Clinical trial NCT01820754
Conditions: Non Small Cell Lung Cancer
Keywords: Non Small Cell Lung Cancer Lung Cancer Non Small Cell
Sponsor: Duke University
Start date: 2013-03-01; Completion date: 2018-04-30
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate whether the combination of neoadjuvant chemotherapy (chemotherapy before surgery) plus ipilimumab for lung cancer increases the number of patients with detectable circulating T cells with specificities against tumor associated antigens (TAA) from zero percent (0%) of patients prior to therapy to 20% of patients after neoadjuvant chemotherapy plus ipilimumab.

This is an open label Phase 2 trial. Patients with clinical stage 1B (\>4 cm), 2, (N0-2) or 3 non-small cell lung cancer (NSCLC) and no prior therapy for the current diagnosis of lung cancer will be eligible for the study. Subjects will receive 3 cycles of neoadjuvant chemotherapy (paclitaxel + cisplatin/carboplatin). Ipilimumab will be administered during Cycles 2 and 3 of standard chemotherapy and for up to 4 cycles alone after surgery. Subjects will undergo standard clinically indicated surgical resection of their lung cancer as deemed appropriate by their surgeon.

Standard diagnostic and staging work up will be performed including: pathologic/histologic diagnosis of NSCLC, Positron Emission Tomography (PET)/Computed Tomography (CT) scan, brain imaging, and mediastinoscopy. Three cycles of neoadjuvant chemotherapy will be given. Ipilimumab will be added to neoadjuvant chemotherapy for cycles 2 and 3. Standard surgical evaluation and therapy will be performed following completion of neoadjuvant therapy. Two cycles of single agent ipilimumab will be given after surgery (adjuvantly), followed by 2 cycles of maintenance therapy.

Detailed description:
The investigators propose studying the cell mediated effects of ipilimumab in combination with chemotherapy in the neoadjuvant setting for NSCLC. The overall immune assessment strategy for the proposed ipilimumab neoadjuvant trial will be based on the hypothesis that 1) T cells with specificities against tumor associated antigens expressed by the patient's progressing NSCLC are present, but functionally impaired, at baseline, and 2) that the immunomodulatory effects of chemotherapy plus ipilimumab will impact the suppressive mechanisms, restoring functional reactivity to important anti-tumor effector cell populations.

An important potential biomarker for anti-tumor immune response is the proliferation and stimulation of circulating T cells with specificities against tumor associated antigens (TAA). At baseline few patients with cancer have populations of circulating T cells with specificities against TAA above the detectable level of 0.05% CD8 lymphocytes. The primary endpoint of this clinical trial will be to determine if the addition of ipilimumab to neoadjuvant chemotherapy for non-small cell lung cancer increases the percentage of patients with circulating T cells with specificities against TAA. We will also measure tumor infiltrating lymphocytes in resected tumors.

Study Interventions:

The investigational agent, ipilimumab, will be added to neoadjuvant chemotherapy for cycles 2 and 3. Standard surgical evaluation and therapy will be performed following completion of neoadjuvant therapy. Two cycles of single agent ipilimumab will be given after surgery (adjuvantly), followed by 2 cycles of maintenance therapy.

Neoadjuvant:

Cycle 1: Paclitaxel 175 mg/m2 IV over 3 hours followed by cisplatin 75 mg/m2 over 60 minutes or carboplatin Area Under Curve (AUC) 6 (capped at 900 mg)over 30-60 minutes on day 1 (every 21 days x 1 cycle) Cycles 2 and 3: Ipilimumab 10mg/kg IV over 90 minutes, Paclitaxel 175 mg/m2 over 3 hours followed by cisplatin 75 mg/m2 or carboplatin AUC 6 (capped at 900 mg)IV over 30-60 minutes (every 21 days x 2 cycles) Surgery: Standard surgical evaluation will occur at least 21 days after the last dose (Cycle 3) of chemotherapy followed by surgical therapy.

Post-surgical Therapy: (Total of 4 doses of ipilimumab will be given post-operatively):

Adjuvant: Ipilimumab 10 mg/kg IV every 3 weeks x 2 doses, beginning 4 weeks postoperative (up to 10 weeks if needed for recovery) Maintenance: Ipilimumab 10 mg/kg IV every 12 weeks x 2 doses

Correlative Science Measures: Study specific research blood and tissue test(s) will be conducted:

Blood Specimens:

•Peripheral blood mononuclear cells (PBMC) isolated from freshly drawn anti-coagulated blood will be analyzed for circulating T cells with specificities against tumor-associated antigens (TAA) at 4 time points, namely 1) Baseline prior to treatment, 2) cycle 2, prior to ipilimumab therapy, 3) 21-36 days after completion of cycle 3 chemotherapy prior to surgery, and 4) 3-6 weeks after adjuvant ipilimumab dose #2. Additionally, PBMC from each of the time points will be analyzed for the presence of circulating populations of regulatory T cells, myeloid-derived suppressor cells (MDSC), as well as activated and exhausted T cells.

Tissue Specimens:

•Tumor infiltrating lymphocytes (TILs) will be isolated from the patient's resected tumor and analyzed for infiltrating T cells with specificities against tumor-associated antigens. Additionally, TIL will be analyzed for the presence of infiltrating populations of regulatory T cells, myeloid-derived suppressor cells (MDSC), as well as activated and exhausted T cells.

Arms: arm 1: Neoadjuvant (Pre-Surgery): Cycles 2 and 3: Ipilimumab 10 mg/kg IV over 90 minutes Adjuvant (Post-Surgery): Ipilimumab 10 mg/kg IV every 3 weeks times 2 doses beginning 4 weeks postoperative ( up to 10 weeks if needed for recovery) Maintenance: Ipilimumab 10 mg/kg/IV every 12 weeks times 2 doses
Interventions: intervention 1: Ipilimumab intervention 2: Paclitaxel, Cisplatin, Carboplatin
Intervention descriptions: intervention 1: Neoadjuvant (Pre-Surgery): Cycles 2 and 3: Ipilimumab 10 mg/kg IV over 90 minutes

Adjuvant (Post-Surgery): Ipilimumab 10 mg/kg IV every 3 weeks times 2 doses beginning 4 weeks postoperative ( up to 10 weeks if needed for recovery)

Maintenance: Ipilimumab 10 mg/kg/IV every 12 weeks times 2 doses intervention 2: Neoadjuvant (Pre-Surgery) Cycle 1: Paclitaxel 175 mg/m2 IV over 3 hours , followed by Cisplatin 75 mg/m2 IV over 60 minutes or carboplatin AUC 6 IV over 30-60 minutes on day 1(Every 21 days x 1 cycle)

Cycles 2 and 3: Ipilimumab 10 mg/kg IV over 90 minutes, Paclitaxel 175 mg/m2 IV over 3 hours , followed by Cisplatin 75 mg/m2 IV over 60 minutes or carboplatin AUC 6 IV over 30-60 minutes on day 1(Every 21 days x 2 cycles)

Protocol documents:
Prot_SAP_000.pdf: 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure 
 
Evaluation of Circulating T Cells and Tumor Infiltrating Lymphocytes with 
Specificities Against Tumor Associated Antigens During and After 
Neoadjuvant Chemotherapy and Phased Ipilimumab in Non-small Cell Lung 
Cancer (NSCLC) 
[BMS Protocol Number: CA184-203; NCT01820754] 
Thoracic Oncology Program (TOP) Protocol Number: TOP 1201 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: 
Neal Ready, MD 
Duke Cancer Institute, Thoracic Oncology 
Durham, North Carolina 27710 
Phone: 919.681.6932 
Fax: 919.684.5163 
neal.ready@duke.edu 
 
Correlative Science Study Chair: 
Kent Weinhold, PhD 
Director Immunology Core Laboratory, Duke Translational Research Institute 
Durham, NC 27710 
 
 
 
 
Original Version 00:  February 08, 2013 
 
  Version 1.0:  March 06, 2013 
 
  Version 2.0:  August 22, 2014   Amendment #1 
              Version 3.0   March 10, 2016     Amendment #2 
 
Sponsor: 
PI – Duke Cancer Institute 
Funding Source: 
Bristol-Myers Squibb 
Protocol Source: PI - Duke Cancer Institute 
Duke IRB#: 
Pro00038093 
IND#: 
 
Exempt 


2 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sub-Investigator(s) 
Jeffrey Crawford, MD 
Thoracic Oncology Program-DCI 
Durham, NC 27710 
 
 
 
 
 
 
 
 
 
 
 
Statistician 
Xiaofei Wang, PhD 
Department of Biostatistics 
Duke Cancer Institute  
Durham, North Carolina 27710 
 
 
Lead Study Coordinator 
Debra Shoemaker, RN 
Thoracic Oncology Program-DCI 
Durham, NC 27710 
Debra.shoemaker@duke.edu 
 
Radiology Sub-Investigator 
Jared Christensen, MD                            
Department of Radiology 
Durham, NC 27710 
 
 
Regulatory Coordinator 
Melody Torain, CCRP 
Melody.torain@duke.edu 
 
 
 
 
Data Manager(s) 
Carol Alonso,  RN 
Debra Shoemaker, RN 
Thoracic Oncology Program-DCI 
Durham, NC 27710 
 
 


3 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Statement of Compliance and Signature Page 
STUDY TITLE: Evaluation of Circulating T Cells and Tumor Infiltrating Lymphocytes 
with Specificities Against Tumor Associated Antigens During and After Neoadjuvant  
Chemotherapy and Phased Ipilimumab in Non-small Cell Lung Cancer (NSCLC). 
 
 
PI: Neal Ready, MD 
Provide a statement that the trial will be conducted in compliance with the protocol, International 
Conference on Harmonization Good Clinical Practice E6 (ICH-GCP), and the applicable 
regulatory requirements. Use the applicable regulations and requirements depending on study 
location and sponsor requirements. Examples of requirements that are potentially applicable 
include: 
    • U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46 and 21 CFR 
       including parts 50 and 56 concerning informed consent and IRB regulations, if under IND, 
       21 CFR 312, IDE 21 CFR 812, BBIND 21 CFR 601). 
    • Directive 2001/20/EC on the approximation of the laws, regulations and administrative 
       provisions of the Member States relating to the implementation of good clinical practice in 
       the conduct of clinical trials on medicinal products for human use as amended by 
       Commission Directive 2005/28/EC. For European Trials Only. 
     • Completion of Human Participants Protection Training 
     • Any terms of grant award 
 
This study will be conducted in compliance with the protocol approved by the Duke University 
Health System Institutional Review Board and according to Good Clinical Practice standards. No 
deviation from the protocol will be implemented without the prior review and approval of the 
IRB except where it may be necessary to eliminate an immediate hazard to a research subject. In 
such case, the deviation will be reported to the IRB as soon as possible. The signature below 
constitutes the approval (by the PI) of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local and state legal 
and regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
The Lead Principal Investigator should sign below. A copy of this Signature Page should be filed 
with the holder of the Regulatory documents and a copy should be maintained at the site. 
 
Principal Investigator:  Neal Ready, MD 03-10-2016; Duke University Thoracic Oncology 
Program 
 
 
 
 
_______________________________________________________ 
Print/Type 
Signed: Date: 
Name/Title 
 
 


4 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
TABLE OF CONTENTS 
Schema                                                                                                                                     
List of Abbreviations 
 
 
 
 
 
 
 
 
  
1.0 
            INTRODUCTION  
 
 
 
 
 
 
  12 
  
1.1         
Advanced Stage Lung Cancer                                                                          12 
1.1.2                Ipilimumab and Advanced Melanoma                                                             12 
1.1.3              Ipilimumab and Advanced NSCLC  
 
 
 
 
  12 
1.2. 
  
Early Stage NSCLC  
 
 
 
 
 
 
  13 
1.2.1    
Early Stage and Surgery 
 
 
 
 
                          13 
1.2.2   
Early Stage and Postoperative Chemotherapy 
 
                          13 
1.2.3    
Early Stage and Preoperative Chemotherapy  
                                
  14 
1.3 
 
Proposal:  Ipilimumab and Early Stage Lung Cancer                                      14 
1.4 
  
Clinical Trial Rationale 
 
 
 
 
                          14 
1.4.1   
T-Cells with Specificities Against Tumor Associated Antigens 
              15 
1.4.2  
Longitudinal Analyses of T Cell and MDSC Phenotypes 
 
 
  15 
1.5  
  
Ipilimumab Development:  CTLA-4 and T-Cell Activation  
 
  16 
1.6 
 
Summary of Results of Investigational Program 
 
 
 
  18 
1.61 
 
Pharmacology of Ipilimumab  
 
 
 
 
 
  18 
1.62 
 
Animal Toxicology of Ipilimumab 
 
 
 
 
 
  18 
1.7 
 
Clinical Pharmacology 
 
 
 
 
 
 
  19 
1.7.1  
Mechanism of Action  
 
 
 
 
 
 
  19 
1.7.2  
Pharmacokinetics 
 
 
 
 
 
 
 
  20 
1.8 
 
Clinical Safety with Ipilimumab 
 
 
 
 
 
  22 
1.8.1  
Overview of Clinical Trials Experience 
 
 
 
 
  22 
1.8.2  
Immunogenicity 
 
 
 
 
 
 
 
  27 
1.8.3  
Pregnancy Outcomes  
 
 
 
 
 
 
  27 
1.8.4  
Immune-mediated Adverse Reactions with Ipilimumab 
 
 
  27 
1.8.5  
Ipilimumab and Growth Factor Support 
 
 
 
 
  29 
1.9 
 
Clinical Efficacy:  Melanoma Program 
 
 
 
 
  29 
1.9.1  
Rationale for Using Immune-Related Tumor Assessment 
 
 
  30 
 
1.9.2  
MDX010-20 (Phase 3, 3mg/kg, previously treated melanoma)                      31 
1.9.3  
CA184024 (Phase 3, previously untreated melanoma, 10mg/kg) 
 
  33 
1.9.4  
10mg/kg Dosing with Ipilimumab 
 
 
 
 
 
  35 
1.9.5  
Advanced Melanoma  
 
 
 
 
 
 
  36 
2.0 
 
Overall Risk/Benefit Assessment 
 
 
 
 
 
  38 
3.0  
 
OBJECTIVES  
 
 
 
 
                                     40 
3.1 
  
Primary Objective  
 
 
 
 
                                     40 
3.2 
  
Secondary Objectives  
 
 
 
                                     40 
3.3 
 
Exploratory Objectives 
 
 
 
 
 
 
 40 
4.0  
 
STUDY PLAN / Design 
 
 
 
 
                         40 
5.0 
 
Recruitment 
 
 
 
 
 
 
 
 
 41 
6.0  
 
STUDY POPULATION/Selection of Patients  
 
 
             42 
6.1  
 
Inclusion Criteria  
 
 
 
 
                                     42 
6.2  
 
Exclusion Criteria  
 
 
 
 
                                     43 
6.3 
 
Protocol Eligibility Waivers  
 
 
 
 
 
 44 
7.0 
 
INCLUSION OF WOMEN AND MINORITIES  
 
                         44 


5 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
8.0.  
 
REGISTRATION PROCEDURE  
 
 
 
                         44 
9.0 
 
Study Periods  
 
 
 
 
 
 
 
 44 
9.1 
 
Screening 
 
 
 
 
 
 
 
 
 44 
9.2 
 
Treatment Study Day 1 Cycle 1 Neoadjuvant Chemothearpy 
             45 
9.3 
 
Treatment Study Day 1 Cycle 2 Neoadjuvant Chemotherapy                        45 
9.4 
 
Treatment Study Day 1 Cycle 3 Neoadjuvant Chemotherapy 
 
 46 
9.5 
 
Evaluation at Completion of Neoadjuvant Chemotherapy   
 
 46 
9.6 
 
Surgery 
 
 
 
 
 
 
 
 
 47 
9.7 
 
Post-Surgery Therapy  
 
 
 
 
 
 
 47 
9.71 
 
Adjuvant Ipilimumab                                                                                      47 
9.72 
 
Maintenance Ipilimumab 
 
 
 
 
 
 
 48 
9.8 
 
End of Study (EOS) Final Visit 
 
 
 
 
 
 48 
9.9 
 
Follow-up 
 
 
 
 
 
 
 
 
 49 
10.0   
SAMPLE PROCUREMENT AND HANDLING  
 
                         49 
10.1 
 
Blood Specimens 
 
 
 
 
 
 
 
 49 
10.2 
 
Surgical Specimens 
 
 
 
 
 
 
 
 49 
11.0 
 
TREATMENT 
 
 
 
 
 
 
 
 50 
11.1 
 
Treatments Administered 
 
 
 
 
 
 
 50 
11.2 
 
Materials and Supplies 
 
 
 
 
 
 
 51 
11.2.1  
Paclitaxel, Carblplatin, Cisplatin and Ipilimumab 
 
 
 
 51 
11.2.2  
Paclitaxel 
 
 
 
 
 
 
 
 
 51 
11.2.3  
Cisplatin 
 
 
 
 
 
 
 
 
 52 
11.2.4  
Carboplatin 
 
 
 
 
 
 
 
 
 52 
11.2.5  
Ipilimumab (see section 15.0   for detailed drug information 
 
 53 
11.3 
 
Rationale for Selection of Doses in the Study 
 
 
 
 53 
11.3.1  
Paclitaxel and Cisplatin or Carboplatin and Ipilimumab 
 
 
 53 
11.4 
 
Selection and Timing of Doses 
 
 
 
 
 
 53 
11.4.1  
Special Considerations: Dose Adjustments or Delays for Chemotherapy      54 
 
 
Subsequent Cycles (see Secion 11.5- Ipilimumab Dose Modifications) 
 
11.4.1.1 
Hematologic Toxicity Dose Adjustments 
 
 
 
             55 
11.4.1.2 
Non-Hematologic Toxicity Dose Adjustments 
 
 
 
 56 
11.4.1.3 
Renal Toxicity:  Cisplatin and Paclitaxel 
 
 
 
 
56 
11.4.1.4 
Neurologic Toxicity: Paclitaxel, Cisplatin or Carbolplatin  
 
56 
11.4.1.5 
Auditory Toxicity (Cisplatin)  
 
 
 
 
 
57 
11.4.1.6 
Hepatic Toxicity (Paclitaxel)  
 
 
 
 
 
57 
11.4.1.7 
Hypersensitivity Reactions to Paclitaxel 
 
 
 
 
57 
11.4.1.8 
Other Toxicities from Paclitaxel 
 
 
 
 
 
57 
11.5 
 
Ipilimumab Dose Modifications 
 
 
 
 
 
58 
11.5.1  
Immune-Related Adverse (irAEs)Reactions and Immune-mediated             59 
 
 
Adverse Reactions:  Definition, Monitoring and Treatment  
 
 
11.5.2  
Treatment of Infusion Reactions Associated with Ipilimumab 
 
60 
11.5.3  
Treatment of Ipilimumab-Related Drug Fever 
 
 
 
61 
11.5.4  
Monitoring and Management of Immune-Mediated Adverse Reactions 
62 
11.5.4.1 
Gastrointestinal Tract: Immune-mediated Enterocolitis 
 
 
62 
11.5.4.2 
Liver:  Immune-mediated Hepatitis  
 
 
 
 
64 
11.5.4.3 
Skin:  Immune-mediated Dermatitis  
 
 
 
 
65 


6 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
11.5.4.4 
Neuropathy:  Immune-mediated Neuropathies 
 
 
 
66 
11.5.4.5 
Endocrine:  Immune-mediated Endocrinopathies  
 
 
 
67 
11.5.4.6 
Other:  Immune-mediated Adverse Reactions, Including Ocular                  69             
Manifestions  
 
 
 
 
 
 
 
 
11.5.4.7 
Liver Function Test (LFT) Assessments Required Before Administration   70 
of Ipilimumab  
 
 
 
 
 
 
 
 
11.6 
 
Permanent Discontinuation of Ipilimumab 
 
 
 
 
70 
11.6.1  
Permanent Discontinuation for Related Adverse Events 
 
 
70 
11.6.2  
Exceptions to Permanent Discontinuation 
 
 
 
 
71 
11.7 
 
Dose Modifications for Obese Patients 
 
 
 
 
71 
11.8 
 
Blinding 
 
 
 
 
 
 
 
 
71 
11.9 
 
Concomitant Therapy  
 
 
 
 
 
 
71 
11.9.1  
Colony Stimulating Factors  
 
 
 
 
 
72 
11.9.2  
Antiemetic Agents 
 
 
 
 
 
 
 
72 
11.9.3  
Therapy for Diarrhea  
 
 
 
 
 
 
72 
11.9.4  
Therapy for Patients with Febrile Neutropenia 
 
 
 
73 
12.0 
 
Prohibited Therapies During the Study 
 
 
 
 
73 
13.0 
 
Treatment Compliance 
 
 
 
 
 
 
74 
14.0     
DISCONTINUATION 
 
 
 
 
 
            74 
14.1 
 
Discontinuation of Study Patients 
 
 
 
                        74 
14.2.   
Discontinuation of Study  
 
 
 
 
 
            75 
15.0 
 
Ipilimumab Drug Supply 
 
 
 
 
 
 
76 
15.1 
 
Identification  
 
 
 
 
 
 
 
76 
15.2 
 
Packaging and Labeling 
 
 
 
 
 
 
76 
15.3 
 
Ipilimumab Storage, Handling, Dispensing  
 
 
            76 
15.3.1  
Storage 
 
 
 
 
 
 
 
 
76 
15.3.2  
Handling and Disposal 
 
 
 
 
 
 
76 
15.3.3  
Dispensing 
 
 
 
 
 
 
 
 
77 
15.4 
 
Drug Ordering and Accountability 
 
 
 
 
 
77 
15.4.1  
Initial Orders  
 
 
 
 
 
 
 
77 
15.4.2  
Re-Supply 
 
 
 
 
 
 
 
 
78 
15.4.3  
Ipilimumab Accountability 
 
 
 
 
 
 
78 
15.4.4  
Ipilimumab Destruction 
 
 
 
 
 
 
78 
15.5 
 
Preparation and Administration 
 
 
 
 
 
78 
15.6 
 
Dose Calculations 
 
 
 
 
 
 
 
79 
16.0 
 
OUTCOME MEASUREMENTS  
 
 
 
 
            80 
16.1.   
Criteria for Progression and Relapse (Solid Tumors)  
 
 
80 
16.1.1  
Measurable Disease  
 
 
 
 
 
 
80 
16.1.2  
Non-Measurable Disease 
 
 
 
 
 
 
80 
16.1.3  
Target Lesions 
 
 
 
 
 
 
 
81 
16.1.4  
Non-Target Lesions  
 
 
 
 
 
 
81 
16.1.5  
Guidelines for Evaluation of Measurable/Evaluable Disease 
 
81 
16.2 
 
Response Criteria 
 
 
 
 
 
 
 
82 
16.21  
Ipilimumab Immune Related Response Criteria 
 
 
 
83 
16.3   
Cytology and Histology 
 
 
 
 
 
 
84 
16.4   
Disease-Free Survival  
 
 
 
 
 
 
84 


7 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
16.5 
            Survival 
 
 
 
 
 
 
 
 
84 
17.0 
 
Safety  
 
 
 
 
 
 
 
 
85 
17.1 
 
Documentation of Adverse Events 
 
 
 
 
 
85 
17.1.1  
Adverse Event Reporting 
 
 
 
 
 
 
86 
17.1.2  
Serious Adverse Events 
 
 
 
 
 
 
87 
17.1.3  
Serious Adverse Event Reporting 
 
 
 
 
 
88 
17.1.4  
Assignment of Adverse Event Intensity and Relationship to                         89 
Investigational Product 
 
 
 
 
 
 
 
17.1.5  
Pregnancy 
 
 
 
 
 
 
 
 
90 
17.1.6  
Other Safety Considerations  
 
 
 
 
 
91 
17.1.7  
Safety Oversight Committee (SOC)  
 
 
 
 
91 
18.0 
 
Quality Control and Quality Assurance 
 
 
 
 
92 
18.1 
 
Monitoring Plan 
 
 
 
 
 
 
 
92 
18.2 
 
Audits  
 
 
 
 
 
 
 
 
93 
19.0.                Investigator Responsibilities   
 
 
 
