiling on both tumor and immune cells, t-distributed neighbor 
embedding (t-SNE) analyses will be performed, resulting in the identification of “hot” and 


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“cold” clusters as previously described5,6. Each of the immunologic markers/parameters will be 
analyzed individually and in compilation to form such clusters. We hypothesize that outcomes 
may vary according to the value of such markers and/or hot/cold cluster status. 
 
With respect to the single-cell RNA sequencing analyses, we hope to determine wither or not 
single cell expression profiles can distinguish malignant and non-malignant cell types, and 
whether or not bulk tumors can segregate to distinct clusters on the basis of their inferred cell 
type composition. We hope to evaluate the association of profile and/or cluster type with 
outcomes. 
 
Lastly, the cytokine release studies will study 15-20 different cytokines and their relationship 
with patient outcomes, with the overarching hypothesis that change in cytokines over time will 
be associated with outcome to therapy with immune checkpoint inhibition.  
 
We may employ a variety of statistical techniques for the analyses of these data. The rate of 
change at a particular time point such as 4 weeks may be compared to baseline measures and will 
be analyzed for association with patient demographics and/or disease characteristics using the 
Kruskal Wallis test. Presence or absence of mutations in plasma will be analyzed for association 
with other variables using Fisher’s exact test. To account for the repeated measures over time, 
we may potentially use these data as time varying covariates in multivariable Cox models to 
study their impact on outcomes like PFS and OS. 
 
With a given sample size of 80 patients in this study, we expect that at least 80% of patients 
(n=64) will yield analyzable laboratory results for a given endpoint. For a given marker or 
abnormality occurring at a rate of 50%, the marker can then be used to define two patient cohorts 
with n=32 patients in each group. This sample size provides 91% power to detect differences in 
the rate of another binary variable (such as progression, response, or presence of a resistance 
mutation) with frequencies of 25% and 60%, respectively, while testing with a one-sided 0.10-
level Fisher’s exact test. 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
A maximum total of 80 participants will be enrolled to the trial.  We anticipate accruing 
approximately 3 – 4 subjects per month. Up to an additional three years of follow-up will be 
required on the last participant to observe response to trial therapy, for a total study length of 
approximately 6 years.   
 
 
Table 19: Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
2 
+ 
1 
= 
3 
Not Hispanic or Latino 
39 
+ 
38 
= 
77 
Ethnic Category: Total of all subjects 
41 
(A1) + 
39 
(B1) = 
80 
(C1) 
Racial Category 
 


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American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
1 
+ 
0 
= 
1 
Black or African American 
0 
+ 
2 
= 
2 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
40 
+ 
37 
= 
77 
Racial Category: Total of all subjects 
41 
(A2) + 
39 
(B2) = 
80 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
13.3 
Reporting and Exclusions 
 
13.3.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of study 
medication. 
 
 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  
 
 


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REFERENCES 
 
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(abstract). Journal of Clinical Oncology. 2016;34(suppl; abstr 3001). 
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Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy 
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Lizotte PH, Ivanova EV, Awad MM, et al. Multiparametric profiling of non-small-cell 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.