 
 
94 
20.0                 Departure from the Protocol  
 
 
 
 
 
94   
21.0                 Subject Privacy 
 
 
 
 
 
 
 
95 
22.0                 Institutional Review   
 
 
 
 
 
 
95 
23.0                 Informed Consent/Informed Consent Process  
 
 
 
96 
24.0                 Data Collection and Maintenance  
 
 
 
 
 
97 
24.1 
            Study Documentation  
 
 
 
 
 
 
97 
24.2 
            Case Report Forms 
 
 
 
 
 
 
 
98 
24.3 
 
Study Closure  
 
 
 
 
 
 
 
99 
25.0 
 
Appropriateness of Measurements   
 
 
 
 
99 
26.0 
            Statistical Methods and Analytical Plans 
 
  
 
 
99 
26.1 
 
General Considerations 
 
 
 
 
 
 
99 
27.0                 REFERENCES  
                                                                                   104 
 
APPENDICES 
Appendix A: Study Schedule 
 
 
 
 
 
 
           107 
Appendix B:  Correlative Science Measures 
 
 
 
                       109 
Appendix C: Performance Status Criteria  
 
 
 
 
           
113Appendix D: Cockcroft and Gault Formula for Calculated Creatinine Clearance      
114Appendix E: Patient Eligibility Checklist 
 
 
 
 
 
           
115 
Appendix F: Blood Specimens For Correlative Sciences                                                117 
 
Appendix G: Tumor Tissue Specimen Collection for Correlative Sciences 
           118 
 
Appendix H: Hepatoxicity Management Algorithm                                                        119 
Appendix I:  Endocrinopathy Management Algorithm                                                   120 
Appendix J:  Neuropathy Management Algorithm                                                          121 
Appendix K:  Skin Toxicity Management                                     
 
           122 
Appendix L:  GI Toxicity Management Algorithm                                                          123 
 
 


8 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
                                                                                                 STUDY SCHEMA 
 
STUDY DESIGN 
Patients with clinical stage IB (> 4cm), II, or III (N0-2) NSCLC and no prior therapy for 
the current diagnosis of lung cancer will be eligible for the study. Patients will 
receive three cycles of neoadjuvant chemotherapy. Ipilimumab will be 
given during cycles 2 and 3 of chemotherapy and up to 4 cycles alone 
after surgery. Patients will undergo standard surgical resection of their 
lung cancer as deemed appropriate by their surgeon.   
PATIENT ELIGIBILITY 
• All patients must have histologically documented clinical stage IB (> 4 cm), II, or III(N0-2) 
NSCLC 
• NO prior chemotherapy, radiation therapy or biologic/targeted therapy within 1 month  
• Performance Status ECOG 0-1 
• No active invasive malignancy in the past 2 years other than non-melanoma skin cancer. 
Cancers that are in-situ are not considered invasive. 
• Signed Informed Consent 
• No autoimmune disease that would constitute contraindication to receive ipilimumab 
REQUIRED LABORATORY DATA 
• ANC/AGC > 1500/µL 
• Platelets > 100,000/µL 
• Creatinine clearance ≥ 45 mL/min (creatinine < 2.0 mg/dL to receive cisplatin) 
• AST/ALT 2.5x ULN  
• Bilirubin  2.0 x institutional ULN  
 
 
 
 
 
 
 
 
 
 
 
 
 
           Determination of eligibility and histology  
Neoadjuvant: 
Cycle 1: Paclitaxel  175 mg/m2 IV over 3 hours , followed  by  Cisplatin   75 mg/m2  IV over 60 minutes  or 
carboplatin AUC 6 IV over 30-60 minutes  on day 1(Every 21 days x 1cycle) 
Cycles 2 and 3: Ipilimumab 10 mg/kg IV over 90 minutes,  Paclitaxel  175 mg/m2 IV over 3 hours , followed    by    
Cisplatin  75 mg/m2  IV over 60 minutes  or carboplatin AUC 6  IV over 30-60 minutes  on day 1(Every 21 days  
x 2 cycles)  
 
 
 
                                                      
Surgery: Standard surgical evaluation to occur at least 21 days after the last dose (cycle 3) of chemotherapy 
followed by surgical therapy 
 
 
Post-surgical Therapy: (A total of 4 doses of ipilimumab will be given post-operatively): 
Adjuvant: Ipilimumab 10 mg/kg IV every 3 weeks  times  2 doses  beginning 4 weeks postoperative ( up to 10 weeks  
if needed for recovery) 
Maintenance: Ipilimumab 10 mg/kg/IV every 12 weeks times 2 doses.  


9 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
 
Correlative Science Measures: (refer to Appendix B for further details on the correlative science 
outcomes) 
 
1) Blood for circulating T cells with specificities against tumor associated antigens: prior to 
treatment, after chemotherapy, before surgery, and after adjuvant ipilimumab. Blood also 
to monitor circulating populations of regulatory T cells, myeloid-derived suppressor cells 
(MDSC), as well as activated and exhausted T cells. 
2) Tumor for tumor infiltrating T cells with specificities against tumor associated antigens. 
Tumor also to monitor populations of infiltrating regulatory T cells, myeloid-derived 
suppressor cells (MDSC), as well as activated and exhausted T cells. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


10 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
List of Abbreviations 
ADCC 
Antibody-Dependent Cellular Cytotoxicity 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Transaminase 
ANC/AGC 
Absolute Neutrophil Count/Absolute Granulocyte Count 
APC 
Antigen Presenting Cell 
AST 
Aspartate Transaminase 
AUC 
Area Under the Curve 
BMS 
Bristol-Myers Squibb Company 
BORR 
Best Objective Response Rate 
BSA 
Body Surface Area 
BSC 
Best Supportive Care 
BW 
Body Weight 
CDCC 
Complement-Dependent Cellular Cytotoxicity 
CL 
Systemic Clearance 
CMax 
Peak Concentration 
CMin 
Trough Concentration 
CR  
Complete Response 
CRF 
Case Report Form (sometimes referred to as Clinical Report Form). A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the protocol. 
CRT 
Chemotherapy-Radiation Therapy 
CRU 
Clinical Research Unit 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events; National Cancer Institute, Version 4.0 
CTLA4 
Cytotoxic T-lymphocyte Antigen 
DCI 
Duke Cancer Institute 
DCR 
Disease Control Rate 
DOCR 
Duke Office of Clinical Research 
DUHS/DUMC 
Duke University Health System/Duke University Medical Center 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
ECL 
Electrochemiluminescent 
ECRF 
Electronic Case Report Form (sometimes referred to as an electronic clinical report form). An 
electronic form for recording study participants’ data during a clinical study, as required by the 
protocol. 
Enroll/Randomize 
The act of assigning a patient to a treatment. Patients who are enrolled in the trial are those who have 
been assigned to a treatment or randomized. 
Enter/Consent 
The act of obtaining informed consent for participation in a clinical trial from patients deemed 
eligible or potentially eligible to participate in the clinical trial.  Patients entered into a trial are those 
who sign the informed consent document directly or through their legally authorized representative 
GI 
Gastrointestinal 


11 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
HepB 
Hepatitis B 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator Brochure 
ICD/ICF 
A person responsible for the conduct of the clinical trial at a trial site.  If a team of individuals at a 
trial site conducts a trial, the investigator is the responsible leader of the team and may be called the 
principal investigator. 
irAE 
Immune-Related Adverse Event 
IRB/ERB 
Institutional Review Board/Ethical Review Board: a board or committee (institutional, regional, or 
national) composed of medical, professional and non-medical members whose responsibility it is to 
verify that the safety, welfare, and human rights of the subjects participating in a clinical trial are 
protected. 
irRC 
Immune-Related Response Criteria 
ITT 
Intention to Treat 
IV 
Intravenous, usually referring to a medication or substance given into a vein. 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
mAB 
Monoclonal Antibody 
MDSC 
Myeloid-Derived Suppressor Cells 
mg 
milligram: 1/100 of a gram 
m2 
meters squared 
NCA 
Non-Compartmental Analysis 
NCCN 
National Comprehensive Cancer Network 
NSCLC 
Non-Small Cell Lung Cancer 
OS 
Overall Survival 
Patient 
A subject with a defined disease 
PBMC 
Peripheral Blood Mononuclear Cells 
PFS 
Progression Free Survival 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PK  
Pharmacokinetic 
PPK 
Population Pharmacokinetics 
PR 
Partial Response 
Recist 
Response Evaluation Criteria in Solid Tumor 
RT 
Radiation Therapy/Radiotherapy  
SAE 
Serious Adverse Event 
SD 
Stable Disease 
TAA 
Tumor Associated Antigens 
TIL 
Tumor Infiltrating Lymphocytes 
TNM Staging 
Tumor, Node and Metastasis Staging 
Treg 
Regulatory T Cells 
Wt 
Weight 
 
 


12 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
1.0  INTRODUCTION 
 
1.1  Advanced Stage Lung Cancer 
In advanced stage IV NSCLC, meta-analysis of 8 trials using cisplatin based chemotherapy 
compared to Best Supportive Care resulted in chemotherapy having an absolute survival 
improvement of 10% at 1 year. (1, 2) Median survival, BSC vs. chemo: 4 vs 8+ months, 
respectively. (3) Median survival now is 12+ months in more recent trials of VEGF targeted 
therapy plus platinum doublet. (4) Quality of life benefit was also observed with chemotherapy. 
(5)  First-line chemotherapy for unselected stage IV NSCLC is a platinum doublet as the standard 
platform.  Combining taxanes with other chemotherapeutic agents has been reported to have high 
activity and to be tolerable.  Platinum doublets resulted in 2 year Survival of 15-20%. (6) Scagliotti 
observed a survival advantage selecting doublet chemotherapy based on tumor histology. Using a 
platinum based doublet, the author observed 2 month longer median overall survival for 
adenocarcinoma treated with pemetrexed and 1 month longer for squamous cell carcinoma treated 
with gemcitabine. (7) Molecular targeted agents added to platinum doublet chemotherapy can also 
improve survival.  Anti-VEGF monoclonal antibody, Bevacizumab, added to platinum and 
paclitaxel improved overall survival in adenocarcinoma subset with stage IV disease. (8) Selection 
of targeted agents where target is known can replace first-line chemotherapy (EGFR-TKIs in 
EGFR mutants; ALK fusion mutants treated with MEK TKIs). (9, 10) Identifying better 
biomarkers will lead to better targeting. 
 
1.1.2  Ipilimumab and Advanced Melanoma: 
 
Ipilimumab enhanced T-cell activation leads to pan immune stimulation against human solid tumors. 
Recently reported unresectable stage III or IV melanoma that progressed while they were receiving 
therapy was treated with Ipilimumab dose of 3 mg per kilogram of body weight. The ipilimumab 
treated cohort was observed to have improved median overall survival 10.0 months compared with 
6.4. (30)  
 
1.1.3  Ipilimumab and Advanced Lung Cancer: 
 
In advanced metastatic NSCLC, Ipilimumab 10 mg/kg has been successfully combined with the 
platin doublet, paclitaxel 175 mg/m2 and carboplatin AUC 6, as first-line treatment.  -Abstracts of a  
phase II trial reported that the phased sequence (two courses chemotherapy followed by two courses 
of chemotherapy + Ipilimumab) had superior progression free survival, overall response, and overall 


13 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
survival; 6.4 months, 57%, and 12.9 months, respectively; compared to 5.7 months, 49%, and 9.1 
months, for the concurrent sequence. (31, 32). 
 
 
Final publication by Lynch observed immune related PFS (irPFS) significantly improved using the 
phased regimen compared with the control regimen (HR, 0.72; P = .05), whereas the concurrent 
ipilimumab regimen did not significantly improve irPFS (HR, 0.81; P = .13). As assessed by WHO 
criteria, there was also an improvement in PFS, relative to the control, for phased ipilimumab (HR, 
0.69; P = .02) but not for concurrent ipilimumab (HR, 0.88; P = .25). The median mWHO-PFS was 
4.2 months for the control group, 5.1 months for the phased ipilimumab group, and 4.1 months for 
the concurrent ipilimumab group. Similarly,  improved median overall survival for the phased 
ipilimumab group was 12.2 months, and increase of 3.9 months over the median of 8.3 months for 
the control group (HR, 0.87; P = .23). the median overall survival of 9.7 months for the concurrent 
ipilimumab group was similar to that of the control group (HR, 0.99; P = .48).  Hematologic and 
nonhematologic toxicities were similar between control arm [Paclitaxel and Carboplatin] 
compared to phased arm [Ipilimumab, Paclitaxel, Carboplatin]; and toxicities were typical of 
those associated with Paclitaxel and Carboplatin. Specifically, toxicities observed as Grade 1-2 
occuring > 30% in descending order (control, phased arm): anemia 89,92; alopecia 46,45; 
thrombocytopenia 35, 43; neutropenia 32,34; diarrhea 31,31; AST elevation 32,31; ALT 
elevation 35,29.  Observed Grade 3-4 toxicities were infrequent, interestingly they more frequent  
in the control than phased arm,  less than 9% and 6%, respectively. (59) 
 
 
1.2  
Early Stage Lung Cancer 
 
1.2.1  Early Stage and Surgery 
The natural history of clinically staged (stage I and stage II) non-small cell lung cancer (NSCLC) 
following surgery is a five year survival of 50% and 30%, respectively.(1) Five-year survival in 
surgical pathologic stage IA (T1N0M0) and IB (T2N0M0) disease is 68-83% and 53-65%, 
respectively. Five year survival in surgical pathologic stage IIA (T1N1M0) and IIB (T2N1M0) 
disease is 40-63% and 38-45%, respectively.(2) Clinical implications are pathologically staged 
patients (17-32% stage IA, 35-47% stage IB, 37-60% stage IIA, and 55-62% stage IIB) are destined 
to recur because they harbor regional or distant micro-metastasis outside their surgical resection. 
 
 
1.2.2  Early Stage and Postoperative Chemotherapy 
For early stage NSCLC, the addition of chemotherapy to surgery has been shown to improve 
survival. Postoperative chemotherapy improved 5-year survival from 59% and 40% to 79% and 60% 
for stage IB > 4cm tumors and stage II NSCLC, respectively. (11, 12) Three randomized controlled 
trials of postoperative chemotherapy each reported improved overall survival for chemotherapy in 


14 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
early stages IB, II, and IIIA NSCLC. (13, 14, 15) Similar survival benefit has been seen for adjuvant 
cisplatin based chemotherapy for stage IIIA NSCLC. (16)  
 
1.2.3  Early Stage and Preoperative Chemotherapy 
Preoperative chemotherapy trials have included small phase III and phase II trials which initially 
reported a threefold median survival advantage favoring chemotherapy. (17) (18) However, 
long-term results were not durable, although a trend of improved survival favoring chemotherapy 
persisted. (19) (20) Four additional preoperative chemotherapy phase III trials have been 
conducted. One reported significant OS advantage using a non-taxane platin triplet (21), two 
reported trends to OS advantage using paclitaxel/carboplatin (22, 23), and one was completely 
negative administered older technology chemotherapy (non-taxane/platin) to 88% of patients. 
(24)  Most recently, a phase III trial reported preoperative chemotherapy using gemcitabine plus 
cisplatin improved survival in patients with clinical stage IIB/IIIA NSCLC. The hazard ratios for 
PFS and overall survival were both in favor of chemotherapy. A statistically significant impact 
of preoperative chemotherapy on outcomes was observed in the stage IIB/IIIA subgroup (3-year 
PFS rate: 36.1% v 55.4%; P _ .002). (25) Similar survival benefits have been observed for 
preoperative and postoperative chemotherapy by Meta-analysis. (26, 27, 28, 29)  
 
 
1.3  
Proposal: Ipilimumab and Early Stage Lung Cancer 
 
In early stage NSCLC we propose adding ipilimumab, a T-Cell targeted agent, to enhance T-Cell 
immune response combined with preoperative platinum doublet chemotherapy. Ipilimumab is a 
monoclonal (IgG 1) antibody that co-stimulates T-Cells by targeting the CD28 homolog, CTLA-
4. This enhances T-cell immunity by co-stimulation of T-cells at T-cell receptor and CD28 by B7 
family on the antigen- presenting cell (APC). The combination of enhanced immune response 
together with cytotoxic chemotherapy may improve clinical outcome. We propose to study 
circulating T cells and tumor infiltrating T cells with specificities against tumor associated 
antigens to better understand the effect that ipilimumab has on the immune system in NSCLC. 
 
1.4 
 Clinical Trial Rationale 
 
We propose studying the cell mediated effects of ipilimumab in combination with chemotherapy 
in the neoadjuvant setting for NSCLC.  The overall immune assessment strategy for the proposed 
ipilimumab neoadjuvant trial will be based on the hypothesis that 1) T cells with specificities 
against tumor associated antigens expressed by the patient’s progressing NSCLC are present, but 
functionally impaired, at baseline, and 2) that the immunomodulatory effects of chemotherapy 
plus ipilimumab will impact the suppressive mechanisms, restoring functional reactivity to 
important anti-tumor effector cell populations.   
 
 


15 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
An important potential biomarker for anti-tumor immune response is the proliferation and 
stimulation of circulating T cells with specificities against tumor associated antigens (TAA). At 
baseline few patients with cancer have populations of circulating T cells with specificities 
against TAA above the detectable level of 0.05% CD8 lymphocytes. The primary endpoint of 
this clinical trial will be to determine if the addition of ipilimumab to neoadjuvant chemotherapy 
for non-small cell lung cancer increases the percentage of patients with circulating T cells with 
specificities against TAA. We will also measure tumor infiltrating lymphocytes in resected 
tumors. 
 
1.4.1 T Cells with Specificities Against Tumor Associated Antigens 
 
Functional TAA-specific T cell reactivities will be monitored at 4 time points [1) baseline prior 
to treatment, 2) cycle 2 chemotherapy, prior to ipilimumab administration, 3) 21-36 days after 
last dose (cycle 3) of chemotherapy prior to  surgery, and 4) 3-6 weeks after adjuvant ipilimumab 
dose #2] utilizing a 12-color intracellular cytokine staining (ICS) assay in which functional 
reactivities within maturational subsets of CD4 and CD8 T cells will be assessed.  In this assay, 
TAA driven production of IL-2, IFN-γ, TNF-α, and the degranulation marker CD107a will be 
measured, thus permitting examination of qualitative changes in relative T cell polyfunctionality 
within maturational subsets of CD4+ and CD8+ lymphocytes.  Pools of overlapping 15-mer 
TAA peptides, with 11 amino acid overlaps, will be used for the functional analyses.  The 3 most 
common highly conserved TAA expressed by NSCLC are Survivin, PRAME, and MAGE-A3, 
but peptide pools for CEA, MAGE-A1, MAGE-A4, MART-1, tyrosinase, NY-ESO-1 and gp100 
are also available in the Core laboratory. Although the frequencies of TAA-specific T cells may 
be too low in PBMC to permit direct ex vivo functional assessments, tumor specimens obtained 
at the time of surgical resection, post chemotherapy plus ipilimumab therapy, will be an 
especially rich source of tumor infiltrating lymphocytes (TIL) for analyses.  
 
 
1.4.2 Longitudinal Analyses of T Cell and MDSC Phenotypes   
Phenotypic and functional characterization of T cell populations will be performed on peripheral 
blood mononuclear cells (PBMC), as well as TIL. It will be of critical importance to better 
understand the impact of ipilimumab therapy on: 1) regulatory T cells (Tregs), 2) myeloid-
derived suppressor cells (MDSC), 3) T cell activation, and 4) T cell exhaustion. These 
parameters will all be assessed using a 14-color polychromatic flow cytometry panel specifically  
designed and validated for this trial. 
 
The components of both the 12-color ICS and the 14-color Treg/Activation/Exhaustion/MDSC 
polychromatic flow cytometry panels are delineated in the Table below. 
 
 
 


16 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
1.5  
Ipilimumab Development: CTLA-4 and T Cell Activation 
Figure 1 
Mechanism of Action 
 


17 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Advances in the understanding of the mechanisms that regulate T cell activation have allowed 
the rational design of new strategies for immunotherapy of tumors, including melanoma. It has 
been known for some time that engagement of the T cell antigen receptor by itself is not 
sufficient for full T cell activation; a second co-stimulatory signal is required for induction of IL-
2 production, proliferation and differentiation to effector function of naive T cells. Abundant 
data now indicate that the primary source of this costimulation is mediated by engagement of 
CD28 on the T cell surface by members of the B7 family on the antigen-presenting cell (APC).i 
(33) (Figure 1.) 
Expression of B7 has been shown to be limited to “professional” antigen presenting cells; that is, 
specialized cells of the hematopoietic lineage, including dendritic cells, activated macrophages, 
and activated B cells. It has been suggested that this sharply-defined restriction of B7 expression 
is a fail-safe mechanism for maintenance of peripheral T cell tolerance, insuring that T cell 
activation can only be stimulated by appropriate APCs.ii (34) The fact that tumor cells do not 
express B7 contributes to their poor capacity to elicit immune responses. (35, 36) 
The demonstration that induction of expression of B7 on many tumor cells by transfection, 
transduction, or other mechanisms can heighten tumor immunogenicity led to great interest in 
pursuing this as an approach to tumor immunotherapy. As demonstrated in vivo in murine tumor 
models, the utility of B7 expression as a vaccination approach is limited by the following factors: 
(1) B7-expressing tumor cell vaccines are only effective when the tumor cells have a high degree 
of inherent immunogenicity; (2) while B7-expressing vaccines have been shown in many cases 
to be effective in inducing protective immune responses, they have demonstrated only limited 
utility in inducing responses to established tumors; and (3) inactivation of tumor cells by 
radiation has been shown to destroy the immuno-enhancing activity of the B7 gene product. (37, 
38) 
In the past few years it has become apparent that co-stimulation is even more complex than 
originally thought. After activation, T cells express CTLA-4, a close homologue to CD28. 
CTLA-4 binds members of the B7 family with a much higher affinity than CD28. (39) Although 
there was initially some controversy as to the role of CTLA-4 in regulating T cell activation, it 
has become clear that CTLA-4 down-regulates T cell responses. (40) 
  
This was initially suggested by the following in vitro observations: (1) blockade of CTLA-4/B7 
interactions with antibody enhanced T cell responses; (2) cross-linking of CTLA-4 with CD3 and 
CD28 inhibited T cell responses; and (3) administration of antibodies to CTLA-4 in vivo 
enhanced the immune response to peptide antigens or superantigens in mice. (41, 42, 43, 44) 
Blocking CTLA-4-B7 interaction while preserving signaling via CD28 resulted in enhanced T 
cell responses in vitro (42). 


18 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Perhaps the most convincing demonstration of the down-regulatory role of CTLA-4 came from 
examination of mice with a null mutation. (45, 46, 47) CTLA-4 knockout mice appear to have 
spontaneously activated T cells evident at approximately 1 week after birth, followed by rampant 
lymphoproliferation and lymphadenopathy. These mice die at approximately 3 weeks of age, 
either as a result of polyclonal T cell expansion and tissue destruction or as a result of toxic 
shock resulting from lymphokine production by the T cells. Since thymocyte differentiation and 
selection proceed normally in CTLA-4-deficient mice, the rampant T cell expansion that occurs 
in the mice indicates that CTLA-4 plays a critical role in down-regulating T cell responses in the 
periphery. (44) 
 
1.6  
Summary of Results of Investigational Program  
1.6.1    Pharmacology of Ipilimumab 
Ipilimumab is a human immunoglobulin G (IgG1)κ anti-CTLA-4 monoclonal antibody (mAb). 
In vitro studies were performed with ipilimumab to demonstrate that it is specific for CTLA-4, 
actively inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any cross-reactivity 
with human B7.1, B7.2 negative cell lines, and stains the appropriate cells without non-specific 
cross-reactivity in normal human tissues, as demonstrated by immunohistochemistry. 
Ipilimumab does cross-react with CTLA-4 in non-human primates including cynomolgus 
monkeys. 
1.6.2 Animal Toxicology of Ipilimumab 
The effects of ipilimumab on prenatal and postnatal development in monkeys have not been fully 
investigated. Preliminary results are available from an ongoing study in cynomolgus monkeys. 
Pregnant monkeys received ipilimumab every 21 days from the onset of organogenesis in the 
first trimester through delivery, at dose levels either 2.6 or 7.2 times higher than the clinical dose 
of 3 mg/kg of ipilimumab (by AUC). No treatment-related adverse effects on reproduction were 
detected during the first two trimesters of pregnancy. Beginning in the third trimester, the 
ipilimumab groups experienced higher incidences of abortion, stillbirth, premature delivery (with 
corresponding lower birth weight), and higher incidences of infant mortality in a dose-related 
manner compared to controls. 
Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-), the target for ipilimumab, 
appeared healthy and gave birth to healthy CTLA-4+/- heterozygous offspring. Mated CTLA-
4+/- heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, 
CTLA-4-/-). The CTLA-4-/- homozygous negative offspring appeared healthy at birth, exhibited 


19 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3–4 weeks of 
age with massive lymphoproliferation and multiorgan tissue destruction. 
Complete information on the pre-clinical toxicology studies can be found in the Ipilimumab 
Investigator Brochure (IB). Non-clinical toxicity assessments included in vitro evaluation for the 
potential of ipilimumab to mediate complement-dependent cellular cytotoxicity (CDCC) or 
antibody-dependent cellular cytotoxicity (ADCC), and toxicology assessments in cynomolgus 
monkeys alone and in the presence of vaccines. 
The in vitro studies demonstrated that ipilimumab did not mediate CDCC of PHA- or (CD)3-
activated human T cells. However, low to moderate ADCC activity was noted at concentrations 
up to 50 ug/mL. These data are consistent with the requirement of high levels of antigen 
expression on the surface of target cells for efficient ADCC or CDCC. Since ipilimumab is a 
human IgG1, an isotype generally capable of mediating CDCC and ADCC, the lack of these 
activities is likely due to a very low expression of CTLA-4 on activated T cells. Therefore, these 
data suggest that ipilimumab treatment would not result in depletion of activated T cells in vivo. 
Indeed, no depletion of T cells or T cell subsets were noted in toxicology studies in cynomolgus 
monkeys. 
No mortality or signs of toxicity were observed in three independent 14-day intravenous 
toxicology studies in cynomolgus monkeys at multiple doses up to 30 mg/kg/dose. Furthermore, 
ipilimumab was evaluated in sub-chronic and chronic toxicology studies in cynomolgus 
monkeys with and without Hepatitis B (HepB) Vaccine and Melanoma Vaccine. Ipilimumab was 
well tolerated alone or in combination in all studies. There were no significant changes in clinical 
signs, body weight values, clinical pathology values or T cell activation markers. In addition, 
there were no significant histopathology changes in the stomach or colon. 
 
1.7   Clinical Pharmacology 
1.7.1 Mechanism of Action 
CTLA-4 is a negative regulator of T-cell activation. Ipilimumab 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. The mechanism of action of ipilimumab’s effect in 
patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune 
responses. 


20 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
1.7.2  Pharmacokinetics 
The pharmacokinetics of ipilimumab was studied in 499 patients with unresectable or metastatic 
melanoma who received doses of 0.3, 3, or 10 mg/kg administered once every 3 weeks for four 
doses. Peak concentration (C max), trough concentration (Cmin), and area under the curve 
(AUC) of ipilimumab were found to be dose proportional within the dose range examined. Upon 
repeated dosing of ipilimumab administered every 3 weeks, ipilimumab clearance was found to 
be time-invariant, and minimal systemic accumulation was observed as evident by an 
accumulation index of 1.5-fold or less. Ipilimumab steady-state concentration was reached by the 
third dose. The following mean (percent coefficient of variation) parameters were generated 
through population pharmacokinetic analysis: terminal half-life of 14.7 days (30.1%); systemic 
clearance (CL) of 15.3 mL/h (38.5%); and volume of distribution at steady-state (Vss) of 7.21 L 
(10.5%). The mean (±SD) ipilimumab Cmin achieved at steady-state with the 3-mg/kg regimen 
was 21.8 mcg/mL (±11.2). 
Specific Populations: Cross-study analyses were performed on data from patients with a variety 
of conditions, including 420 patients with melanoma who received single or multiple infusions of 
ipilimumab at doses of 0.3, 3, or 10 mg/kg. The effects of various covariates on ipilimumab 
pharmacokinetics were assessed in population pharmacokinetic analyses. 
Ipilimumab CL increased with increasing body weight; however, no dose adjustment of 
ipilimumab is required for body weight after administration on a mg/kg basis. The following 
factors had no clinically meaningful effect on the CL of ipilimumab: age (range 26 to 86 years), 
gender, concomitant use of budesonide, performance status, HLA-A2*0201 status, positive anti-
ipilimumab antibody status, prior use of systemic anticancer therapy, or baseline lactate 
dehydrogenase (LDH) levels. The effect of race was not examined as there were insufficient 
numbers of patients in non-Caucasian ethnic groups. 
Renal Impairment: Creatinine clearance at baseline did not have a clinically important effect on 
ipilimumab pharmacokinetics in patients with calculated creatinine clearance values of 29 
mL/min or greater. 
Hepatic Impairment: Baseline AST, total bilirubin, and ALT levels did not have a clinically 
important effect on ipilimumab pharmacokinetics in patients with various degrees of hepatic 
impairment. 
Pharmacokinetic (PK) profiles for ipilimumab have been analyzed. The primary objective of 
Protocol MDX010-015 was to determine the safety and PK profile of single and multiple doses 
of ipilimumab derived from a transfectoma or hybridoma cell line. Mean plasma concentrations 
of ipilimumab administered at doses of 3 mg/kg (hybridoma-derived drug product); 2.8 mg/kg, 
5 mg/kg, 7.5 mg/kg, 10 mg/kg, 15 mg/kg, and 20 mg/kg (transfectoma-derived drug product) 


21 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
demonstrated approximate dose proportionality. Equimolar doses of hybridoma-derived and 
transfectoma-derived drug product had comparable PK profiles. The range of mean volume of 
distribution at steady state (Vss) across cohorts 2.8, 3, 5, 7.5, 10, 15, and 20 mg/kg, was 57.3 to 
82.6 mL/kg, indicating drug distribution was mostly limited to the intravascular space. The 
clearance was low (range 0.11 to 0.29 mL/h/kg) and reflective of the half-life (range 297 to 
414 h), which is consistent with the long terminal disposition phase of ipilimumab. There was 
moderate variability in the PK parameters among subjects, with CV of 11% to 48% in AUC (0-
21d), 20% to 59% in CL, and 17% to 46% in Vss. 
Ipilimumab was originally produced and purified from a hybridoma clone. Ipilimumab drug 
substance is currently manufactured using Process B. A new drug substance manufacturing 
process (Process C) has been developed utilizing a higher producing sub-clone of the current 
Master Cell Bank, and modified cell culture and purification steps. The new drug substance 
manufacturing process is intended to replace the current drug substance manufacturing process. 
The biocomparability of Process C relative to Process B was assessed in Study CA184087. 
 
PK in Phase 1 Study CA184087 (Process B and Process C)  
The PK of ipilimumab was assessed when manufactured by a newer process C relative to current 
process B as an IV infusion (1.5-hr), in subjects with advanced melanoma (CA184087). Upon 
meeting eligibility criteria, subjects were randomized (1:1) to receive either ipilimumab Process 
B (Arm A, reference) or ipilimumab Process C (Arm B, test) at a dose of 10 mg/kg IV 
administered over 90 minutes every 3 weeks on Days 1, 22, 43, and 64 (Weeks 1, 4, 7, and 10) 
during induction therapy. Randomization was stratified by baseline body weight (BW) and LDH 
values since both were identified as potential covariates in a population PK assessment. 
The primary endpoint of PK data at week 4 demonstrated that the PK of Process B and Process C 
are biocomparable as the 90% CIs for the ratio of geometric means of AUC(0-21d) and Cmax - 
both adjusted or not adjusted for covariates - were entirely contained with the pre-specified 
equivalence interval (80 - 125%). 
 
Population Pharmacokinetics 
The population pharmacokinetics (PPK) of ipilimumab was developed with 420 subjects (1767 
serum concentrations) with advanced melanoma in phase 2 studies (CA184007, CA184008, and 
CA184022). (50, 51, 52) subsequently, the final PPK model was evaluated by an external model 
validation dataset from CA184004 (79 subjects with 328 serum concentration data). The PPK 
analysis demonstrated that PK of ipilimumab is linear and exposures are dose proportional across 


22 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
the tested dose range of 0.3 to 10 mg/kg, and the model parameters are time-invariant. The 
ipilimumab CL of 15.3 mL/h from PPK analysis is consistent with that determined by PK 
analysis as assessed in MDX010-15 as 12.8 mL/h for a dose of 2.8 mg/kg and 15.7 mL/h for a 
dose of 10 mg/kg. The terminal half-life and Vss of ipilimumab calculated from the model were 
14.7 days, and 7.21 L, which are consistent with that determined by non-compartmental analysis 
(NCA). Volume of central and peripheral compartment were found to be 4.16 and 3.22 L, 
respectively, suggesting that ipilimumab first distributes into plasma volume and subsequently 
into extracellular fluid space. Clearance of ipilimumab was found to increase with increase in 
body weight, supporting dosing of ipilimumab based on a weight normalized regimen. Other 
covariates had effects that were either not statistically significant or were of minimal clinical 
relevance. 
 
1.8   Clinical Safety with Ipilimumab 
 
1.8.1  Overview of Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates 
observed cannot be directly compared with rates in other clinical trials or experience with 
therapeutics in the same class and may not reflect the rates observed in clinical practice. 
The clinical development program excluded patients with active autoimmune disease or those 
receiving systemic immunosuppression for organ transplantation. Exposure to ipilimumab 3 
mg/kg for four doses given by intravenous infusion in previously treated patients with 
unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study 
(MDX010-20). One hundred thirty-one patients (median age 57 years, 60% male) received 
ipilimumab as a single agent, 380 patients (median age 56 years, 61% male) received ipilimumab 
with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 
54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 
doses (range 1 to 4 doses). Ipilimumab was discontinued for adverse reactions in 10% of 
patients. (48) 
 
The most common adverse reactions (≥5%) in patients who received ipilimumab at 3 mg/kg 
were fatigue, diarrhea, pruritus, rash, and colitis. 


23 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
Table 1 presents selected adverse reactions from MDX010-20, which occurred in at least 5% of 
patients in the ipilimumab-containing arms and with at least 5% increased incidence over the 
control gp100 arm for all-grade events and at least 1% incidence over the control group for 
Grade 3–5 events. 
Table 1: 
Selected Adverse Reactions in MDX010-20 
 
Percentage (%) of Patientsa 
 
YERVOY 3 mg/kg 
n = 131 
YERVOY 3mg/kg  
+ gp100  
n = 380 
gp100 
n = 132 
System Organ 
Class/Preferred 
Term 
Any 
Grade 
Grade 3-
5 
Any 
Grade 
Grade 3-
5 
Any 
Grade 
Grade 3-
5 
Gastrointestinal 
Disorders 
 
 
 
 
 
 
Diarrhea 
32 
5 
37 
4 
20 
1 
Colitis 
8 
5 
5 
3 
2 
0 
Skin and 
Subcutaneous Tissue 
Disorders 
 
 
 
 
 
 
Pruritus 
31 
0 
21 
<1 
11 
0 
Rash 
29 
2 
25 
2 
8 
0 
General Disorders 
and Administration 
Site Conditions  
 
 
 
 
 
 
Fatigue 
41 
7 
34 
5 
31 
3 
a Incidences presented in this table are based on reports of adverse events regardless of causality. 
Source: Yervoy Prescribing Information, Bristol-Myers Squibb, March 2011. 
 
 
 
 
 
Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated 
adverse reactions from MDX010-20. 
 


24 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
 
 
Table 2: 
Severe to Fatal Immune-mediated Adverse Reactions in 
MDX010-20 
 
Percentage (%) of Patients  
 
YERVOY 3 mg/kg 
n = 131 
YERVOY 3 mg/kg + gp100  
n = 380 
Any Immune-mediated Adverse Reaction  
15 
12 
Entercolitis a,b 
7 
7 
Hepatotoxicity a 
1 
2 
Dermatitis a 
2 
3 
Neuropathy a 
1 
< 1 
Endocrinopathy 
4 
1 
Hypopituitarism 
4 
1 
Adrenal insufficiency 
0 
1 
Other 
 
 
Pneumonitis 
0 
< 1 
Meningitis 
0 
< 1 
Nephritis 
1 
0 
Eosinophilia c 
1 
0 
Pericarditis a,c 
0 
< 1 
a Including fatal outcome 
b Including intestinal perforation 
c Underlying etiology not established 
Source: Yervoy Prescribing Information, Bristol-Myers Squibb, March 2011. 
 
 
 
 
 
 


25 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
CA184024 evaluated the addition of 10 mg/kg ipilimumab to dacarbazine in patients with 
previously untreated, metastatic melanoma.  A total of 502 patients were randomized to receive 
up to 8 cycles of dacarbazine 850 mg/m2 q3w, with either ipilimumab 10 mg or placebo for 
cycles 1-4 and as maintenance after completion of chemotherapy.  Ipilimumab AEs were 
consistent with previous studies and predominantly affected skin, I tract, liver, and the endocrine 
system.  Events were managed with established guidelines and were generally responsive to dose 
interruption/discontinuation, corticosteroids and/or other immunosuppressants.  Select adverse 
events associated with the mechanism of action of ipilimumab, regardless of attribution by the 
investigator are shown in Table 3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Error! Bookmark not defined. 
1 (0.4%) hypophysitis was reported on Day 364. 
 
 
Table 3: 
CA184024 Select Adverse Events 
 
Ipilimumab + DTIC 
n = 247 
Placebo + DTIC 
n = 251 
Total 
Grade 3 - 4 
Total 
Grade 3 - 4 
% Patients 
Dermatologic 
 
 
 
 
 Pruritis 
29.6 
2.0 
8.8 
0 
 Rash 
24.7 
1.2 
6.8 
0 
Gastrointestinal (GI) 
 
 
 
 
 Diarrhea 
36.4 
4.0 
24.7 
0 
 Colitis 
4.5 
2.0 
0.4 
0 
 GI perforation 
0 
0 
0 
0 
Hepatic 
 
 
 
 
 Increased ALT 
33.2 
21.9 
5.6 
0.8 
 Increased AST 
29.1 
18.2 
5.6 
1.2 
Endocrine 
 
 
 
 
 Hypothyroidism 
1.6 
0 
0.4 
0 
 Autoimmune thyroiditis 
0.8 
0 
0 
0 
 Hyperthyroidism 
0.4 
0 
0.4 
0 
 Hypophysitisa 
0 
0 
0 
0 


26 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
Safety Profile of Ipilimumab at a Dose of 10 mg/kg (Phase 2 data) 
 
The safety profile of ipilimumab at a dose of 10 mg/kg was characterized in a total of 
325 subjects who received multiple doses of 10 mg/kg ipilimumab as monotherapy in the 4 
completed melanoma studies (CA184004, -007, -008, and -022). (49, 50, 51, 52) Overall, the 
incidence of Grade 3/4 AEs attributable to study drug was 31%. The target organ system, the 
incidence and the severity of the most commonly observed irAEs are displayed in Table 4. 
 
Table 4: 
Summary of irAE Safety Data for 10 mg/kg in Melanoma 
 
Total 
Low-grade 
(Grade 1 - 2) (%) 
High-grade 
(Grade 3 - 4) (%) 
Median Time to 
Resolution of 
Grade 2 - 4 irAEs 
(weeks) 
All irAEs 
72.3 
46.2 
25.2 
- 
Skin (eg, rash, pruritus) 
52.0 
49.2 
2.8 
6.14 
GI (eg, colitis, diarrhea) 
37.2 
24.9 
12.3 
2.29 
Liver (eg, LFT elevations) 
8.0 
0.9 
6.8 
4.0 
Endocrine (eg, hypophysitis, 
hypothyroid) 
6.2 
3.7 
2.5 
20.1 
 
Overall, the 10 mg/kg had an acceptable safety regimen, while being the most active dose. The 
study drug related deaths across the program are in Section 5 of the investigators brochure. 
 
Across clinical studies that utilized ipilimumab doses ranging from 0.3 to 10 mg/kg, the 
following adverse reactions were also reported (incidence less than 1% unless otherwise noted): 
urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal 
failure, and infusion reaction. 
 
Based on the experience in the entire clinical program for melanoma, the incidence and severity 
of enterocolitis and hepatitis appear to be dose dependent. 
 
 
 


27 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
1.8.2  Immunogenicity 
In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against 
ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial 
limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-
related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not 
reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected. 
Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was 
performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable 
patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against 
ipilimumab. 
Immunogenicity assay results are highly dependent on several factors including assay sensitivity 
and specificity, assay methodology, sample handling, timing of sample collection, concomitant 
medications, and underlying disease. For these reasons, comparison of incidence of antibodies to 
ipilimumab with the incidences of antibodies to other products may be misleading. 
 
1.8.3  Pregnancy Outcomes 
Based on animal data, ipilimumab may cause fetal harm. The use of ipilimumab during human 
pregnancy has not been formally studied in clinical trials. There have been 7 known pregnancies 
during ipilimumab treatment: in 3 female subjects and in the partners of 4 male study subjects. 
Two (2) of the 3 female pregnancies ended with elected terminations. The third female subject 
had a history of seizures and delivered the baby at 36 weeks gestation. The baby had respiratory 
complications that resolved by birth week 16. Three (3) of the 4 partners of male study subjects 
had full term, normal babies. The fourth baby had small ureters, which are expected to grow as 
the baby matures. Although these outcomes do not indicate that stillbirths or other severe 
abnormalities will occur, pregnancy should be avoided during treatment with ipilimumab. 
 
 
1.8.4 Immune-mediated Adverse Reactions with Ipilimumab  
Ipilimumab can result in severe and fatal immune-mediated reactions due to T-cell activation and 
proliferation. 
 
 


28 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Immune-related Gastrointestinal Events 
The clinical presentation of GI immune-related AEs included diarrhea, increase in the frequency 
of bowel movements, abdominal pain, or hematochezia, with or without fever. Fatalities due to 
GI perforation have been reported in clinical trials of ipilimumab. Patients should be carefully 
monitored for GI symptoms that may be indicative of immune-related colitis, diarrhea, or GI 
perforation. Diarrhea or colitis occurring after initiation of ipilimumab therapy should be 
evaluated to exclude infectious or alternate etiologies. In clinical trials, immune-related colitis 
was associated with evidence of mucosal inflammation, with or without ulcerations, and 
lymphocytic infiltration. 
Immune-related Hepatotoxicity 
Hepatic immune-related AEs were mostly clinically silent and manifested as transaminase or 
bilirubin laboratory abnormalities. Fatal hepatic failure has been reported in clinical trials of 
ipilimumab. Serum transaminase and bilirubin levels must be evaluated before each dose of 
ipilimumab as early laboratory changes may be indicative of emerging immune-related hepatitis. 
Elevations in liver function tests (LFTs) may develop in the absence of clinical symptoms. 
Increase in LFT or total bilirubin should be evaluated to exclude other causes of hepatic injury, 
including infections, disease progression, or medications, and monitored until resolution. Liver 
biopsies from patients who had immune-related hepatotoxicity showed evidence of acute 
inflammation (neutrophils, lymphocytes, and macrophages). 
Immune-related Skin Toxicity 
Skin immune-related AEs presented mostly as a rash and/or pruritus. Some subjects reported 
vitiligo associated with ipilimumab administration. Fatal toxic epidermal necrolysis has been 
reported in clinical trials of ipilimumab.  
Immune-related Endocrinopathy 
Ipilimumab can cause inflammation of the endocrine system organs, specifically hypophysitis, 
hypopituitarism, and adrenal insufficiency and patients may present with nonspecific symptoms, 
which may resemble other causes such as brain metastasis or underlying disease. The most 
common clinical presentation includes headache and fatigue. Symptoms may also include visual 
field defects, behavioral changes, electrolyte disturbances, and hypotension. Adrenal crisis as a 
cause of the patient’s symptoms should be excluded. Based on the available data with known 
outcome, most of the subjects symptomatically improved with hormone replacement therapy. It 
is possible that long-term hormone replacement therapy will be required for subjects developing 
hypophysitis/hypopituitarism after treatment with ipilimumab. 
 


29 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Immune-related Neurological Events 
Neurological manifestations included muscle weakness and sensory neuropathy. Fatal Guillain-
Barré syndrome has been reported in clinical trials of ipilimumab. Patients may present with 
muscle weakness. Sensory neuropathy may also occur. Unexplained motor neuropathy, muscle 
weakness, or sensory neuropathy lasting more than 4 days should be evaluated and non-
inflammatory causes such as disease progression, infections, metabolic syndromes, and 
medications should be excluded. 
Other Immune-related AEs 
Ocular inflammation, manifested as Grade 2 or Grade 3 episcleritis or uveitis, was associated 
with concomitant diarrhea in a few subjects (< 1%) and occasionally occurred in the absence of 
clinically apparent GI symptoms. Other presumed immune-related AEs reported include, but 
were not limited to, arthritis/arthralgias, pneumonitis, pancreatitis, autoimmune (aseptic) 
meningitis, autoimmune nephritis, pure red cell aplasia, noninfective myocarditis, polymyositis, 
and myasthenia gravis, of which were individually reported for < 1% of subjects.  
Overall, immune-related AEs commonly started within 3 to 10 weeks from first dose, were 
successfully managed in most instances by omitting doses, discontinuing dosing, and/or through 
administering symptomatic or immunosuppressive therapy, including corticosteroids, as 
mentioned above and detailed in Section 11. Immune-related AEs generally resolved within days 
to weeks in the majority of subjects.  
 
1. 85    Ipilimumab and Growth Factor Support 
Phase I data observed it was safe to combine ipilimumab with the hematopoietic growth factor, 
granulocyte macrophage colony-stimulating factor (GM-CSF), sargramostim. Ipilimumab was 
escalated from 0.5 to 3 mg/kg q 4 weeks with GM-CSF subcutaneous at fixed dose 250mcg/m2 
for 14 days each cycle. Ipilimumab was successfully escalated to 3 mg/kg where 2/6 grade 3 
irAEs were observed: 1 pan-hypopituitarism, 1 diarrhea. Both irAEs were easily treated. 1 grade 
3 temporal arteritis was also observed unknown if related to ipilimumab? Interestingly, immune 
induced antitumor T cells were observed at highest dose and tumor response >50% drop in PSA 
was observed only in patiens with grade 3 irAEs.(58) 
 
1.9   Clinical Efficacy: Melanoma Program 
The clinical efficacy of ipilimumab as a single agent at a dose of 3 mg/kg administered every 3 
weeks for 4 doses has been established in MDX010-20 (a randomized, controlled study in 
second line, locally advanced/metastatic melanoma), which led to approval of ipilimumab by the 


30 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
FDA for the treatment of unresectable or metastatic melanoma. In study CA184024, the addition 
of 10 mg/kg ipilimumab to dacarbazine led to a prolongation of overall survival in patients with 
previously untreated melanoma and was feasible with an acceptable safety profile. 
Overall survival and other efficacy endpoints were assessed in ipilimumab studies. 
Overall Survival: Prolongs survival in patients with metastatic melanoma who have failed prior 
treatment. 
Best Objective Response Rate (BORR): By the conventional mWHO criteria confirmed 
objective responses have been observed in subjects receiving ipilimumab. These responses tend 
to be durable with the majority of subjects who achieve objective responses progression-free at 
the end of long observation periods. 
Disease Control Rate (DCR): Disease stabilization in subjects receiving ipilimumab is a key 
characteristic of anti-tumor activity. Stable disease, sometimes of long duration, or slow steady 
decline of tumor lesion size over long periods of time, has been observed. Consequently, SD as 
well as objective responses (both captured in DCR) are important for completely characterizing 
anti-tumor activity of ipilimumab 
Progression-Free Survival (PFS): Some subjects demonstrate initial tumor volume increase 
before response, possibly due to T-cell infiltration as shown by biopsies. Consequently, PFS 
incompletely captures all patterns of activity and may underestimate the clinical activity of 
ipilimumab. 
 
1.9.1   Rationale for Using Immune-Related Tumor Assessment   
Ipilimumab is an immuno-stimulating antibody with evidence of anti-cancer activity (durable 
objective response and stable disease) in subjects with advanced melanoma, including subjects 
with established brain disease. Observations of clinical activity defined by tumor response 
endpoints defined by conventional criteria (eg, mWHO) may be inadequate to realize the kinetics 
and magnitude of clinical benefit achieved with ipilimumab. 
Histopathologic evidence has demonstrated ipilimumab can produce an influx or expansion of 
tumor infiltrating lymphocytes. Therefore, early increases in lesion size detected radiologically 
or upon gross examination could be misinterpreted as progressive tumor growth and precede 
objective tumor shrinkage. In addition the appearance of new lesions may have categorized a 
subject to have progressive disease using conventional tumor assessment criteria despite the 
concurrent observation of objective tumor responses in pre-existing lesions and a net reduction in 
global tumor burden that includes the new lesions. 


31 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Therefore, patients with evidence of possible target lesion growth or new lesion appearance will 
not be presumed to have progressed and will proceed to surgery as long as all possible sites of 
disease are deemed resectable by the surgeon. 
 
1.9.2   MDX010-20 (Phase 3, 3 mg/kg, previously treated melanoma) 
MDX010-20, 
a 
randomized 
(3:1:1), 
double-blind, 
double-dummy 
study 
included 
676 randomized subjects with unresectable or metastatic melanoma previously treated with one 
or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. 
Of these 676 subjects, 403 were randomized to receive ipilimumab at 3 mg/kg in combination 
with an investigational peptide vaccine with incomplete Freund’s adjuvant (gp100), 137 were 
randomized to receive ipilimumab at 3 mg/kg, and 136 were randomized to receive gp100 alone. 
The study enrolled only subjects with HLA A2*0201 genotype; this HLA genotype facilitates 
the immune presentation of the investigational peptide vaccine. The study excluded subjects with 
active autoimmune disease or those receiving systemic immunosuppression for organ 
transplantation. Ipilimumab/placebo was administered at 3 mg/kg as an intravenous infusion 
every 3 weeks for 4 doses. Gp100/placebo was administered at a dose of 2 mg peptide by deep 
subcutaneous injection every 3 weeks for four doses. Assessment of tumor response was 
conducted at Weeks 12 and 24, and every 3 months thereafter. Subjects with evidence of 
objective tumor response at 12 or 24 weeks had assessment for confirmation of durability of 
response at 16 or 28 weeks, respectively.(48) 
The major efficacy outcome measure was overall survival (OS) in the ipilimumab + gp100 arm 
compared to that in the gp100 arm. Secondary efficacy outcome measures were OS in the 
ipilimumab + gp100 arm compared to the ipilimumab arm, OS in the ipilimumab arm compared 
to the gp100 arm, best overall response rate (BORR) at Week 24 between each of the study arms, 
and duration of response.  
Of the randomized subjects, 61%, 59%, and 54% in the ipilimumab + gp100, ipilimumab, and 
gp100 arms, respectively, were men. Twenty-nine (29%) percent were  65 years of age, the 
median age was 57 years, 71% had M1c stage, 12% had a history of previously treated brain 
metastasis, 98% had ECOG performance status of 0 and 1, 23% had received aldesleukin and 
38% had elevated LDH level. Sixty-one (61%) percent of subjects randomized to either 


32 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
ipilimumab -containing arm received all 4 planned doses. The median duration of follow-up was 
8.9 months. 
 
 
The OS results are shown in Table 5 and Figure 2. 
Table 5: 
MDX010-20 Overall Survival Results 
 
Ipilimumab 
n = 137 
Ipilimumab + gp100 
n = 403 
gp100 
n = 136 
Hazard Ratio (vs gp100) 
 
(95% CI) 
0.66 
(0.51, 0.87) 
0.68 
(0.55, 0.85) 
 
 
p-value 
p = 0.0026a 
p = 0.0004 
 
Hazard Ratio (vs ipilimumab) 
 
(95% CI) 
 
1.04 
(0.83, 1.30) 
 
Median (months) 
 
(95% CI) 
10 
(8.0, 13.8) 
10 
(8.5, 11.5) 
6 
(5.5, 8.7) 
a Not adjusted for multiple comparisons. 
 
Figure 2: 
MDX010-20 - Overall Survival by Treatment (ITT Population) 
 


33 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
The best overall response rate (BORR) as assessed by the investigator was 5.7% (95% CI: 3.7%, 
8.4%) in the ipilimumab + gp100 arm, 10.9% (95% CI: 6.3%, 17.4%) in the ipilimumab arm, 
and 1.5% (95% CI: 0.2%, 5.2%) in the gp100 arm. The median duration of response was 11.5 
months in the ipilimumab + gp100 arm and has not been reached in the ipilimumab or gp100 
arm. 
1.9.3   CA184024 (Phase 3, previously untreated melanoma, 10 mg/kg) 
CA184024 evaluated the addition of 10 mg/kg ipilimumab to dacarbazine in patients with 
previously untreated, metastatic melanoma. A total of 502 patients were randomized to receive 
up to 8 cycles of dacarbazine 850 mg/m2 q3w, with either ipilimumab 10 mg/kg or placebo 
cycles 1-4, and as maintenance after completion of chemotherapy.  
The two arms were well balanced regarding most baseline characteristics, as shown in Table 6. 
Table 6: 
CA184024 Baseline Characteristics 
 
Ipilimumab + DTIC 
n = 250 
Placebo + DTIC 
n = 252 
Age (years) 
 
 
 Mean 
57.5 
56.4 
Gender (%) 
 
 
 Male 
60.8 
59.1 
 Female 
39.2 
40.9 
M Stage (%) 
 
 
 M0 
2.4 
3.2 
 M1a 
14.8 
17.1 
 M1b 
25.6 
24.6 
 M1c 
57.2 
55.2 
ECOG PS (%) 
 
 
 0 
70.8 
71.0 
 1 
29.2 
29.0 
LDH (%) 
 
 
  ULN  
62.8 
55.6 
 > ULN  
37.2 
43.7 
  2x ULN 
86.4 
85.3 
 > 2x ULN 
13.6 
13.9 
Prior adjuvant therapy (%) 
26.4 
26.6 
Prior therapy for advanced disease (%) 
0 
0 
 


34 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Patients on the ipilimumab arm received a median of 3 ipilimumab induction doses, versus 4 
placebo induction doses on the placebo arm. A total of 17.4% and 21.1% of patients continued to 
receive maintenance ipilimumab or placebo, for a median of 4 and 2 doses, respectively. The 
number of patients who received all 8 dacarbazine doses was 12.2% in the ipilimumab arm, and 
21.5% in the placebo arm. 
The study met its primary end-point of prolonging overall survival in patients treated with 
ipilimumab (HR 0.72 (95% CI, 0.59 – 0.87), median OS 11.2 vs 9.1 months, p = 0.0009). The 
OS Kaplan-Meier curve is presented in Figure 3. 
 
 
Figure 3: 
CA184024 Kaplan-Meier Plot of Overall Survival - All Randomized 
Subjects 
 
 
One, two and three-year survival rates were 47.3%, 28.5% and 20.8% in the ipilimumab arm, 
and 36.3%, 17.9% and 12.2% in the placebo arm. 
PFS, a secondary end-point, was also prolonged by the addition ipilimumab, HR 0.76 (95% CI, 
0.63 - 0.93). The median PFS was 2.8 months in the ipilimumab and vs 2.6 months in the 
placebo arm, p = 0.006. 
 BORR was increased from 10.3% in the placebo arm to 15.2% in the ipilimumab arm (Table 7). 
More importantly, duration of response was more than twice as long in the ipilimumab arm (19.3 
months) than in the placebo arm (8.1 months). 
PROPORTION ALIVE
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
Ipilimumab + DTIC 
Placebo + DTIC 
Months 


35 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Table 7: 
CA184024 Tumor Response 
 
Ipilimumab + DTIC 
n = 250 
Placebo + DTIC 
n = 252 
Disease Control Rate, n (%) 
83 (33.2) 
76 (30.2) 
BORR (CR + PR), n (%) 
38 (15.2) 
26 (10.3) 
 Complete response 
4 (1.6) 
2 (0.8) 
 Partial response 
34 (13.6) 
24 (9.5) 
 Stable disease 
45 (18.0) 
50 (19.8) 
 Progressive disease 
111 (44.4) 
131 (52.0) 
Duration of response, months 
19.3 
8.1 
 
1.9.4   10 mg/kg Dosing with Ipilimumab 
In melanoma, Phase 3 studies show improved survival at both 3 mg/kg (study MDX010-20) as 
well as with 10 mg/kg (study CA184024). Several additional conducted trials studied the 
efficacy and safety of 10 mg/kg dosing, and additional information gained from these trials is 
listed below: 
 A dose of 10 mg/kg is necessary to ensure a blockade of the CTLA-4 pathway: in vitro a 
concentration of 20 g/mL of ipilimumab was the minimal concentration able to fully 
abrogate the binding of CTLA-4 to B7.1 and B7.2. With a dose of 3 mg/kg q3w 30% 
achieved a trough concentration of ipilimumab greater than 20 g/mL, compared to 95% of 
subjects treated at 10 mg/kg q3w. 
 In addition, in all ipilimumab trials examined to date, mean Absolute Lymphocyte Count 
(ALC) increased after ipilimumab treatment throughout the 12-week induction-dosing 
period, in a dose-dependent manner. In an analysis of ipilimumab at 0.3, 3, or 10 mg/kg in 
melanoma studies CA184007, CA184008, and CA184022 combined, the rate of change in 
ALC after ipilimumab treatment was significantly associated with dose (p = 0.0003), with the 
largest rate at 10 mg/kg ipilimumab. Moreover, the rate of change in ALC over the first half 
of the induction-dosing period was significantly associated with clinical activity in these 
studies (p = 0.009), where clinical activity was defined as CR, PR, or prolonged SD (ie, SD 
lasting at least 6 months from first dose). Although these analyses alone could not determine 
whether the rate of change in ALC was specifically associated with clinical activity in 
response to ipilimumab treatment, as opposed to being generally prognostic, these results do 
suggest a potential benefit to higher rates of ALC increase after ipilimumab treatment.  
 
 
In the three primary studies conducted in advanced melanoma (CA184007, CA184008, and 
CA184022), subjects treated with 10 mg/kg during the induction period had the highest response, 
disease control rates, median OS as well as 1-year and 2-year survival rates compared to other 


36 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
doses. The CA184022 data are summarized in Table 8. (52) Among the 3 doses evaluated, 10 
mg/kg ipilimumab led to the greatest such rates. 
 
 
Table 8: 
Summary of Phase 2 Response Data in Melanoma (CA184022) 
 
10 mg/kg 
(n = 72) 
3 mg/kg 
(n = 72) 
0.3 mg/kg 
(n = 73) 
BORR (mWHO) – % 
(95% CI) 
11.1 
(4.9 - 20.7) 
4.2 
(0.9 - 11.7) 
0 
(0.0 - 4.9) 
DCR (mWHO) – % 
(95% CI) 
29.2 
(19.0 - 41.1) 
26.4 
(16.7 - 38.1) 
13.7 
(6.8 - 23.8) 
Survival rate at 1 year - % 
%, 95% CI 
48.64 
(36.84, 60.36) 
39.32 
(27.97, 50.87) 
39.58 
(28.20, 51.19) 
Survival rate at 2 year - % 
%, 95% CI 
29.81 
(19.13, 41.14) 
24.20 
(14.42, 34.75) 
18.43 
(9.62, 28.22) 
Overall median survival 
95%CI (months) 
11.43 
(6.90, 16.10) 
8.74 
(6.87, 12.12) 
8.57 
(7.69, 12.71) 
 
Finally, the dose and schedule in study CA184156 is the one that was evaluated in the signal 
finding study CA184041, with an acceptable safety profile and improvement of irPFS and OS. 
Treatment with ipilimumab has demonstrated clinically important and durable tumor responses 
in several malignancies including melanoma, prostate cancer, and renal cell carcinoma. 
 
 
1.9.5    Advanced Melanoma 
Ipilimumab prolonged survival in subjects with pre-treated advanced melanoma are based on 
results from MDX010-20 (Phase 3) supported by data from Phase 2 studies; the primary efficacy 
and safety studies are summarized in Table 9. (48, 49, 50, 52, 53, 54, 55, 56) The primary 
endpoint in MDX010-20 was OS, which was also a key secondary endpoint in Phase 2 studies.  
 
 


37 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Table 9: 
Studies Supporting the Efficacy and Safety of Ipilimumab in 
Subjects with Advanced Melanoma 
 
 
 
 
# Randomized or Enrolled/Treated 
Study No. 
(Phase) 
Populations 
Primary 
Efficacy 
Endpoint 
Doses Studies 
3 mg/kg 
10 
mg/kg 
Total 
MDX010-20 
(Phase 3) 
HLA-
A2*0201-
positive, 
previously 
treated, 
unresectable 
Stage III or 
IV 
melanoma 
OS 
3 mg/kg q3 wk x 
4  gp100 
(induction) 
followed by re-
induction  
540/512 
--/-- 
676/643a 
CA184022 
(Phase 2)  
Previously 
treated, 
unresectable 
Stage III or 
IV 
melanoma  
BORR 
0.3, 3, or 10 
mg/kg q3 wk x 4 
(induction) 
followed by 
maintenance 
dosing q12 wk 
72/71 
72/71 
217/214 
CA184004 
(Phase 2) 
Biomarker 
Study 
Unresectable 
Stage III or 
IV 
melanoma  
BORR 
3 or 10 mg/kg q3 
wk x 4 (induction) 
followed by 
maintenance 
dosing q12 wk 
40/40 
42/42 
82/82 
CA184008 
(Phase 2)  
Previously 
treated 
unresectable 
State III or 
IV 
melanoma 
BORR 
10 mg/kg q3 wk x 
4 (induction) 
followed by 
maintenance 
dosing q12 wk 
--/-- 
155/155 
155/155 
CA184007 
Unresectable 
Stage III or 
IV 
melanoma 
BORR 
10 mg/kg q3 wk x 
4  budesonide 
(induction) 
followed by 
maintenance 
dosing q12 wk 
--/-- 
115/115 
115/115 
Additional Studies  
MDX010-
08(Phase 2) 
Chemothera
py-naive 
advanced 
melanoma 
ORR 
3 mg/kg q4 
wk x 4  
DTIC 
(induction) 
78/74 
--/-- 
78/74 
CA184042 
(Phase 2) 
Stage IV 
melanoma 
with brain 
metastases 
DCR 
10 mg/kg q3 
wk x 4 
(induction) 
followed by 
maintenance 
--/-- 
28/28b 
28/28b 


38 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Table 9: 
Studies Supporting the Efficacy and Safety of Ipilimumab in 
Subjects with Advanced Melanoma 
 
 
 
 
# Randomized or Enrolled/Treated 
dosing q12 
wk 
MDX010-28 
(Phase 2) 
Survival 
Follow-up 
Study 
Subjects 
enrolled in 
earlier 
Medarex 
studies, 
including 
MDX010-08 
and 
MDX010-
15c 
OS 
N/A 
--/N/A 
--/NA 
--/N/A 
BORR = best overall response rate; DCR = disease control rate; DTIC = dacarbazine; N/A = not applicable; ORR = 
overall response rate; OS = overall survival; PK = pharmacokinetics. 
a Total includes 136 randomized/131 treated subjects in the gp100 treatment group. 
b Information is presented only for subjects enrolled in MDX010-20, Arm A. 
c MDX010-15 was primarily a PK study that evaluated ipilimumab at single and multiple doses.  
Source:   
 
2.0 
  Overall Risk/Benefit Assessment 
Ipilimumab is the first drug to demonstrate prolonged survival in subjects with pre-treated 
advanced melanoma, based on a large, multinational, double-blind, pivotal, Phase 3 study 
supported by a comprehensive Phase 2 program.  
The unique immune-based mechanism of action is reflected in the clinical patterns of anti-cancer 
activity in some patients. Ipilimumab impacts tumor cells indirectly, 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 subjects who are not 
experiencing rapid clinical deterioration, confirmation of progression is recommended, at the 


39 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
investigator’s discretion, to better understand the prognosis as well as to avoid unnecessarily 
initiating potentially toxic alternative therapies in subjects who might be benefitting from 
treatment. Immune-related (ir) 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 slow, steady decline in tumor burden over many months, sometimes improving 
to partial and/or complete responses. Thus, the immune-based mechanism of action of 
ipilimumab results in durable disease control, sometimes with novel patterns of response, which 
contribute to its improvement in OS. 
The immune-based mechanism of action is also reflected in the safety profile. The most common 
drug-related AEs are immune-mediated, consistent with the mechanism of action of the drug and 
generally medically manageable with topical and/or systemic immunosuppressants. As 
previously discussed, the immune-mediated adverse reactions primarily involve the GI tract, 
skin, liver, endocrine glands, and nervous system. 
The early diagnosis of immune-mediated adverse reactions is important to initiate therapy and 
minimize complications. Immune-mediated adverse reactions are generally manageable using 
symptomatic or immunosuppressive therapy as recommended through detailed diagnosis and 
management guidelines, as described fully in the current IB. The management guidelines for 
general immune-mediated adverse reactions and ipilimumab-related GI toxicities, hepatotoxicity, 
endocrinopathy, and neuropathy are provided in the appendices of the current IB.  
In summary, ipilimumab offers clinically meaningful and statistically significant survival benefit 
to patients with pre-treated advanced melanoma 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-
mediated toxicities, suggest an acceptable benefit to risk ratio. In this trial, ipilimumab has the 
potential to have additive therapeutic benefit with standard NSCLC chemotherapy by enhancing 
anti-tumor immune activity. The overall risk-benefit ratio for patients entering this protocol is 
therefore at least comparable to and possibly better than alternative options. 


40 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
 
3.0  OBJECTIVES 
 
3.1 
 Primary objective:  
Evaluate whether the combination of neoadjuvant chemotherapy plus ipilimumab for lung cancer 
increases the number of subjects with detectable circulating T cells with specificities against 
tumor associated antigens (TAA) from zero percent of subjects prior to therapy to 20% of 
subjects after neoadjuvant chemotherapy plus ipilimumab. 
 
3.2 
Secondary Objectives: 
1. 
Evaluate feasibility/tolerability of neoadjuvant chemotherapy plus ipilimumab and 
surgery in early stage NSCLC. 
2. 
Evaluate disease-free survival and patterns of metastases after neoadjuvant chemotherapy 
plus ipilimumab in early stage NSCLC. 
3. 
Evaluate the relationship between pathologic response and the RECIST response after 
neoadjuvant chemotherapy and ipilimumab. 
 
3.3 
Exploratory Objectives: (refer to Appendix B for further detail) 
1. 
Determine the percentage of patients with detectable tumor infiltrating lymphocytes 
(TILs) after neoadjuvant chemotherapy plus ipilimumab. 
2. 
Estimate the rate of pathologic response rate for neoadjuvant chemotherapy plus 
ipilimumab in early stage NSCLC. 
3. 
Estimate the objective response rate of neoadjuvant chemotherapy and ipilimumab in 
early stage NSCLC. 
4. 
Determine if the immunomodulatory effects of neoadujvant chemotherapy plus 
ipilimumab impact the suppressive mechanisms, restoring functional reactivity to 
important anti-tumor effector cell populations. 
5. 
Explore an alternative definition for detectability suitable for expression values and 
determining the percentage of patients with circulating T cells meeting this definition. 
6. 
Evaluate whether presence, quantity or quality of detectable TILs is associated with 
pathologic response rate to neoadjuvant therapy. 
 
 
4.0  
STUDY PLAN / DESIGN 
 
Standard diagnostic and staging work up will be performed including: pathologic/histologic 
diagnosis of non-small cell lung cancer, PET/CT scan, brain imaging, and mediastinoscopy.  Three 
cycles of neoadjuvant chemotherapy will be given. Ipilimumab will be added to neoadjuvant 
chemotherapy for cycles 2 and 3. Standard surgical evaluation and therapy will be performed 
following completion of neoadjuvant therapy. Two cycles of single agent ipilimumab will be given 
after surgery (adjuvantly), followed by 2 cycles of maintenance therapy.  


41 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
  
Neoadjuvant: 
Cycle 1: Paclitaxel 175 mg/m2  IV over 3 hours followed by  cisplatin 75 mg/m2   over 60 minutes or 
carboplatin AUC 6 over 30-60 minutes on day 1 (every 21 days x 1 cycle)  
 
Cycles 2 and 3: Ipilimumab 10mg/kg IV over 90 minutes, Paclitaxel 175 mg/m2 over 3 hours 
followed by cisplatin 75 mg/m2 or carboplatin AUC 6 IV over 30-60 minutes (every 21 days x 2 
cycles). 
  
Surgery: 
Standard surgical evaluation to occur at least 21 days after the last dose (cycle 3) of 
chemotherapy followed by surgical therapy.  
 
 
Post-surgical Therapy: (Total of 4 doses of ipilimumab will be given post-operatively): 
 
Adjuvant: Ipilimumab 10 mg/kg IV every 3 weeks  x 2 doses, beginning 4 weeks postoperative  
(up to 10 weeks if needed for recovery) 
Maintenance: Ipilimumab 10 mg/kg IV every 12 weeks x 2 doses. 
 
Correlative Science Measures (refer to Appendix B for further details on the correlative science 
outcomes) 
1. 
Peripheral blood mononuclear cells (PBMC) isolated from freshly drawn anti-coagulated blood 
will be analyzed for circulating T cells with specificities against tumor-associated antigens 
(TAA) at 4 time points, namely 1) Baseline prior to treatment, 2) cycle 2, prior to 
ipilimumab therapy, 3) 21-36 days after completion of cycle 3 chemotherapy prior to 
surgery, and 4) 3-6 weeks after adjuvant ipilimumab dose #2. Additionally, PBMC from each 
of the time points will be analyzed for the presence of circulating populations of regulatory T 
cells, myeloid-derived suppressor cells (MDSC), as well as activated and exhausted T cells. 
2. 
Tumor infiltrating lymphocytes (TILs) will be isolated from the patient’s resected tumor and 
analyzed for infiltrating T cells with specificities against tumor-associated antigens. 
Additionally, TIL will be analyzed for the presence of infiltrating populations of regulatory T 
cells, myeloid-derived suppressor cells (MDSC), as well as activated and exhausted T cells. 
 
 
5.0 
 Recruitment 
 
Patients will be recruited for this study as follows: Upon determination that a patient’s tumor histology 
and/or radiographic findings are compatible with the eligibility criteria of this protocol, the clinical study 
will be briefly explained to the patient by the principal investigator (PI) or colleague. If the patient 
indicates interest in study participation, patient education sheets (if available) and possibly the approved 
protocol consent form will be provided to the patient as these provide the most comprehensive 
explanation of the study in lay terms. If the patient shows continued interest, the PI or designee will 
thoroughly explain the required elements of informed consent and all aspects of the study to the patient 
including inclusion/exclusion criteria, risks, benefits and alternatives to study participation. 


42 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
6.0  
Study Population/Selection of Patients 
The following guidelines are to assist physicians in selecting patients for whom protocol therapy is safe 
and appropriate.  Physicians should consider the risks and benefits of any therapy, and therefore only 
enroll patients for whom this treatment is appropriate.   For entry into the study, the following criteria 
MUST be met. 
 
6.1. Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following criteria: 
 
1. Histologically or cytologically documented NSCLC. 
 
2. Clinical stage IB (≥4cm per CT), Stage IIA/IIB, or Stage III (N0-2) amenable to surgical resection.  
 
3.  Patient must be deemed a surgical candidate. 
 
4.   ECOG performance status of 0 or 1 (Appendix C). 
 
5.   NO prior chemotherapy for current diagnosis of lung cancer. 
 
6. Age ≥18 years. 
 
7. No active invasive malignancy in the past 2 years other than non-melanoma skin cancer. Cancers 
that are in-situ are not considered invasive. 
 
8. Signed written informed consent including HIPAA according to institutional guidelines. 
 
9. Adequate Organ Function:  
 ANC or AGC ≥1500 per uL 
 Platelets ≥100,000 per uL 
 Total bilirubin ≤  1.5 mg/dL 
 creatinine clearance ≥45mL/min (Appendix D); (Creatinine <2 mg/dL to receive cisplatin) 
 SGOT/SGPT ≤2.5x institutional ULN.  
 
10. 
Females of child-bearing potential (not surgically sterilized and between menarche and 1 year 
post menopause) must test negative for pregnancy within 48  hours  prior to  any initial study 
procedure based on a serum pregnancy test. Both sexually active males and females of 
reproductive potential must agree to use a reliable method of birth control, as determined by the 
patient and their health care team, during the study and for 3 months following the last dose of 
study drug. If subject uses appropriate contraceptive methods (the use of two forms at the same 
time) from the time of the initial serum pregnancy test, then the subsequent pregnancy test can be 
done within 72 hours of receiving study drug administration. If appropriate contraceptive 
measures are not begun immediately with the first serum pregnancy test, then subsequent serum 
pregnancy tests must be done within 48 hours prior to the study drug administration.   
 
11.    Patients must agree to research blood sampling to participate in study. 


43 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
6.2. Exclusion Criteria 
 
Patients will be excluded from the study if they meet any of the following criteria: 
 
1. Treatment within the last 30 days with a drug that has not received regulatory approval for any 
indication at the time of study entry. 
 
2. Concurrent administration of any other anti-tumor therapy. 
 
3. Inability to comply with protocol or study procedures. 
 
4. Active infection requiring IV antibiotics, antifungal or antiviral agents, that in the opinion of the 
investigator would compromise the patient’s ability to tolerate therapy.  
 
5. Major surgery (other than definitive lung cancer surgery) within two weeks of study or other serious 
concomitant systemic disorders that, in the opinion of the investigator, would compromise the safety 
of the patient or compromise the patient’s ability to complete the study. 
 
6. Myocardial infarction having occurred less than 6 months before inclusion, any known uncontrolled 
arrhythmia, symptomatic angina pectoris, active ischemia, or cardiac failure not controlled by 
medications. 
  
7.  Contraindication to corticosteroids. 
 
8.  Unwillingness to stop taking herbal supplements while on study. 
 
9.  Female patients who are pregnant or breast-feeding.  
     10. Autoimmune disease. Patients with a history of inflammatory bowel disease, including  
ulcerativecolitis and Crohn’s Disease, are excluded from this study, as are patients with a history of 
symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], 
systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener’s Granulomatosis]); motor 
neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia 
Gravis). 
     11. Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month  
before or after any dose of ipilimumab). 
      12. A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4 inhibitor or  
agonist. 
       13. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of   
either psychiatric or physical (e.g., infectious) illness. 
 
 


44 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
6.3   Protocol Eligibility Waivers 
 
No waivers of inclusion or exclusion criteria will be granted.  All prospective patients must meet all 
entry criteria prior to enrollment in the study.  If there are any questions regarding the interpretation of a 
criterion for a potential patient, contact the principal investigator to discuss the potential patient to 
confirm eligibility. 
 
7.0   Inclusion of Women and Minorities 
 
There are no exclusions based on gender, race or ethnicity in this trial. There is no evidence to suggest 
that outcomes will differ. 
 
 
8.0   Registration Procedure 
 
Patient registration for all patients signing informed consent will be completed through the Duke Cancer 
Institute (DCI) Clinical Research Unit (CRU) into eResearch (DOCR).  The investigator and/or designee 
will enter the patient information into the DOCR Subject Registry within 1 business day of obtaining 
consent.  Patients will be enrolled only after all pre-treatment evaluations are completed and all 
eligibility criteria are met.  
 
 
9.0 
Study Periods 
For the purpose of scheduling evaluations and to allow for patient and investigator schedules, holidays 
and weather or other emergencies requiring clinical facilities to be closed, all patient visits can be 
performed ±3 days of scheduled visits. 
 
 
9.1 
Screening 
 
The following procedures and tests are to be performed within 30 days (unless otherwise specified) of 
study enrollment to confirm eligibility. Baseline and Cycle 1 Day 1 procedures may be completed on the 
same day. However, screening assessments for eligibility MUST have already been determined. Refer to 
appendix A for details. 
 Informed Consent  


45 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 Medical history including demographics/smoking history 
 Height and weight (BSA calculation) 
 Vital signs (temp, B/P, pulse) 
 Performance status 
 Physical exam 
 Routine blood work   
 Thyroid Functions  
 Negative Pregnancy test  for WOCBP only 
 EKG 
 Tumor Histology 
 Staging PET/CT  of chest/abdomen, Brain MRI or CT (as per standard of care) These may be 
obtained within 42 days 
 Tumor measurements 
 
Additional Studies: 
 Pretreatment blood will be collected to assess activated CD8+ T cells with specificity against 
tumor antigens and CD4 and CD8 functional memory. 4 tubes of 8.5-ml each will be 
collected. The tubes used will be ACD anti-coagulated Vacutainer (yellow tops) and will be 
processed by Dr. Weinhold’s lab. 
 
  9.2 Treatment Study Day 1 Cycle 1 Neoadjuvant Chemothearpy  
          (to be performed prior to receiving treatment) 
 Weight (BSA calculation) 
 Creatinine Clearance 
 Vital signs (temp, B/P, pulse) 
 Performance status 
 Physical exam 
 Adverse events assessments 
 Routine blood work  
 Pregnancy test ≤ 3 days (72 hrs) prior to first dose of ipilimumab (for WOCBP only)  
 Chemotherapy infusion 
 
 
9.3 
Treatment Study Day 1  Cycle 2  Neoadjuvant Chemotherapy 
 Weight (BSA calculation)  
 Creatinine Clearance 
 Vital signs (temp, B/P, pulse) 


46 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 Performance status 
 Physical Exam 
 Adverse events Assessment 
 Routine blood work 
 Dose # 1 Ipilimumab  
 Chemotherapy infusions 
 Pregnancy test ≤ 3 days (72 hrs) prior to first dose of ipilimumab (for WOCBP only)  
 Research blood will be collected to assess activated CD8+ T cells with specificity against 
tumor antigens and CD4 and CD8 functional memory. 4 tubes of 8.5-ml each will be 
collected. The tubes used will be ACD anti-coagulated Vacutainer (yellow tops) and will be 
processed by Dr. Weinhold’s lab.  To be collected prior to receiving ipilimumab. 
 
 
9.4 
Treatment Study Day 1 Cycle 3 Neoadjuvant Chemotherapy 
 Weight (BSA calculation) 
 Creatinine Clearance 
 Vital signs (temp, B/P, pulse) 
 Performance status 
 Physical Exam 
 Adverse events assessment 
 Routine blood work 
 Thyroid Functions 
 Pregnancy test ≤ 3 days (72 hrs) prior to first dose of ipilimumab (for WOCBP only)  
 Dose #2 Ipilimumab  
 Chemotherapy infusions 
 
 
9.5 
Evaluation at Completion of Neoadjuvant Chemotherapy 
Subjects to undergo medical and surgical evaluation at least 21 days after completion of neoadjuvant 
chemotherapy 
 Weight (BSA calculation) 
 Vital signs (temp, B/P, pulse) 
 Performance Status 
 Physical Exam 
 Routine Blood work 
 Repeat imaging to evaluate tumor (Chest CT) 
 Adverse events assessment 


47 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
Research blood will be collected 21-36 days after completion of cycle 3 chemotherapy to assess 
activated CD8+ T cells with specificity against tumor antigens and CD4 and CD8 functional memory. 4 
tubes of 8.5-ml each will be collected. The tubes used will be ACD anti-coagulated Vacutainer (yellow 
tops) and will be processed by Dr. Weinhold’s lab.  
 
9.6 
Surgery 
Surgery to occur 4-12 weeks after last dose of chemotherapy or subject will be removed from trial 
unless approved by PI. 
 
The ability to perform surgery will be assessed by the surgeon and will be based on physical exam 
and radiological evaluation. Surgical therapy will be individualized based on the surgical judgment 
and patient preference and is not dictated by study protocol. Tumor tissue samples will also be 
collected at time of surgical resection 
 
9.7 
Post-Surgery Therapy 
For subjects with bulky residual adenopathy such that resection was not attempted will be removed from 
protocol therapy and should receive standard oncology care as deemed appropriate by the treating 
physician. 
 
Subjects with positive surgical margins or N2 disease will be removed from protocol and considered for 
standard of care post-operative radiation +/- chemotherapy as deemed appropriate by treating physician. 
 
For subjects that will go on to receive post-operative ipilimumab, please see below. 
 
9.71 
Adjuvant Ipilimumab  
Ipilimumab to start 4-10 weeks after surgery.  Doses will be given every 3 weeks x 2 doses.  The 
following assessments will be done prior to the each dose of adjuvant ipilimumab administration. 
 Weight (BSA calculation)  
 Creatinine Clearance 
 Vital signs (temp, B/P, pulse) 
 Performance status 
 Physical Exam 
 Adverse events Assessment 
 Routine blood work 
 Thyroid Functions 
 Pregnancy test ≤ 3 days (72 hrs) prior to first dose of ipilimumab (for WOCBP only)  
 Adjuvant Dose Ipilimumab  


48 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
Research blood will be collected to assess activated CD8+ T cells with specificity against tumor 
antigens and CD4 and CD8 functional memory. 4 tubes of 8.5-ml each will be collected. The tubes used 
will be ACD anti-coagulated Vacutainer (yellow tops) and will be processed by Dr. Weinhold’s lab.  
This blood sample to be collected 3-6 weeks after dose # 2 adjuvant ipilimumab. 
 
 
9.72 
Maintenance Ipilimumab 
Maintenance doses of ipilimumab will be given every 12 weeks x 2 doses starting 12 weeks after dose 
#2 adjuvant ipilimumab administration.  The following assessments will be done prior to each dose of 
maintenance ipilimumab administration. 
 
 Weight (BSA calculation)  
 Creatinine Clearance 
 Vital signs (temp, B/P, pulse) 
 Performance status 
 Physical Exam 
 Adverse events Assessment 
 Routine blood work 
 Thyroid Functions 
 Chest CT  
 Pregnancy test ≤ 3 days (72 hrs) prior to first dose of ipilimumab (for WOCBP only)  
 Maintenance Dose Ipilimumab  
 
 
9.8 
End of Study (EOS) Final Visit 
 
For subjects that have completed maintenance ipilimumab, end of study evaluation is to occur 
approximately 12 weeks after 2nd maintenance dose. Final visit for those subjects that come off 
treatment early for progression of disease, intolerance to protocol therapy, other reasons or consent 
withdrawal, to occur 30 days (+/- 5 days) after last dose ipilimumab for safety evaluation. 
 Vital signs (temp, B/P, pulse) 
 Weight 
 Performance status 
 Physical exam 
 Routine blood work 
 Adverse events assessment 
 Chest CT if applicable (per radiologic evaluation appendix A) 


49 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
9.9 
Follow-up 
Surveillance after end of study evaluation will occur every 3-4 months for 2 years then every 6 months 
until 5 years, then yearly thereafter. These evaluations may be coordinated with visits for radiologic 
disease evaluation or occur via phone follow-up. 
 
 
 
 
10.0   SAMPLE PROCUREMENT AND HANDLING  
 
10.1 Blood Specimens 
 
Blood will be collected 4 times to assess activated CD8+ T cells with specificity against tumor antigens and 
CD4 and CD8 functional memory. At each blood collection, 4 tubes of 8.5-ml each will be collected. The 
tubes used will be ACD anti-coagulated Vacutainer (yellow tops). The following time points will have 
blood collections (see appendix F): 
 
Collection 1: Baseline prior to treatment 
Collection 2: Cycle 2 day 1 chemotherapy prior to ipilimumab administration  
Collection 3: 21-36 days after completion of cycle 3 chemotherapy prior to surgery  
Collection 4: 3-6 weeks after adjuvant ipilimimab dose #2. 
 
 
 
10.2 Surgical Specimens 
 
Patients will be approached to participate in the “DUHS Biospecimen Repository and Processing Core 
(BRPC)” eIRB 35974 protocol prior to surgery.  Tissue will be collected and released as described in this 
protocol to ensure proper involvement of pathology to minimize the chance that a tissue collection event 
interferes with appropriate clinical tissue processing and diagnosis. 
 
Tumor specimen samples will be collected at time of definitive surgical resection of tumor. Lung tissue is 
harvested in the frozen section or gross dissection area of the surgical pathology suite.  The tissue is first 
examined by a certified anatomic pathologist or surrogate (resident, pathology assistant). Relevant margins 
are inked, removed and examined by frozen section analysis, if necessary. It is imperative that harvesting 
tissue for use in research trials does not impede accurate initial assessment of critical features of the tumor 
resection, most notably margin status.  After the specimen has been processed for margin status, the frozen 
section assessment of the specimen is complete, (appendix G), a specimen of excess tumor will be released 
and acquired by the tumor immunology correlative science staff for isolation of tumor infiltrating 
lymphocytes for purposes of this protocol.  


50 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Patients will be approached to participate in the “DUHS Biospecimen Repository and Processing Core 
(BRPC)” protocol (eIRB 35974), prior to surgery to help coordinate and facilitate tissue acquisition. Tissue 
will be collected and released as described in this protocol to ensure proper involvement of pathology to 
minimize the chance that a tissue collection event interferes with appropriate clinical tissue processing and 
diagnosis.  For those subjects that decline participation in this biorepository tissue will be processed as 
outlined above. 
 
11.0  Treatment 
Bristol-Myers Squibb (BMS) will provide ipilimumab at no cost for this study. The investigational 
product is defined as a pharmaceutical form of an active ingredient being tested as a reference in the 
study, whether blinded or unblinded. In this study, the investigational product is ipilimumab. Other 
medications used in the study as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, are considered non-
investigational products. In this protocol, non-investigational product(s) is/are: paclitaxel, carboplatin 
and cisplatin. 
 
 
11.1. Treatments Administered 
Patients will receive neoadjuvant combination chemotherapy as follows: 
 
Cycle 1: Paclitaxel 175mg/m2  intravenously over 3 hours, followed by cisplatin 75 mg/m2 over 60 
minutes or carboplatin AUC 6 (capped at 900 mg) intravenously over 30-60 minutes Day 1 (21 day 
cycle x 1).* 
Cycles 2 and 3: Ipilimumab 10 mg/kg IV** intravenously over 90 minutes followed  by paclitaxel 
175mg/m2 intravenously over 3 hours, followed by cisplatin 75 mg/m2 over 60 minutes or carboplatin 
AUC 6 (capped at 900 mg) intravenously over 30-60 minutes Day 1 (every 21 days x 2 cycles)*  
 
Surgery: Standard surgical evaluation to occur at least 21days after the last dose of chemotherapy 
followed by surgical therapy. 
 
Post-surgical Treatment: A total of 4 doses of ipilimumab will be given post-operatively 
 
Adjuvant: Ipilimumab 10 mg/kg/IV** every 3 weeks x2 doses beginning 4 weeks postoperatively      
 (up to 10 weeks if needed for recovery) 
 
Maintenance: Ipilimumab 10 mg/kg/IV** every 12 weeks x 2 doses 
 
*The total administered dose of chemotherapy may be rounded up or down within a range of +/- 5 % of 
the actual calculated dose. 


51 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
**The total dose must be calculated using the most recent subject weight (obtained within 3 days of the 
dosing visit, and prior to the infusion). Dose only to change if there is a weight change >10% from 
baseline. 
 
11.2. Materials and Supplies 
 
Qualified personnel who are familiar with procedures that minimize undue exposure to themselves and 
to the environment should undertake the preparation, handling and safe disposal of chemotherapeutic 
agents in a self-contained, protective environment. Unused portions of injectable chemotherapeutic 
agents that do not contain a bacteriostatic agent or are prepared with unpreserved diluents (i.e., Sterile 
Water of Injection USP or 0.9% Sodium Chloride for Injection) should be discarded within eight hours 
of vial entry to minimize the risk of bacterial contamination. 
 
11.2.1. Paclitaxel, Carboplatin,  Cisplatin and Ipilimumab 
 
Paclitaxel, carboplatin, and/or cisplatin and ipilimumab will be intravenously administered only at the 
investigational site. As a result, patient compliance is ensured. 
 
 
11.2.2. Paclitaxel 
 
Paclitaxel is commercially available as a sterile solution concentrate, 6 mg/ml in 5 ml vials (30 mg/vial) 
in poluxyethylated castor oil (Cremophor EL) 50% and dehydrated alcohol, USP, 50%. Paclitaxel must 
be prepared in glass or polyolefin containers due to leaching of diethylexlphthalate (DEHP) plasticizer 
from polyvinyl chloride (PVC) bags and intravenous tubing by the Cremophor vehicle in which 
paclitaxel is solubilized. Each bag/bottle should be prepared immediately before administration. 
Formulation of a small number of fibers in collation (within acceptable limits established by the USP 
Particulate Matter Test for LVP's) has been observed after preparation of paclitaxel.  Therefore, in line 
filtration is necessary for administration of paclitaxel solution. In line filtration should be accomplished 
by incorporating a hydrophilic, microporous filter of pore size not greater than 0.22 microns (e.g., 
IVEX-II or IVEX-HP or equivalent) into the IV fluid pathway distal to the infusion pump.  Although 
particulate formulation does not indicate loss of drug potency, solutions exhibiting excessive particulate 
matter formation should not be used. The intact vials should be stored under refrigeration (2-8 °C). All 
solutions of paclitaxel exhibit a slight haziness directly proportional to the concentration of drug and the 
time elapsed after preparation, although when prepared as  described above, solutions of Paclitaxel 
(0.3-1.2 mg/ml) are physically and chemically stable for 24 hours. Drug will be diluted in order to 
administer an IV rate of 167 ml per hour for 3 hours. Paclitaxel will be administered via an infusion 
control device (pump) using non-PVC tubing and connectors, such as the IV administration sets 
(polyethylene or polyolefin) which are used to infuse parenteral Nitroglycerin. Nothing else is to be 
infused through the line where paclitaxel is being administered. Patients will be attended by medical 


52 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
personnel for the first 15 minutes of infusion and then have blood pressure checked every 15 minutes for 
one hour, then every four hours.  Medications for  acute management of anaphylaxis should be readily 
available in the location where the patient is being treated. 
 
 
11.2.3. Cisplatin  
 
Cisplatin (cis-Diamminedichloroplatinum; cis-DDP) is commercially available. It is available as 1 
mg/ml concentration aqueous injection in multidose vials of 50 ml. It should be stored at room 
temperature (15C to 25C) and protected from light. Solutions diluted in 0.9% or 0.45% NaCl to a 
concentration of 0.05-2 mg/ml are stable for up to 72 hours at room temperature and should be protected 
from light. Since no antibacterial preservatives are contained in the formulation, it is recommended that 
any cisplatin solutions admixed for infusion be discarded after 8 hours from the time of dilution. 
Cisplatin will be administered as an intravenous infusion over 60 minutes. It should be administered in 
250-1000 ml NaCl, following intravenous hydration with at least 1000 ml NaCl. Needles, syringes, 
catheters or IV administration sets containing aluminum parts should not be used as contact with 
cisplatin yields a black precipitate. 
 
11.2.4. Carboplatin 
Carboplatin is supplied commercially as a sterile lyophilized powder available in single-dose vials  
containing 50 mg, 50 mg and 450 mg of carboplatin.  Each vial contains equal parts by weight of 
carboplatin and mannitol. Preparation:  Immediately before use, the content of each vial must be 
reconstituted with either Sterile Water for injection, USP, 5% dextrose in water, or 0.9% Sodium 
Chloride injection, USP, to produce a carboplatin concentration of 10 mg/ml.  When prepared as 
directed, Carboplatin solutions are stable for 8 hours at room temperature.  Since no antibacterial 
preservative is contained in the formulation, it is recommended that carboplatin solutions be discarded 8 
hours after dilution. Note: aluminum reacts with carboplatin causing precipitate formation and loss of 
potency; therefore, needles or intravenous sets containing aluminum parts that may come in contact with 
the drug must not be used for the preparation or administration of carboplatin. Storage and Stability:  
Unopened vials of carboplatin are stable for the life indicated on the package when stored at controlled 
room temperature and protected from light. Administration:  Administer over 30-60 minutes after 
completing the paclitaxel infusion.  The Crockcroft Gault formula (Dose=AUC (CCC+25) will be used 
to achieve the desired AUC where CCC=Wt Kg x (140-age)/72xCr (using actual body weight for both 
female and male and if female use 85%). Capped AUC 6 dose of 900 mg. Appendix D. 
 


53 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
11.2.5   Ipilimumab (see section 15.0 for detailed drug information) 
Ipilimumab is available in concentrations of 5 mg/mL (50 mg/10 mL and 200 mg/40 mL). Ipilimumab 
injection must not be administered as an IV push or bolus injection. The total dose must be calculated 
using the most recent subject weight (obtained within three days of the dosing visit prior to the infusion). 
Dose only to change if there is a weight change >10% from baseline. 
For cycles 2-3 neoadjuvant chemotherapy, Ipilimumab will be administered over 90 minutes followed 
by paclitaxel then cisplatin or carboplatin.  Ipilimumab will be administered as a single agent after 
surgery. 
 
 
11.3 Rationale for Selection of Doses in the Study 
 
11.3.1   Paclitaxel and Cisplatin or Carboplatin and Ipilimumab 
 
The combination of ipilimumab 10 mg/kg, cisplatin 75 mg/m2 or carboplatin AUC 6 and paclitaxel 175 
mg/m2 was found to be safe and effective. In advanced metastatic NSCLC, Ipilimumab 10 mg/kg has 
been successfully combined with the chemotherapy doublet, paclitaxel 175 mg/m2 and carboplatin AUC 
6, as first-line treatment.  A recent phase II trial reported that the phased sequence (two courses 
chemotherapy followed by two courses of chemotherapy + Ipilimumab) had superior progression free 
survival, overall response, and overall survival; 6.4 months, 57%, and 12.9 months, respectively; 
compared to 5.7 months, 49%, and 9.1 months, for the concurrent sequence. (31, 32) Overall safety was 
similar to the control arm with grade ¾ adverse events being 57%, 54% and 40% in the three study 
arms, (concurrent ipilimumab+Paclitaxel/carboplatin, phased ipilimumab+Paclitaxel/carboplatin, and 
paclitaxel/carboplatin alone), respectively. Hematologic abnormalities observed were those generally 
expected with paclitaxel/carboplatin alone. Most common (> 5% in any arm) treatment related grade ¾ 
adverse events (concurrent vs phased vs Paclitaxel/carboplatin alone) were: fatigue (10% vs 7% vs 6%) 
and diarrhea (10% vs 7% vs 4%) among nonsquamous patients; nausea (0% vs 5% vs 7%), vomiting 
(0% vs 5% vs 7%) and dyspnea (0% vs 0% vs 7%) among squamous patients. (31)Lynch et al, abstr 
701, 14th World Conf on Lung Cancer, July, 2011; (32)Grossi et al, abstr M004, 14th World Conf on 
Lung Cancer, July, 2011).  
 
  
11.4. Selection and Timing of Doses 
Patients in this study will receive chemotherapy on a 21-day cycle for paclitaxel, plus cisplatin or 
carboplatin. Chemotherapy alone will be given during cycle 1 of neoadjuvant therapy and ipilimumab 
will be given with neoadjuvant chemotherapy during cycles 2 and 3. A cycle of ipilimumab, paclitaxel, 


54 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
and cisplatin and or carboplatin comprises one treatment of each agent on day 1 at least 21 days between 
day 1 dosing. A delay of cycle as a result of holidays, weekends, bad weather, or other unforeseen 
circumstances will be permitted and not counted as a protocol violation. The actual dose of ipilimumab 
will be determined by the patients’ weight in kilograms. The actual dose of paclitaxel , or cisplatin, to be 
administered will be determined by calculating the body surface area at the beginning of each cycle, on 
day 1. Carboplatin dose will be determined using the Crockcroft Gault Formula (Dose=AUC (CCC+25) 
will be used to achieve the desired AUC where CCC=Wt (140-age)/72xCr (using actual body weight for 
both female and male and if female use 85%). A 1.5% variance in the calculated total dose will be 
allowed for ease of dose administration (Appendix D).   Institutional guidelines will be utilized for 
capping the carboplatin dose.  CrCl cap will be 125ml/min using the (AUC 6 capped dose = 900mg).  
Ipilimumab will be administered first in sequence, followed by paclitaxel, followed by cisplatin or 
carboplatin. Always give ipilimumab 30-60 minutes before premeds for paclitaxel.  Cisplatin or 
carboplatin will be given following administration of paclitaxel on the day of therapy. A total of 3 cycles 
of chemotherapy will be given, and ipilimumab will be given during cycles 2 and 3. 
Ipilimumab will be administered alone beginning 4-10 weeks after surgery to consist of adjuvant therapy 
every 3 weeks for 2 cycles followed by maintenance therapy every 12 weeks for two cycles   Patients 
receiving post-operative radiation for standard clinical criteria such as N2 metastatic disease or surgical 
margin sub-optimal, should receive radiation prior to adjuvant ipilimumab or at least 2 weeks after the 
most recent dose of ipilimumab. 
 
11.4.1. Special Treatment Considerations: Dose Adjustments or Delays for Chemotherapy  
Subsequent Cycles. (See section 11.5-Ipilimumab Dose Modifications)   
 
Ipilimumab dosing will be concurrent with paclitaxel/carboplatin/cisplatin dosing. Therefore, if 
paclitaxel/platin is delayed due to AEs, ipilimumab will be delayed.  
 
If ipilimumab is delayed due to AEs, paclitaxel/platin will be delayed up to two weeks. If ipilimumab is 
delayed more than two weeks due to ipilimumab related AE, then ipilimumab will be discontinued from 
cycle 3 of chemotherapy (and will not be made up) and chemotherapy should be given as otherwise 
appropriate. If ipilimumab is held from cycle three of neoadjuvant chemotherapy, ipilimumab may be 
given adjuvantly as per protocol, if ipilimumab AE has resolved and all other criteria for giving 
ipilimumab as per protocol are met.   
 


55 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Any patient who requires a dose reduction of paclitaxel/platin will continue to receive a reduced dose for 
the remainder of the study. No dose escalations are permitted in this study. 
 
Paclitaxel/platin treatment may be delayed for up to 21days. Patients on a 21-day cycle regimen may 
have treatment delayed for up to 42 days from Day 1 of the current cycle to allow sufficient time to 
recover from study therapy-related toxicity. A patient who cannot be administered neoadjuvant study 
therapy within 42 days of scheduled day 1 of a cycle will stop neoadjuvant study therapy and proceed to 
surgery as deemed appropriate by the surgical team so there is no excessive delay in surgery.  If there 
was no grade ≥3 toxicity from ipilimumab, the patient may still receive adjuvant ipilimumab. 
 
 
Chemotherapy dose modifications are allowed as per institutional standard practice for treatment- 
related toxicity.  Listed below are guidelines for chemotherapy modifications. 
 
 
11.4.1.1. Hematologic Toxicity Dose Adjustments 
 
ANC/AGC must be ≥1500/L and platelets ≥100,000/L prior to the 1st cycle. Dose adjustments at the start 
of a subsequent cycle of therapy will be based on platelet and neutrophil counts on the day of 
scheduled treatment. Treatment should be delayed to allow sufficient time for recovery. Upon 
recovery, if treatment is resumed, it should be according to the guidelines in Table 10 and Table 11. 
 
Table 10 Chemotherapy dose Adjustments Based on Day 1 Hematologic Values 
ANC/AGC (µL) 
Platelets (µL) 
Percent of Previous Dose 
≥1500 
AND 
≥100,000 
100% 
<1500 
OR 
<100,000 
Repeat counts weekly, when ANC/AGC 
≥1500 and platelets ≥100,000, retreat at 
100% previous dose. Remove from the 
study if delay >21 days. 
Febrile Neutropenia 
as defined by CTC 
 
 
Delay treatment as appropriate, once fully 
recovered (<21 days). Retreat at 75% of 
previous dose. 
ANY 
AND 
<10,000 
Delay until recovered, as above, then 
retreat at 75% of previous dose. Remove 
from study if delay >21 days. 
For hemoglobin <8g/dL, transfusion should be considered without interruption of chemotherapy, 
erythropoietin may be used. 
Growth factor support (G-CSF or pegylated G-CSF) may be used at the discretion of the treating 
physician. 
 


56 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
11.4.1.2. Non-Hematologic Toxicity Dose Adjustments 
 
For non-hematologic toxicities, ≥ Grade 3 (CTCAE), treatment must be delayed until resolution to 
≤CTCAE grade 1 (or patient’s original baseline grade) before proceeding. Treatment should resume at 
75% of the previous dose level of all chemotherapy agents if deemed appropriate by the treating 
physician. 
 
11.4.1.3    Renal Toxicity: Cisplatin and Paclitaxel  
 
Renal Toxicity Cisplatin 
Cisplatin therapy should be delayed if the creatinine is >2.0 mg/dL. If treatment is delayed for renal 
toxicity, re-evaluate the serum creatinine weekly. If the serum creatinine is ≤2.0 mg/dL proceed with 
cisplatin at 75% of previous dose. If serum creatinine is not ≤2.0 mg/dL after 14 days, start next cycle 
without cisplatin. Missed cisplatin doses will not be made up. If creatinine is still not ≤2.0 mg/dL after a 
total of 42 days, the patient must be discontinued from study therapy unless continuation is approved by 
the principal investigator. If creatinine is > 2.0 mg/dL but creatinine clearance is > 45 mL/min, may 
switch from cisplatin to carboplatin and continue treatment if all other criteria for therapy are met.  
 
Renal Toxicity Paclitaxel 
 
No dose adjustments needed for renal toxicity. 
 
 
11.4.1.4   Neurologic Toxicity: Paclitaxel, Cisplatin or Carboplatin 
Dose of cisplatin, carboplatin and paclitaxel should be reduced for neurologic toxicity (Table11).  
 
Table 11 
Grade of Toxicity Paclitaxel, Cisplatin, or Carboplatin Doses 
0 
100% 
1 
100% 
2 
Hold treatment until patient recovers to grade 1, 
then resume treatment at 75% dose.* 
≥3 
Hold treatment until patient recovers to grade 1, 
then resume treatment at 50% dose.* 
*Dose reductions for neurotoxicity are permanent. 
 
 
 


57 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
11.4.1.5   Auditory Toxicity (Cisplatin) 
 
Cisplatin is well known to cause high-frequency hearing loss. Continued use of the drug does not always 
result in hearing loss, although it may. If grade 2 or worse hearing loss is noted, the patient should be 
presented with a discussion of the relative risks of hearing loss versus the potential benefit of continuing 
cisplatin therapy, and a decision made as to continuation of agent. Grade 3 or 4 hearing loss will warrant 
discontinuation of agent. 
 
 
11.4.1.6   Hepatic Toxicity (Paclitaxel) 
 
Table 12: Treatment day values should be used in determining dose. 
SGOT/AST 
 
Alkaline  
Phosphatase 
 
Bilirubin 
Paclitaxel Dose 
≤1.5x ULN 
and ≤1.5x ULN 
and 
 WNL 
100% 
>1.5-5x ULN 
and >1.5-5x ULN 
and 
 WNL 
50% 
>5x ULN 
and >5x ULN 
Or 
  >NL 
Hold* 
Repeat LFTs weekly. If recovered, reduce dose by 25%. If not recovered within 3 weeks, discontinue 
protocol therapy. If paclitaxel is withheld due to hepatic toxicity on day 1, cisplatin or carboplatin 
should also be withheld and administered when paclitaxel is resumed. There are no dose reductions of 
cisplatin or carboplatin for hepatic toxicity unless > grade 3. 
 
 
11.4.1.7   Hypersensitivity Reactions to Paclitaxel  
 
For grade 3 reactions, in the subsequent cycle, use double dose steroids pretreatment and decrease the 
paclitaxel infusion rate for the first 1/3 of the infusion. For the last 2/3 of the infusion, double the rate of 
the infusion. For documented Grade 4 hypersensitivity reactions to paclitaxel, discontinue paclitaxel. 
 
 
11.4.1.8   Other Toxicities from Paclitaxel 
 
If a patient develops chest pain, hypotension, or arrhythmia other than asymptomatic sinus brachycardia, 
the paclitaxel infusion should be stopped and patients should not receive further paclitaxel. For 
asymptomatic sinus brachycardia, the infusion need not be stopped, but the patient should be followed 
carefully. 


58 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
11.5  Ipilimumab Dose Modifications 
Ipilimumab Dose Skipping Rule  
Decisions to skip an ipilimumab dose must be made on specified safety criteria. Treatment with 
ipilimumab will be skipped or discontinued if the subject experiences at least one adverse event, 
specified below, considered by the investigator to be “possibly,” probably,” or “certainly” related to 
ipilimumab treatment. The investigator should contact BMS for any adverse event that will prompt a 
skipped dose or discontinuation of ipilimumab. If the adverse event is associated with ipilimumab 
during preoperative chemotherapy cycle 2 delay up to 2 weeks, then give cycle 3 chemotherapy alone 
and proceed to surgery as clinically indicated. In the postoperative adjuvant or maintenance ipilimumab 
therapy, delay ipilimumab up to 4 weeks for ipilimumab related toxicity and if not recovered to < grade 
1, discontinue ipilimumab. 
 
The following criteria will be used to determine dose skipping, restarting doses, or discontinuing 
ipilimumab. 
It may be necessary to skip study drug dosing for the following related adverse event(s): 
 
 Any ≥ Grade 2 non-skin related adverse event (including immune-mediated adverse reactions), 
except for laboratory abnormalities 
 Any ≥ Grade 3 laboratory abnormality 
 Any adverse event, laboratory abnormality or intercurrent illness that, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued dosing. 
 
It is necessary to skip study drug dosing for the following adverse events: 
 Any ≥ Grade 3 skin related adverse event regardless of causality. 
 


59 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
Restart ipilimumab dosing if/when the adverse event(s) resolve(s) to ≤ Grade 1 severity or returns 
to baseline: 
 If the adverse event is associated with ipilimumab during preoperative chemotherapy cycle 2, 
delay up to 2 weeks, then give cycle 3 chemotherapy alone, and proceed to surgery as clinically 
indicated. If ipilimumab adverse event has resolved to ≤ grade 1 after surgery, then post-
operative ipilimumab may be started. 
 For postoperative adjuvant or maintenance ipilimumab therapy, delay ipilimumab up to 4 weeks 
for ipilimumab related toxicity and if not recovered to <   grade 1, discontinue ipilimumab. 
11.5.1   Immune-Related Adverse Events (irAEs) Reactions and Immune-mediated Adverse 
Reactions: Definition, Monitoring, and Treatment 
Blocking CTLA-4 function may permit the emergence of auto-reactive T cells and resultant clinical 
autoimmunity. Rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis, and hypopituitarism were 
drug-related, presumptive autoimmune events, now termed immune-mediated adverse reactions, noted 
in previous ipilimumab studies. 
For the purposes of this study, an immune-related adverse reaction is defined as an adverse reaction of 
unknown etiology associated with drug exposure and consistent with an immune phenomenon. Efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes prior to 
labeling an event an immune-related adverse reaction. Serologic, immunologic, and histologic (biopsy) 
data should be used to support the diagnosis of an immune-related toxicity. Suspected immune-related 
adverse reactions must be documented on an AE or SAE form. Another term for an irAE is an immune-
mediate adverse reaction, as it is termed in the Ipilimumab US Prescribing Information. Both terms may 
be used in this protocol document.  
Patients should be informed of and carefully monitored for evidence of clinically significant systemic 
immune-mediated adverse reactions (e.g., systemic lupus erythematosus-like diseases) or organ-specific 
immune-mediated adverse reaction (e.g., rash, colitis, uveitis, hepatitis or thyroid disease). If an 
immune-mediated adverse reaction is noted, appropriate work-up (including biopsy if possible) should 
be performed, and steroid therapy may be considered if clinically necessary.   


60 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
It is unknown if systemic corticosteroid therapy has an attenuating effect on ipilimumab activity. 
However, clinical anti-tumor responses have been maintained in patients treated with corticosteroids and 
discontinued from ipilimumab. If utilized, corticosteroid therapy should be individualized for each 
patient. Prior experience suggests that colitis manifested as ≥ Grade 3 diarrhea requires corticosteroid 
treatment. 
Specific treatment algorithms for immune-mediated adverse reactions adverse events are included 
see Appendix K. 
 
11.5.2   Treatment of Infusion Reactions Associated with Ipilimumab  
Since ipilimumab contains only human protein sequences, it is less likely that any allergic reaction will 
be seen in patients. However, it is possible that infusion of ipilimumab will induce a cytokine release 
syndrome that could be evidenced by fever, chills, rigors, rash, pruritus, hypotension, hypertension, 
bronchospasm, or other symptoms. No prophylactic pre-medication will be given unless indicated by 
previous experience in an individual patient. Reactions should be treated based upon the following 
recommendations. 
 For mild symptoms (e.g., localized cutaneous reactions such as mild pruritus, flushing, rash): 
 Decrease the rate of infusion until recovery from symptoms, remain at bedside and 
monitor patient. 
 Complete the ipilimumab infusion at the initial planned rate. 
 Diphenhydramine 50 mg IV may be administered at the discretion of the treating 
physician and patients may receive additional doses with close monitoring. 
 Premedication with diphenhydramine may be given at the discretion of the investigator 
for subsequent doses of ipilimumab. 
 For moderate symptoms (any symptom not listed above [mild symptoms] or below [severe 
symptoms] such as generalized pruritus, flushing, rash, dyspnea, hypotension with systolic 
BP >80 mmHg):  
 Interrupt ipilimumab. 
 Administer diphenhydramine 50 mg IV. 
 Monitor patient closely until resolution of symptoms. 
 Corticosteroids may abrogate any beneficial immunologic effect, but may be 
administered at the discretion of the treating physician. 
 Resume ipilimumab infusion after recovery of symptoms. 


61 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 At the discretion of the treating physician, ipilimumab infusion may be resumed at one 
half the initial infusion rate, then increased incrementally to the initial infusion rate. 
 If symptoms develop after resumption of the infusion, the infusion should be 
discontinued and no additional ipilimumab should be administered that day. 
 The next dose of ipilimumab will be administered at its next scheduled time and may be 
given with pre-medication (diphenhydramine and acetaminophen) and careful 
monitoring, following the same treatment guidelines outlined above. 
 At the discretion of the treating physician additional oral or IV antihistamine may be 
administered prior to dosing with ipilimumab. 
 For severe symptoms (e.g., any reaction such as bronchospasm, generalized urticaria, systolic 
blood pressure 80 mm Hg, or angioedema): 
 Immediately discontinue infusion of ipilimumab, and disconnect infusion tubing from the 
subject. 
 Consider 
bronchodilators, 
epinephrine 
1 mg 
IV 
or 
subcutaneously, 
and/or 
diphenhydramine 50 mg IV, with solumedrol 100 mg IV, as needed. 
 Patients should be monitored until the investigator is comfortable that the symptoms will 
not recur. 
 No further ipilimumab will be administered. 
 In case of late-occurring hypersensitivity symptoms (e.g., appearance within one week after 
treatment of a localized or generalized pruritus), symptomatic treatment may be given (e.g., 
oral antihistamine, or corticosteroids). 
 
 
11.5.3   Treatment of Ipilimumab-Related Isolated Drug Fever 
In the event of isolated drug fever, the investigator must use clinical judgment to determine if the fever 
is related to the ipilimumab or to an infectious etiology. If a patient experiences isolated drug fever, for 
the next dose, pre-treatment with acetaminophen or non-steroidal anti-inflammatory agent (investigator 
discretion) should be instituted and a repeated antipyretic dose at 6 and 12 hours after ipilimumab 
infusion, should be administered. The infusion rate will remain unchanged for future doses. If a patient 
experiences recurrent isolated drug fever following premedication and post dosing with an appropriate 
antipyretic, the infusion rate for subsequent dosing should be decreased to 50% of the previous rate. If 
fever recurs following infusion rate change, the investigator should assess the patient’s level of 
discomfort with the event and use clinical judgment to determine if the patient should receive further 
ipilimumab. 
 


62 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
11.5.4    Monitoring and Management of Immune-Mediated Adverse Reactions 
Suggested Evaluation and Treatment for Immune-related Adverse Events: 
Early diagnosis and treatment intervention for high-grade irAEs can help prevent the occurrence of 
complications such as GI perforation.  Gastrointestinal (diarrhea) and skin (rash) related toxicities are 
the most common irAEs reported in studies with ipilimumab. Suggested evaluation procedures for 
suspected irAEs of the GI tract, liver, skin, eye, pituitary, and adrenal gland are described below.  When 
sypmptomatic therapy is inadequate or inappropriate, an irAE should be treated with systemic 
corticosteroids followed by a gradual taper.  Infrequently, subjects with irAEs may require courses of 
corticosteroid or other immunosuppressive agents that exceed 4 weeks in duration. It is recommended 
that subjects receiving immunosuppressive agents beyond 4 to 6 weeks should also receive 
antimicrobial prophylaxis to protect against the emergence of opportunistic infections. Such 
prophylaxis should include protection against Pneumocystis jiroveci (formerly Pcarinii) and prevalent 
fungal strains, as well as considerations for any additional pathogens that may be indicated by the 
medical history (e.g., herpes simplex virus, cytomegalovirus) or the environment (e.g., occupation, 
recent travel) of the subject. Consultation with infectious disease specialists may be considered. 
Immune-related (ir)AE management algorithms for general irAEs, and ipilimumab related diarrhea, 
hepatotoxicity, endocrinopathy, and neuropathy have been developed and are listed below. 
 
11.5.4.1   Gastrointestinal Tract:  Immune-mediated Enterocolitis 
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or 
blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In 
symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or 
severe symptoms. 
Permanently discontinue ipilimumab in patients with severe enterocolitis and initiate systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 
1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, 
rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some 
patients. 


63 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Withhold ipilimumab dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if 
persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day 
prednisone or equivalent.  
The differential diagnosis for subjects presenting with abdominal pain should include colitis, 
perforation, or pancreatitis. Additionally, a few subjects with abdominal pain also had acute swelling of 
the cecal wall on CT scan that may have represented localized inflammation. 
Diarrhea (defined as either first watery stool, or increase in frequency 50% above baseline with urgency 
or nocturnal bowel movement, or bloody stool) should be further evaluated and infectious or alternate 
etiologies ruled out. Subjects should be advised to inform the investigator if any diarrhea occurs, even 
if it is mild. An algorithm for managing subjects with diarrhea or suspected colitis is provided in 
Appendix L. 
The majority of subjects with ipilimumab-induced diarrhea or colitis responded to symptomatic therapy 
or corticosteroids. Permanent discontinuation of ipilimumab and starting high dose corticosteroid 
therapy (e.g., methylprednisolone 2 mg/kg once or twice per day or equivalent) is strongly 
recommended for ipilimumab related ≥ Grade 3 diarrhea/colitis and steroids should be slowly tapered 
according to symptomatic response over at least 1 month. Subjects with ipilimumab-related Grade 2 
diarrhea/colitis have to skip ipilimumab dosing and may be initially treated conservatively with 
loperamide, fluid replacement or budesonide, but should be immediately switched to corticosteroids 
(prednisone 1 mg/kg or equivalent) if symptoms persist for 3-5 days or worsen. Most subjects with 
diarrhea/colitis will rapidly respond to initiation of corticosteroids. The dose should be gradually 
tapered over at least a 1-month duration. Lower doses of prednisone may be considered for less severe 
cases of colitis. It is suggested that prednisone (for oral administration) or methylprednisolone (for IV 
administration) be the corticosteroids of choice in the treatment of colitis. Caution should be taken in 
the use of narcotics in patients with abdominal pain or colitis/diarrhea as narcotic use may mask the 
signs of colonic perforation. Infrequently, subjects will appear refractory to corticosteroids or will flare 
following taper of corticosteroids. In these subjects, unless contraindicated (i.e., sepsis, perforation and 
other serious infections), a single dose of infliximab at 5 mg/kg may provide benefit. For patients with 
concomitant hepatitis, use of mycophenolate mofetil is recommended in place of infliximab. For 
patients with long term immunosuppressive therapy, administer antimicrobial prophylactics as 
appropriate per institutional guidelines. Such cases should be discussed with the sponsor study medical 


64 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
monitor. If the event is prolonged or severe or is associated with signs of systemic inflammation or 
acute phase reactants (e.g., increased CRP or platelet count; or bandemia), it is recommended that 
sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy of 3 to 5 specimens for standard 
paraffin block be performed. If possible, 1 to 2 biopsy specimens should be snap-frozen and stored.  
Tests should also be performed for stool calprotectin and WBCs. 
 
11.5.4.2   Liver:  Immune-mediated Hepatitis 
Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and 
symptoms of hepatotoxicity before each dose of ipilimumab. In patients with hepatotoxicity, rule out 
infectious or malignant causes and increase frequency of liver function test monitoring until resolution. 
Permanently discontinue ipilimumab in patients with Grade 3–5 hepatotoxicity and administer systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests 
show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper 
over 1 month. Across the clinical development program for ipilimumab, mycophenolate treatment has 
been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. 
Withhold ipilimumab in patients with Grade 2 hepatotoxicity. 
Liver function tests should always be performed and reviewed prior to administration of all ipilimumab 
doses. Patients treated with ipilimumab may develop elevation in LFT in the absence of clinical 
symptoms. In addition, subjects presenting with right upper quadrant abdominal pain, unexplained 
nausea, or vomiting should have LFTs performed immediately and reviewed before administering the 
next dose of study drug. Any increase in LFT should be evaluated to rule out non-inflammatory causes 
of hepatotoxicity including infections, disease progression or medications and followed with frequent 
LFT monitoring at 3-day intervals until resolution. 
Any LFTs ≥ Grade 2 (for subjects with normal baseline LFT) or LFT ≥ 2 times baseline values (for 
subjects with baseline LFT of Grade 1 or 2) should prompt treating physicians to: (1) contact the PI; (2) 
increase frequency of monitoring LFTs to at least every 3 days until LFT have stabilized or improved; 
(3) investigate to rule out non-irAE etiologies; and (4) initiate an autoimmunity evaluation.  
Disease progression, other malignancies, concurrent medications, viral hepatitis, and toxic etiologies 
should be considered and addressed, as appropriate. Imaging of the liver, gall bladder, and bile ducts 


65 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
should be considered to rule out neoplastic or other non-irAE-related causes for the increased LFTs. An 
ANA, perinuclear anti-neutrophil cytoplasmic antibody (pANCA), and anti-smooth muscle antibody 
test should be performed if an autoimmune etiology is considered. If the LFTs are > 5 times the upper 
limit of normal (ULN) or total bilirubin is > 3 times the ULN, then ipilimumab dosing should be held 
according to the dose modification guidelines. 
Subjects with LFT elevations > 8x the ULN that are judged to be due to ipilimumab should initiate 
high-dose corticosteroid therapy (e.g., methylprednisolone 2 mg/kg once or twice daily or equivalent) 
and permanently stop administration of ipilimumab. In subjects with > 8x ULN, LFT should be 
performed daily until stable or declining for 5 consecutive days. LFT should be monitored for at least 2 
consecutive weeks to ensure sustained treatment response. If symptoms or LFT elevations are 
controlled, the corticosteroid dose should be gradually tapered over a period of at least 1 month. Flare 
in LFTs during this taper may be treated with an increase in the dose of steroid and a slower taper. In 
subjects without response to corticosteroid therapy within 3 to 5 days or who have an LFT flare during 
steroid tapering that is not responsive to an increase in steroids, addition of immunosuppression with 
mycophenolate mofetil should be considered after a gastroenterology/hepatology consult. Patients 
receiving immunosuppression for more than 4 weeks should be evaluated for prophylaxis of 
opportunistic infections per institutional guidelines. (Appendix H). 
11.5.4.3   Skin: Immune-mediated Dermatitis 
Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate 
etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.   
Permanently discontinue ipilimumab in patients with Stevens-Johnson syndrome, toxic epidermal 
necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic 
manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or 
equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 
month. Withhold ipilimumab dosing in patients with moderate to severe signs and symptoms.  
For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer 
topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.  
 


66 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
A dermatologist should evaluate persistent or severe rash or pruritus. A biopsy should be performed if 
appropriate and if possible, photos of the rash should also be obtained. 
Patients with low-grade ipilimumab-mediated skin toxicity (Grade 1 or 2) may remain on therapy and 
could be treated with symptomatic therapy (e.g., antihistamines). Low-grade symptoms persisting for 1 
to 2 weeks and relapsing should be treated with topical or oral corticosteroid therapy (e.g., prednisone 1 
mg/kg once daily or equivalent). High-grade (Grade 3 or 4) symptoms require high-dose IV 
corticosteroid therapy (e.g., methylprednisolone 2 mg/kg once or twice per day or equivalent) to control 
initial symptoms. A skin biopsy should be performed if appropriate. Once rash or pruritis is controlled, 
the initiation of corticosteroid taper should be based on clinical judgment; however, the corticosteroid 
dose should be gradually tapered over a period of at least 1 month. Patients with any high-grade skin 
related toxicity (Grade 3 regardless of causality) have to skip ipilimumab and may only continue 
treatment with ipilimumab if the initial symptoms have improved to ≤ Grade 1, while patients with 
grade 4 skin toxicities have to permanently discontinue ipilimumab. (Appendix K) 
 
11.5.4.4   Neuropathy:  Immune-mediated Neuropathies 
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory 
alterations, or paresthesia. Permanently discontinue ipilimumab in patients with severe neuropathy 
(interfering with daily activities) such as Guillain-Barré-like syndromes.  Institute medical intervention 
as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a 
dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold ipilimumab dosing 
in patients with moderate neuropathy (not interfering with daily activities).  
Subjects presenting with sensory symptoms lasting more than 5 days or motor symptoms confirmed by 
physical examinations should be evaluated and non-inflammatory causes such as disease progression, 
infections (including Lyme disease), metabolic syndromes and medications (such as taxanes and/or 
platinum salts) should be ruled out. A neurology consult should be obtained and diagnostic  
 
 
 


67 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 characterization of the neurological syndrome (electromyogram, nerve conduction studies) should be 
started. The next dose of ipilimumab should be skipped if the event of a Grade 2 neuropathy (sensitive 
or motor) is related to study drug. The administration of ipilimumab should be permanently discontinued 
in patients with Grade 3 or 4 sensory neuropathy suspected to be related to study drug. Patients should 
be treated according to institutional guidelines and the administration of IV steroids (e.g., 
methylprednisolone 2 mg/kg once or twice per day or equivalent) should be considered.  
The administration of ipilimumab should be permanently discontinued in patients with Grade 3 or 4 
motor neuropathy regardless of the causality to study drug. Patients with Grade 3 or 4 motor neuropathy 
who are clinically stable should be treated according to institution guidelines and the administration of 
IV steroids therapy (e.g., methylprednisolone 2 mg/kg once or twice per day or equivalent) should be 
considered. 
Patients with Grade 3 or 4 motor neuropathy who are not clinically stable or who have atypical 
symptoms should be hospitalized and the IV administration of steroids should be initiated and IV 
immunoglobulin (IVIg) or other immunosuppressive therapies (as appropriate) should be considered. 
(Refer to Appendix J)  
11.5.4.5   Endocrine:  Immune-mediated Endocrinopathies  
Monitor patient for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including 
adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status 
changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms that may 
resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has 
been identified, signs or symptoms of endocrinopathies should be considered immune-mediated. 
Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as 
clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by 
imaging studies through enlargement of the pituitary gland. Withhold ipilimumab dosing in 
symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or 
equivalent, and initiate appropriate hormone replacement therapy. 


68 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Most subjects with hypopituitarism presented with nonspecific complaints such as fatigue, visual field 
defects, confusion, or impotence. Some have had headache as the predominant presentation. The 
majority of subjects with hypopituitarism demonstrated enlarged pituitary glands based on brain MRI. 
Low adrenocorticotropic hormone (ACTH) and cortisol were the most common biochemical 
abnormality; low TSH, free T4,T3, testosterone or prolactin have also been reported in some subjects. 
Subjects with unexplained symptoms such as fatigue, myalgias, impotence, mental status changes, or 
constipation should be investigated for the presence of thyroid, pituitary or adrenal endocrinopathies. An 
endocrinologist should be consulted if an endocrinopathy is suspected. If there are any signs of adrenal 
crisis such as severe dehydration, hypotension, or shock, IV corticosteroids with mineralocorticoid 
activity (e.g., methylprednisolone) should be initiated immediately. If the patient’s symptoms are 
suggestive of an endocrinopathy but the patient is not in adrenal crisis, an endocrine laboratory results 
should be evaluated before corticosteroid therapy is initiated. 
Endocrine work-up should include at least thyroid stimulating hormone (TSH) and free T4 levels. These 
should be obtained to determine if thyroid abnormalities are present.  THS, prolactin and a morning 
cortisol level will help to differentiate primary adrenal insufficiency from primary pituitary 
insufficiency. 
Radiographic imaging (e.g., MRI) with pituitary cuts should be performed. If the pituitary scan and/or 
endocrine laboratory tests are abnormal, a short course of high dose corticosteroids (e.g., dexamethasone 
4 mg every 6 hours or equivalent) should be considered in an attempt to treat the presumed pituitary 
inflammation, but it is currently unknown if this will reverse the pituitary dysfunction. Abrupt 
discontinuation of corticosteroids should be avoided due to possible prolonged adrenal suppression. 
Once symptoms or laboratory abnormalities are controlled, and overall patient improvement is evident, 
the initiation of steroid taper should be based on clinical judgment; however the corticosteroid dose 
should be gradually tapered over a period of at least 1 month. Appropriate hormone replacement therapy 
should be instituted if an endocrinopathy is documented, and it is possible that subjects may require life-
long hormone replacement. (Refer to Appendix I) 


69 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
11.5.4.6   Other:  Immune-mediated Adverse Reactions, Including Ocular Manifestations 
The following clinically significant immune-mediated adverse reactions were seen in less than 1% of 
ipilimumab-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, 
and hemolytic anemia. Across the clinical development program for ipilimumab, the following likely 
immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, 
angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, 
episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, 
and autoimmune thyroiditis. 
Permanently discontinue ipilimumab for clinically significant or severe immune-mediated adverse 
reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for 
severe immune-mediated adverse reactions. 
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently 
discontinue ipilimumab for immune-mediated ocular disease that is unresponsive to local 
immunosuppressive therapy. 
Ocular inflammation (episcleritis or uveitis) was reported in a few subjects. These conditions responded 
to topical corticosteroid therapy. An ophthalmologist should evaluate visual complaints with 
examination of the conjunctiva, anterior and posterior chambers, and retina. Visual field testing and an 
electroretinogram should also be performed. Examination and testing should be documented on the 
appropriate case report form (CRF). Ipilimumab-related uveitis orepiscleritis may be treated with topical 
corticosteroid eye drops. 
Symptoms of abdominal pain associated with elevations of amylase and lipase suggestive of pancreatitis 
may be associated with anti-CTLA-4 monoclonal antibody administration. The differential diagnosis of 
acute abdominal pain should include pancreatitis. Appropriate evaluation should include serum amylase 
and lipase tests. 
 


70 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
11.5.4.7   Liver Function Test (LFT) Assessments Required Before Administration of Ipilimumab 
Liver function tests (AST, ALT, T. bilirubin) will be evaluated for every subject prior to administration 
of ipilimumab. Blood samples must be collected and analyzed at local or central labs within 3 days prior 
to dosing. LFT results must be reviewed by the principal investigator (or designee) to meet dosing 
criteria specifications:  2.5 x ULN for AST, ALT and  1.5 x ULN for T. bilirubin unless liver 
metastases are present in which case LFT  5 x ULN for AST, ALT and T. bilirubin  3.0 x ULN) prior 
to dosing.  
If, during the course of treatment abnormal LFT values are detected, the subject must be managed using 
the hepatotoxicity algorithm Appendix H.     
11.6 Permanent Discontinuation of Ipilimumab 
11.6.1 Permanent Discontinuation for Related Adverse Events  
Permanently discontinue ipilimumab for any of the following: 
 Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg 
prednisone or equivalent per day. 
 Failure to complete full treatment course within 18 weeks from administration of first dose. 
 Severe or life-threatening adverse reactions, including any of the following: 
Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (7 or 
more over baseline), stool incontinence, need for intravenous hydration for more than 24 hours, 
gastrointestinal hemorrhage, and gastrointestinal perforation 
 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper 
limit of normal or total bilirubin >3 times the upper limit of normal 
 Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full 
thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations 
 Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis 
 Severe immune-mediated reactions involving any organ system (eg, nephritis, 
pneumonitis, pancreatitis, non-infectious myocarditis) 
 Immune-mediated ocular disease that is unresponsive to topical immunosuppressive 
therapy 
 Any adverse event, laboratory abnormality or intercurrent illness which, in the  
            judgement of the investigator presents a substantial clinical risk to the patient with 
            continued dosing.  
 Clinical deterioration of subject’s condition such that further benefit from ipilimumab dosing 
is unlikely or requires a change of therapy. 


71 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
11.6.2 Exceptions to Permanent Discontinuation   
 Potentially reversible inflammation (< Grade 4), attributable to a local anti-tumor reaction 
and a potential therapeutic response. This includes inflammatory reactions at sites of tumor 
resections or in draining lymph nodes, or at sites suspicious for, but not diagnostic of 
metastasis. 
 Hospitalization for ≤ Grade 2 adverse events where the primary reason for hospitalization is 
to expedite the clinical work-up. 
 Patients with the following conditions where in the investigator’s opinion continuing study 
drug administration is justified: 
 Ocular toxicity that has responded to topical therapy. 
 Endocrinopathies where clinical symptoms are controlled with appropriate hormone 
replacement therapy. Note: Ipilimumab may not be restarted while the patient is being 
treated with systemic corticosteroids except for patients on stable doses of hormone 
replacement therapy such as hydrocortisone. 
 
11.7  Dose Modifications for Obese Patients 
 
There is no clearly documented adverse impact of treatment of obese patients when dosing is performed 
according to actual body weight. Therefore, all dosing is to be determined solely by (1) the patient’s 
BSA as calculated from actual weight or (2) actual weight without any modifications unless explicitly 
described in the protocol. This will eliminate the risk of calculation error and the possible introduction 
of variability in dose administration. Physicians who are uncomfortable with administering 
chemotherapy dose(s) based on actual body weight should not enroll obese patients. 
 
11.8. Blinding 
 
This is an open-label study; therefore, each patient will be aware of his or her own assigned treatment. 
All staff involved in treating and caring for study patients will have full knowledge of treatment 
assignments for those patients under their care. 
 
11.9. Concomitant Therapy 
Patients are allowed to receive full supportive care therapies concomitantly during the study. All 
standard pretreatment and supportive care medications for chemotherapy may be used including 
corticosteroids used for that purpose. Any disease progression requiring other forms of specific anti-


72 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
tumor therapy will be cause for early discontinuation of study therapy. The following concomitant 
therapies warrant special attention: 
 
11.9.1  Colony Stimulating Factors (CSFs) 
 
 The American Society of Clinical Oncology guidelines for use of CSF should be followed 
(http://www.asco.org/guidelines/wbcgf) [64]. Granulocyte colony-stimulating factor (G-CSF) may be 
used for patients who have ANC 0.5x109/L, neutropenic fever, or documented infections while 
neutropenic. Duration of uncomplicated neutropenia before initiation of G-CSF treatment is left to the 
investigator’s discretion. Granulocyte colony-stimulating factor must be discontinued at least 24 hours 
prior to the start of the next cycle of chemotherapy. If a patient develops hematologic toxicities, 
chemotherapy dose reduction and acute treatment of neutropenia are recommended, rather than 
chemotherapy dose maintenance and pre-emptive treatment with G-CSFs. Use of erythropoietin (e.g., 
Aranesp, Procrit) is allowed. Use of stimulators of thrombopoiesis is not allowed. 
 
 
11.9.2 Antiemetic Agents 
 
For patients in both study arms, the use of a prophylactic anti-emetic regimen including a 5-HT3 
antagonist is suggested. Aprepitant may be used prior to cisplatin.  Anti-emetic therapy should be 
administered according to standard local practice for patients receiving mildly to moderately emetic 
chemotherapy regimens and is at the discretion of the treating physician.  
 
11.9.3  Therapy for Diarrhea 
 
In the event of CTC Grade 3 or 4 diarrhea, it will be treated like ipilimumab immune related diarrhea 
(see section 11.5.4 Enterocolotis. Refer to Appendix L). The following supportive measures are 
allowed: corticosteroids, hydration, octreotide, and antidiarrheals. 
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or severe 
neutropenia (Grade 3 or 4), broad-spectrum antibiotics should be prescribed. Patients with severe 


73 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
diarrhea or any diarrhea associated with severe nausea or vomiting should be hospitalized for 
intravenous hydration, correction of electrolyte imbalances, and other treatment as necessary. 
 
11.9.4 Therapy for Patients with Febrile Neutropenia 
 
Patients experiencing chemotherapy related febrile neutropenia should be managed in a hospital setting 
according to standard procedures, with the urgent initiation of intravenous antibiotic therapy. Refer to 
section 11.9.1 for use of CSFs. 
 
12.0 Prohibited Therapies During the Study 
 
Prohibited Therapies 
 
Patients in this study may not use vaccines for the treatment of cancer or prevention of disease unless 
indicated as a component of the protocol regimen (including those for common medical conditions) for 
up to one-month pre and post dosing with ipilimumab. Concomitant systemic or local anti-cancer 
medications or treatments are prohibited in this study while receiving ipilimumab treatments. 
 
Patients may not use any of the following therapies during the study:  
 Any non-study anti-cancer agent (investigational or non-investigational) this includes 
chemotherapy, immunotherapy, hormonal cancer therapy, biologics/targeted therapies, 
radiation therapy, surgery for cancer, or experimental medications patients. Any disease 
progression requiring other forms of specific anti-tumor therapy will be cause for early 
discontinuation of study therapy 
 Any other investigational agents 
 Any other CTLA-4 inhibitors or agonists. 
 Any anti-PD1 inhibitor or agonist. 
 CD137 agonists 
 Immunosuppressive agents [except those used to treat ipilimumab related immune related 
adverse events (irAEs) and standard antiemetics & premedication for paclitaxel or platins]. 
 Chronic systemic corticosteroids unless as physiologic dose for adrenal function 
replacement. 
 Any non-oncology vaccine therapies used for the prevention of infectious diseases (for up to 
30 days prior to or after any dose of study drug). 
 


74 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
13.0  Treatment Compliance 
 
Patient compliance with study medication will be assessed at each visit. Deviation(s) from the 
prescribed dosage regimen should be recorded in the comments section of the CRF. 
 
 
14.0   Discontinuation 
 
14.1. Discontinuation of Study Patients 
 
If a patient who does not meet enrollment criteria is inadvertently enrolled, that patient should be 
discontinued from the study treatment and the principal investigator must be contacted. In addition, 
patients will be discontinued from study treatment in the following circumstances: 
 
 There is clear evidence of progressive disease.  
 In previous studies with ipilimumab in solid tumors there has been transient increase in lesion 
size due to inflammatory immune response followed by clear evidence of lesion regression. 
Therefore, CAT scan evidence of progression in the global tumor burden will not be criteria for 
discontinuation or by itself deemed evidence of progression on therapy. It is possible index 
tumor may enlarge > 25% or new lesions appear after 2 doses Ipilimumab before repeat CAT 
scan. Surgical staging at time of resection will verify progression or whether robust 
inflammatory response was mis-interpreted as progression on repeat CAT scans. 
 There is toxicity deemed by the investigator or patient as unacceptable. 
 The patient is noncompliant with study procedures. 
 The investigator decides that the patient should be withdrawn.  
 Pregnancy:  All WOCBP should be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g. missed or late menstrual period) at any time during study 
participation. Institutional policy and local regulations should determine the frequency of no 
study pregnancy tests for WOCBP enrolled in the study. The investigator must immediately 
notify BMS in the event of a confirmed pregnancy in a patient participating in the study. 
The patient or attending physician requests that the patient be withdrawn from the study. 
 The investigator, for any reason, stops the study or stops the patient's participation in the study. 


75 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 Termination of the study by Bristol-Myers Squibb (BMS) 
 The patient, for any reason, requires treatment with another systemic agent potentially effective 
for treatment of the study indication. In this case, discontinuation from the study occurs 
immediately upon introduction of the new agent. 
 A patient who cannot be administered the study drug after a 21-day delay must be discontinued 
from the study treatment. 
 Bulky residual adenopathy such that resection is not attempted will be removed from protocol 
therapy and should receive standard oncology care as deemed appropriate by the treating 
physician. 
 Subjects with positive surgical margins or N2 disease post-surgery. 
 Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
 Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the opinion of 
the investigator, indicates that continued treatment with study therapy in not in the best interest 
of the subject 
 The compulsory detention for the treatment of either a psyhchiatric or physical (e.g. infections 
disease) illness. 
 
For patients who discontinue the study treatment early, every effort must be made to complete the post 
treatment summary visit during which time the end-of-therapy procedures described in the Study 
Schedule (Appendix A) should be performed. The post treatment summary visit (End of Study=EOS) 
will commence approximately 30 days from the last dose of study drug. 
 
14.2. Discontinuation of Study  
This study can be terminated at any time for any reason by the PI-sponsor or the IRB.  If this occurs, all 
subjects on study should be notified as soon as possible.  Additional procedures and/or follow up should 
occur in accordance with Section 9.0 which describes procedures and process for prematurely 
withdrawn patients. 
 
 
 
 


76 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
15.0  Ipilimumab Drug Supply 
 
Bristol-Myers Squibb (BMS) will provide ipilimumab at no cost for this study. 
15.1.    Identification 
Ipilimumab is available in concentrations of 5 mg/mL (50 mg/10 mL and 200 mg/40 mL). The sterile 
solution in the vial is clear and colorless. Ipilimumab is administered via intravenous infusion only. 
 
15.2 
 Packaging and Labeling 
BMS will provide ipilimumab at no cost for this study. Ipilimumab will be provided in open-label 
containers.  The labels will contain the protocol prefix, batch number, content, storage conditions, and 
dispensing instructions along with the Investigational New Drug (IND) caution statement. 
 
15.3 
Storage, Handling, and Dispensing 
15.3.1  Storage 
Ipilimumab must be stored in a secure area according to local regulations. The investigator must ensure 
that it is stored at a temperature  2C and  8C. 
 
15.3.2   Handling and Disposal 
As with all injectable drugs, care should be taken when handling and preparing ipilimumab. Whenever 
possible, ipilimumab should be prepared in a laminar flow hood or safety cabinet using standard  
precautions for the safe handling of intravenous agents applying aseptic technique. Latex gloves are 
required. If ipilimumab concentrate or solution comes in contact with skin or mucosa, immediately and 
thoroughly wash with soap and water. After final drug reconciliation, unused ipilimumab solution 
should be disposed at the site following procedures for the disposal of anticancer drugs. 
 
 
 
 


77 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
15.3.3   Dispensing 
It is the responsibility of the investigator to ensure that ipilimumab is only dispensed to study subjects. 
The ipilimumab must be dispensed only from official study sites by authorized personnel according to 
local regulations. 
 
15.4 
Drug Ordering and Accountability 
 
15.4.1 Initial Orders 
Following submission and approval of the required regulatory documents, a supply of ipilimumab may 
be ordered from BMS. Investigators must complete a Drug Request Form and email it to: 
distribution.allentown@thermofisher.com. 
 
If for any reason the e-mail drug request form is not successfully transmitted, contact Emily Kahora at 
Fisher Clinical Services: 
Phone: +1 484.538.2121 
Fax: +1 610.871.9382 
Email: emily.kahora@thermofisher.com or www.fisherclinicalservices.com. 
It is recommended you send a test message to the Fisher Clinical Service e-mail address upon receipt of 
the Drug Request Form. Please include in the subject line: “BMS IST Drug Order -- Test.” This will 
ensure your site is recognized by Fisher and your future orders will be received without incident. 
Ipilimumab vials (40 mL) are shipped in quantities of five. The initial order should be limited to 25 vials 
(5 cartons of 5 vials each). Allow 5 business days for shipment of drug from BMS receipt of the Drug 
Request Form. Drug is protocol specific, but not patient specific. All product will be shipped via Federal 
Express in a temperature-controlled container. Shipments will be made from Fisher Clinical Services on 
Monday through Thursday for delivery onsite Tuesday through Friday. There will be no weekend or 
holiday delivery of drugs. 
It is possible that sites may have more than one ipilimumab clinical study ongoing at the same time. It is 
imperative that only product designated for this protocol number be used for this study. To help 
segregate product for this study from other investigational or marketed product, stickers bearing the 
BMS protocol number will be provided and should be affixed to the front of the outer carton just above 
the company names so as not to obscure any marking. 
 


78 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
15.4.2   Re-Supply 
Reorders 
should 
be 
emailed 
directly 
to 
Fisher 
Clinical 
Services 
(distribution.allentown@thermofisher.com) for shipment within 5 business days. When assessing need 
for resupply, institutions should keep in mind the number of vials used per treatment dose, and that 
shipments may take 5 business days from BMS receipt of request. Drug is not patient specific. Be sure 
to check with your pharmacy regarding existing investigational stock to assure optimal use of drug on 
hand. 
 
15.4.3   Ipilimumab Accountability 
It is the responsibility of the investigator to ensure that a current record of ipilimumab disposition is 
maintained at each study site where ipilimumab is inventoried and disposed. Records or logs must 
comply with applicable regulations and guidelines, and should include: 
 Amount received and placed in storage area. 
 Amount currently in storage area. 
 Label ID number or batch number and use date or expiry date. 
 Dates and initials of person responsible for each ipilimumab inventory entry/movement. 
 Amount dispensed to and returned by each subject, including unique subject identifiers. 
 Amount transferred to another area/site for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted, broken). 
 Amount destroyed at study site. 
  
15.4.4   Ipilimumab Destruction 
If ipilimumab is to be destroyed on site, it is the investigator’s responsibility to ensure that arrangements 
have been made for disposal and that procedures for proper disposal have been established according to 
applicable regulations, guidelines, and institutional procedures. Appropriate records of the disposal must 
be maintained. 
 
15.5    Preparation, and Administration 
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. 
 Do not shake product. 


79 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 Inspect parenteral drug products visually for particulate matter and discoloration prior to 
administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution 
may have pale yellow color), or there is foreign particulate matter other than translucent-to-
white, amorphous particles. 
 
Preparation of Solution 
 Allow the vials to stand at room temperature for approximately 5 minutes prior to preparation 
of infusion. 
 Withdraw the required volume of ipilimumab and transfer into an intravenous bag. 
 Store the prepared solution for no more than 24 hours under refrigeration (2°C to 8°C, 36°F 
to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F). 
 Discard partially used vials or empty vials of ipilimumab. 
 
Administration Instructions 
 Do not mix ipilimumab with, or administer as an infusion with, other medicinal products. 
 Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 0.5% Dextrose 
Injection, USP after each dose. 
 Administer diluted solution over 90 minutes through an intravenous line containing a 
sterile, non-pyrogenic, low-protein-binding in-line filter 0.2 micron filter. 
See the current Investigator Brochure for additional information on allowable filter types.  The 
infusion must be completed in 90 minutes with a 10 ml normal saline flush at the end. 
Ipilimumab should be administered under the supervision of a physician experienced in the use 
of intravenous (IV) agents. Ipilimumab is administered as an IV infusion only. 
 
15.6   Dose Calculations 
Each patient will receive ipilimumab: 
Calculate Total Dose as follows: 
Patient body weight in kg x (x) mg = total dose in mg 
Calculate Total Infusion Volume as follows: 
Total dose in mg ÷ 5 mg/mL = infusion volume in mL 
Calculate Rate of Infusion as follows: 
 Infusion volume in mL ÷ 90 minutes = rate of infusion in mL/min x 60 = ml/hr. 


80 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
For example, a patient weighing 114 kg (250 lb) would be administered 1140 mg of ipilimumab (114 
kg x 10 mg/kg = 1140 mg) with an infusion volume of 228 mL (1140 mg ÷ 5 mg/mL = 228 mL) at a 
rate of approximately 2.5 mL/min (228 mL ÷ 90 minutes) x 60 minutes = 150 ml/hr. 
The total dose must be calculated using the most recent subject weight (obtained within 3 days of the 
dosing visit, and prior to the infusion). Rounding to a whole number is acceptable. Dose does not 
change unless weight changes > 10% from baseline. 
 
16. OUTCOME MEASUREMENTS 
 
16.1 Criteria for Response, Progression, and Relapse (Solid Tumors) 
 
Patients should be reevaluated by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) after 
completion of neoadjuvant ipilimumab and chemotherapy (planned 3 cycles). Unidimensional 
measurements in the largest diameter will be used. 
 
 
16.1.1 Measurable Disease 
 
Measurable lesions are defined as those that can be accurately measured (select largest, most 
reproducible lesions) in at least one dimension (largest diameter in the plane of measurement is to be 
recorded) as ≥20 mm with x-ray or ≥10 mm with CT scan (CT scan slice thickness ≤5 mm) or MRI. If 
scan has slice thickness >5mm, the minimum size for a measurable lesion should be twice the slice 
thickness. Measurable lesions will also include those that can be directly measured on physical exam 
with calipers and are at least 10 mm. Lesions which cannot be accurately measured with calipers should 
be recorded as non-measurable. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
 
16.1.2 Non-Measurable Disease 
 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with x-ray or 
<10 mm using CT or MRI scan), are considered non-measurable disease. Lesions considered non-
measurable include: bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitic involvement of skin or lungs, inflammatory breast disease, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging techniques. 
 
 
 
 


81 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
16.1.3 Target Lesions 
 
All measurable lesions up to a maximum of two lesions per organ (total 5 maximum target lesions) are 
considered target lesions. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques 
or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD.  
The baseline sum LD will be used as reference by which to characterize the objective tumor response. 
 
 
16.1.4 Non-Target Lesions 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Non-target lesions include measurable lesions that exceed the maximum numbers 
per organ or total of all involved organs as well as non-measurable lesions. Measurements of these 
lesions are not required but the presence or absence of each should be noted throughout follow-up. 
 
 
16.1.5 Guidelines for Evaluation of Measurable/Evaluable Disease  
 
If subject has measurable disease, all measurements should be taken and recorded in metric notation. For 
subjects with evaluable disease only, the sites of disease will be noted at baseline and followed for 
increase or decrease in size and/or new disease. All baseline evaluations should be performed as closely 
as possible to the beginning of treatment and never more than 30 days before the beginning of the 
treatment, unless otherwise specified. 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 when both methods have been used to 
assess the antitumor effect of a treatment. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm 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. 
 
CT and MRI: These techniques should be performed with cuts of 5 mm or less in slice 
thickness contiguously. If scan has slice thickness >5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. CT is currently the best available 
and reproducible method to measure lesions for response assessment. 
 
Laryngoscopy, Endoscopy: Such techniques can be useful to evaluate patients for 
response in SCCHN and may be used in tumor measurement. 


82 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
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). 
 
 
16.2   Response Criteria 
 
Evaluation of Target Lesions 
       Complete Response (CR): Disappearance of all target lesions 
 
Partial Response (PR): At least a 30% decrease in the sum of the largest diameter (LD) of 
target lesions, taking as reference the baseline sum LD 
 
Progressive Disease (PD): At least a 20% increase and a 5 mm absolute increase in the 
sum of the LD of target lesions, taking as reference the smallest sum LD recorded since 
the treatment started or the appearance of one or more new lesions. If scan showing new 
lesion is of anatomical region which was not included in baseline scans, it is PD. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the treatment started 
 
 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level 
 
Incomplete Response/Stable Disease (SD): 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 (not attributable to different scanning technique or non-tumor) of existing 
non-target lesions. (‘Unequivocal progression’ must be an overall level of substantial 
worsening in non-target disease that is of a magnitude that, even in the presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.) If scan showing new lesion is of anatomical region which 
was not included in baseline scans, it is PD. 
 
 
 
 


83 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Table 10: Evaluation of Best Overall Response 
 
 
 
16.21      
16.I 
 
 
 
 
 
 
 
 
 
 
 
 
 
16.21  Immune-Related Tumor Assessment 
 
Ipilimumab is an immuno-stimulating antibody with evidence of anti-cancer activity (durable 
objective response and stable disease) in subjects with advanced melanoma, including subjects 
with established brain disease. Observations of clinical activity defined by tumor response 
endpoints defined by conventional criteria (eg, mWHO) may be inadequate to realize the kinetics 
and magnitude of clinical benefit achieved with ipilimumab. 
 
Histopathologic evidence has demonstrated ipilimumab can produce an influx or expansion of 
tumor infiltrating lymphocytes. Therefore, early increases in lesion size detected radiologically or 
upon gross examination could be misinterpreted as progressive tumor growth and precede objective 
tumor shrinkage. In addition the appearance of new lesions may have categorized a subject to 
have progressive disease using conventional tumor assessment criteria despite the concurrent 
observation of objective tumor responses in pre-existing lesions and a net reduction in global 
tumor burden that includes the new lesions. 
Therefore, patients with evidence of possible target lesion growth or new lesion appearance will not be 
presumed to have progressed and will proceed to surgery as long as all possible site of disease are 
deemed resectable by the surgeon. 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


84 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
 
16.3 Cytology and Histology 
 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. These techniques can be used to differentiate between PR and CR in rare cases (for 
example, 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. 
 
Pathologic Response Criteria 
After receiving preoperative chemotherapy + Ipilimumab, criteria for examining resected tumor will be 
as follows: 
 No Response no evidence of cell death or tumor necrosis. 
 Partial Response ≥30% tumor necrosis or cell death. 
 Complete Response no evidence of viable tumor in surgical specimen (includes lung tissue 
and dissected lymph nodes) 
 
 
16.4 Disease-Free Survival 
 Disease-free survival (DFS) is defined as the time from surgical resection to disease recurrence (first 
disease recurrence or death, whichever comes first) after surgery. 
 
 
16.5 Survival 
Survival will be measured from the date of enrollment. 
 
 
 
 


85 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
 
17.0   Safety 
All patients who receive at least one dose of ipilimumab will be considered evaluable for safety 
parameters. Additionally, any occurrence of non-SAE or SAE from time of consent forward, up to and 
including follow-up visits will be reported as per Adverse Event Reporting sections below. Safety will 
be evaluated for all treated patients using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE), Version 4.0 (http://ctep.cancer.gov). Safety assessments will be 
based on medical review of adverse event reports and the results of vital sign measurements, physical 
examinations, and clinical laboratory tests. 
 
 
 
 17.1   Documentation of Adverse Events 
 
Investigators are responsible for monitoring the safety of patients who have entered this study and       
for alerting BMS or its designee to any event that seems unusual, even if this event may be considered 
an unanticipated benefit to the patient. The investigator is responsible for appropriate medical care of 
patients during the study. The investigator remains responsible for following, through an appropriate 
health care option, adverse events that are serious or that caused the patient to discontinue before 
completing the study. The patient should be followed until the event is resolved or explained. Frequency 
of follow-up evaluation is left to the discretion of the investigator. Safety measures that will be used in 
the study include physical examinations, and clinical laboratory tests (e.g., hematology, blood 
chemistries, and CrCl). Patients will be rated for toxicity prior to each cycle using the NCI CTCAE scale 
version 4.0. Refer to the Study Schedule (Appendix A) for timing of safety measures. 
 
An adverse event (AE) is the development of an unfavorable or unintended sign, symptom, disease or 
the deterioration of a pre-existing condition that occurs while a patient is enrolled on a clinical trial, 
whether the event is considered related or unrelated to the study treatment. An adverse event is any 
adverse change from the subject’s baseline (pretreatment) condition; including any clinical or lab test 
abnormality that occurs during the course of research after treatment has started.  Adverse events will 
use the descriptions and grading scales found in the NCI Common Toxicity Criteria for Toxicity and 
Adverse Event Reporting, Version 4.0 (CTCAE; CTEP home page: http://ctep.info.nih.gov). 
 
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.) 
 
 


86 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
17.1.1. Adverse Event Reporting 
 
 
All adverse clinical experiences, whether revealed by observation, physical examination or other 
diagnostic procedures by the investigator, or reported by the patient, must be recorded regardless of 
treatment or suspected causal relationship. Information for the adverse event should include a 
description with details as to the duration and intensity of each event, the causal relationship to the study 
drug, the action taken with respect to the study drug, and the patient’s outcome. Any adverse event that 
is expected, not serious or not related to the research study should be reported as part of the routine 
clinical data. All adverse events should be recorded in the patient’s medical record and on the case 
report form. 
 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its 
individual symptoms. The following information should be captured for all AEs: onset, duration, 
intensity, seriousness, relationship to investigational product, action taken, and treatment required. If 
treatment for the AE was administered, it should be recorded in the medical record.  
 
 
Subjects having adverse events will be monitored with relevant clinical assessments and laboratory tests 
as determined by the investigator. All adverse events are to be followed to satisfactory resolution or 
stabilization of the event(s). 
 
Any actions taken and follow-up results must be recorded on the appropriate page of the case report 
form as well as the subject’s source documentation (medical record). 
 
For all adverse events that require the subject to be discontinued from the study, relevant clinical 
assessments and laboratory tests must be repeated at clinically appropriate intervals until satisfactory 
resolutions or stabilization of the event(s). 
 
Cases of pregnancy that occur during maternal or paternal exposures to study drugs should be reported 
for tracking purposes. Additional data on fetal outcome and breastfeeding are collected for regulatory 
reporting and drug safety evaluation. This data also includes cases of pregnancies that occur during 
paternal exposures to Bristol Myers Squibb study drug. Lack of drug effect is not an adverse event in 
clinical trials because the purpose of the clinical trial is to establish drug effect. 
 
If a patient never receives study drug, but experiences an adverse event after the informed consent 
document is signed, ONLY events the investigator believes may have been caused by a protocol 
procedure will be reported. 
 
 


87 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
All adverse events occurring after enrollment will be documented and recorded on the CRF and any 
additional required forms. Adverse events are to be reported for 30 days after the patient’s last dose of 
study drug and for any events beyond that time in which the investigator believes the event is related to 
study drug or study related procedures. 
 
Events leading to the clinical outcome of death due to NSCLC will be included as part of the safety 
and efficacy analyses for this study, and will not be reported as adverse events via CRF unless the 
investigator believes the event may have been caused by the study drug or drug delivery system. 
 
 
17.1.2. Serious Adverse Events  
 
Study site personnel must alert BMS and the principal investigator immediately of any “serious” 
(defined below) adverse event experienced by a patient. In addition, adverse events must be reported to 
regulatory authorities according to the definitions and timelines specified in the local laws and 
regulations. 
An unexpected adverse event is any adverse drug experience where the specificity or severity is not 
consistent with the current investigator brochure; or, if an investigator brochure is not available, the 
specificity or severity of which is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. 
Serious events are those that result in: 
 death 
 initial or prolonged inpatient hospitalization 
 a life-threatening experience (that is, immediate risk of dying) 
 persistent or significant disability/incapacity 
 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.)   
 
The following hospitalizations are not considered SAEs: 
 a visit to the emergency room or other hospital department lasting less than 24 hours that does 
not result in admission (unless considered an “important medical event” or a life-threatening 
event) 
 admissions as per protocol for a planned medical/surgical procedure 
 routine health assessment requiring admission for baseline/trending of health status (eg, routine 
colonoscopy) 


88 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 medical/surgical admission for purpose other than remedying ill health state that was planned 
before study entry. 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). 
 
 
Hospitalization for elective surgery or routine clinical procedure (such as for study drug administration) 
that are not the result of an adverse experience (e.g. elective surgery for a pre-existing condition) are not 
considered SAE’s and should be recorded on the appropriate case report form. Hospitalization and/or 
death that are unequivocally due to progression of disease should not be reported as an SAE. 
 
Exception: BMS will be alerted to a study-specific clinical outcome of death due to progressive disease 
as a serious adverse event only if the investigator deems it to be related to use of the study drug. 
 
Serious adverse event collection begins after the patient has signed informed consent and has received a 
study drug. If a patient experiences an SAE after signing informed consent, but prior to receiving study 
drug, the event will normally NOT be collected unless the investigator believes the event may have been 
caused by a protocol procedure.  
 
Serious adverse events will be collected for 30 days after the last dose of study drug, and serious adverse 
events occurring 30 days after a patient is discontinued from the study will NOT be reported unless the 
investigator feels that the event may have been caused by the study drug or a protocol procedure. 
 
 
17.1.3. Serious Adverse Event Reporting 
 
All serious adverse event (SAE) reports should include the patient study number, age, sex, weight, 
severity or reaction, relationship to the study drug(s), date of administration of test medications and all 
concomitant medication and medical treatment provided. This information is to be recorded on FORM 
3500, which can be located at: www.fda.gov/medwatch/getforms.htm. 
 
The SAE report should be comprised of full written summary detailing relevant aspects of the adverse 
event in question. Where applicable, information from relevant hospital case records and autopsy reports 
should be obtained. If the investigator does not have all information regarding the event, he/she will not 
wait to received additional information, but file the information currently available and update the 
summary when additional information is received. The investigator is to provide an assessment of 
causality at the time of the initial report. 
 
Any adverse event that is serious, unexpected, and/or study related which occurs in any patient in the 
course of their treatment on the research study or within 30 days following cessation of treatment must 


89 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
be reported within 24 hours of the investigator learning of its occurrence. This can be by phone and 
should be followed promptly by a detailed, written report. In addition, any serious event that is 
unexpected (i.e. not in the current package inserts or the Investigator Brochures) and associated with use 
of the study drug(s), must be reported to the FDA within 15 calendar days, or within 7 calendar days if 
the SAE is life-threatening or fatal.  
 
Copies of completed Medwatch forms (FORM 3500) should be sent to: 
 FDA:  Fax # 1-800-FDA-0178 
 Principal Investigator:  Neal Ready, MD: Fax # 919-684-8926 
 All SAEs should be faxed or emailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
Serious adverse events that occur on any Duke subject and/or IND safety reports that are received from 
BMS will be processed by the DCI Safety Desk. SAEs/IND Safety reports will be reported to the DUHS 
IRB per institutional reporting guidelines. 
 
 
17.1.4  Assignment of Adverse Event Intensity and Relationship to Investigational 
Product 
All adverse events, including those that are serious will be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0. 
 
The following categories and definitions of causal relationship to investigational product as determined 
by a physician should be used: 
 
Related: There is a reasonable causal relationship to investigational product administration and  
the adverse event. 
 
Not Related: There is not a reasonable causal relationship to investigational product 
administration and the adverse event. 
 
The expression “reasonable causal relationship” is meant to convey in general that there are facts (e.g., 
evidence such as de-challenge/re-challenge) or other arguments to suggest a positive causal relationship. 
 
 
 


90 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
17.1.5   Pregnancy 
 
Sexually active WOCBP must use an effective method of birth control during the course of the study, in 
a manner such that risk of failure is minimized. Before enrolling WOCBP in this clinical study, the 
investigator must review the guideline about study participation for WOCBP which can be found in the 
GCP Manual for Investigators. The topics include the following: 
 General Information 
 Informed Consent Form 
 Pregnancy Prevention Information Sheet 
 Drug Interactions with Hormonal Contraceptives 
 Contraceptives in Current Use 
 Guidelines for the Follow-up of a Reported Pregnancy. 
 
Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during 
study participation and the potential risk factors for an unintentional pregnancy. The subject must sign 
an informed consent form documenting this discussion. 
All WOCBP MUST have a negative pregnancy test within 72 hours before receiving ipilimumab. 
The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG. If the 
pregnancy test is positive, the subject must not receive ipilimumab and must not be enrolled in the study. 
 
In addition, all WOCBP should be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
 
If, following initiation of the investigational product, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of investigational product exposure, including during at 
least 6 half-lives after product administration, the investigational product will be permanently 
discontinued in an appropriate manner (e.g., dose tapering if necessary for subject safety). The 
investigator must immediately notify BMS of this event and record the pregnancy on the Pregnancy 
Surveillance Form (not an SAE form). Initial information on a pregnancy must be reported immediately 
to BMS, and the outcome information provided once the outcome is known. Completed Pregnancy 
Surveillance Forms must be forwarded to BMS according to SAE reporting procedures. 


91 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Any pregnancy that occurs in a female partner of a male study participant should be reported to the 
sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the subject 
unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy follow-up 
procedures should be considered if indicated. In addition, the investigator must report to BMS, and 
follow-up on information regarding the course of the pregnancy, including perinatal and neonatal 
outcome. Infants should be followed for a minimum of 8 weeks. 
 
 
17.1.6   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 in the medical record. 
 
17.1.7   Safety Oversight Committee (SOC) 
 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS sponsor-
investigator phase I and II, therapeutic interventional studies that do not have an independent Data 
Safety Monitoring Board (DSMB). The primary focus of the SOC is review of safety data, toxicities and 
new information that may affect subject safety or efficacy. Annual safety reviews includes but may not 
be limited to review of safety data, enrollment status, stopping rules if applicable, accrual, toxicities, 
reference literature, and interim analyses as provided by the sponsor-investigator.  The SOC in concert 
with the DCI Monitoring Team (see Section 12.1 for Monitoring Team description) oversees the 
conduct of DUHS cancer-related, sponsor-investigator therapeutic intervention and prevention 
intervention studies that do not have an external monitoring plan, ensuring subject safety and that the 
protocol is conducted, recorded and reported in accordance with the protocol, standing operating 
procedures (SOPs), Good Clinical Practice (GCP), and applicable regulatory requirements. 
 
 
 


92 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
18.0 Quality Control and Quality Assurance 
 
18.1   Monitoring Plan 
Review of this protocol begins with an initial review by the CPC, Cancer Center Protocol Committee 
(CPC), which performs a risk assessment of the trial. The PI will abide by their assessment of the level 
of risk, which will determine the intensity of subsequent external monitoring. Documentation of this 
assessment will be maintained. 
 
The clinical research study will be monitored both internally by the PI and by the Duke Cancer Institute 
(DCI) Monitoring Team in accordance with their NCI-approved “Institutional Protocol Monitoring 
Procedures and Guidelines for NIH-sponsored Research Involving Human Subjects”.  The monitoring 
team will conduct visits to ensure subject safety and to ensure that the protocol is conducted, recorded 
and reported in accordance with the protocol, standard operating procedures, good clinical practice, and 
applicable regulatory requirements.  As specified in the DCI monitoring plan, they will conduct routine 
monitoring after the third subject is enrolled, followed by annual monitoring of 1-3 subjects until the 
study is closed to enrollment and subjects are no longer receiving study interventions that are more than 
minimal risk. 
Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of 
serious and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and 
DCI leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee (SOC), the 
sponsor, Principal Investigator, or the IRB.  All study documents must be made available upon request 
to the DCI Monitoring Team and other authorized regulatory authorities, including but not limited to the 
National Institute of Health, National Cancer Institute, and the FDA. 
 
In terms of internal review, the PI (with the help of the statistician) will continuously monitor and 
tabulate adverse events. Appropriate reporting to the Duke University Medical Center IRB will be made. 
If an unexpected frequency of grade 3 or 4 events occurs, depending on their nature, action appropriate 
to the nature and frequency of these adverse events will be taken. This may require a protocol 
amendment, dose de-escalation, or potentially closure of the study. The PI of this study will also 
continuously monitor the conduct, data, and safety of this study to ensure that: 
 
 


93 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 Interim analyses occur as scheduled (if applicable); 
 Stopping rules for toxicity and/or response are met; 
 Risk/benefit ratio is not altered to the detriment of the subjects; 
 Appropriate internal monitoring of adverse events and outcomes is done; 
 Over-accrual does not occur; 
 Under-accrual is addressed with appropriate amendments or actions; 
 Data are being appropriately collected in a reasonably timely manner. 
 
 
 
18.2 Audits 
 
The Duke School of Medicine Clinical Trials Quality Assurance (CTQA) office may conduct audits to 
evaluate compliance with the protocol and the principles of GCP.  The PI agrees to allow the CTQA 
auditor(s) direct access to all relevant documents and to allocate his/her time and the time of the study 
team to the CTQA auditor(s) in order to discuss findings and any relevant issues. 
 
CTQA audits are designed to protect the rights and well-being of human research subjects. CTQA audits 
may be routine or directed (for cause). Routine audits are selected based upon risk metrics generally 
geared towards high subject enrollment, studies with limited oversight or monitoring, Investigator 
initiated Investigational Drugs or Devices, federally-funded studies, high degree of risk (based upon 
adverse events, type of study, or vulnerable populations), Phase I studies, or studies that involve 
Medicare populations. Directed audits occur at the directive of the IRB or an authorized Institutional 
Official. 
 
CTQA audits examine research studies/clinical trials methodology, processes and systems to assess 
whether the research is conducted according to the protocol approved by the DUHS IRB. The primary 
purpose of the audit/review is to verify that the standards for safety of human subjects in clinical trials 
and the quality of data produced by the clinical trial research are met. The audit/review will serve as a 
quality assurance measure, internal to the institution. Additional goals of such audits are to detect both 
random and systemic errors occurring during the conduct of clinical research and to emphasize “best 
practices” in the research/clinical trials environment. 
 


94 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
19.0. Investigator Responsibilities 
 
The conduct of the study will comply with all FDA safety reporting requirements. 
Serious adverse events (SAE) will be recorded on the Duke IRB Adverse Event Reporting Form and 
will be reviewed and signed by the principal investigator. Only adverse events that are deemed to be 
serious, unexpected and related, or possibly related to the research must be reported to the Duke 
Institutional Review Board (IRB) in accordance with institutional policy. 
 
If the investigator learns of any SAE, including death or congenital abnormality at any time after a 
subject has been discharged from the study, and he/she considers the event reasonable related to the 
study drug, the investigator should promptly file a report. 
 
 
 
20.0. Departure from the Protocol 
 
There should be no departure from the protocol if at all possible. If an emergency occurs that requires 
departure from this protocol, the principal investigator or other physician in attendance in such an 
emergency will, if circumstances and time permit, contact the PI immediately by phone. Such contacts 
with the PI will be made to permit a decision as to whether or not the subject will be continued on study. 
Such departures need to be clearly documented on the Duke Notification of Protocol 
Deviation/Violation form. A protocol deviation or violation is reportable to the IRB if the event is likely 
to adversely affect: (i) the rights and welfare of the research subject; (ii) the safety of the research 
subject; (iii) the integrity of the research data; and/or (iv)the subject’s willingness to continue study 
participation. Such events should be reported to the DUHS IRB within 10 business days of the time the 
PI becomes aware of the event; however, an unanticipated study-related death must be reported to 
the DUHS IRB within 24 hours of the occurrence of the event. 
 
 
 
 
 


95 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
21.0. Subject Privacy 
 
All subject data will be identified by a subject identification number and subject initials only to protect 
the subject’s privacy. The data will be blinded accordingly in all data analysis. Subject names or 
identifiers will not be used in reports, presentations at scientific meetings, or publications in scientific 
journals. 
However, in compliance with federal guidelines, the investigator will permit representatives from the 
Duke School of Medicine Compliance Office and/or Duke Cancer Institute Monitoring team to review 
that portion of the subject’s medical record that is directly related to the study. This will include all 
relevant study documentation including medical histories to verify eligibility, laboratory test results to 
verify transcription accuracy, X-ray reports, admission/discharge summaries for hospital/outpatient 
admissions while the subject is on-study, and autopsy reports for deaths occurring during the study. As 
part of the required content of the informed consent, the subject will be informed that his medical record 
may be reviewed. Should access to the medical record require a separate waiver or authorization, it is 
the PI’s responsibility to obtain such permission from the patient in writing before the subject is entered 
into the study. 
 
22.0. Institutional Review  
Prior to patient accrual, this protocol and the protocol informed consent must be approved in writing by 
the Cancer Center Protocol Committee (CPC) of the Duke Comprehensive Cancer Center and the DUHS 
Institutional Review Board (IRB). A signed and dated statement that the protocol and informed consent 
have been approved by the CPC/IRB will be kept in the study binder in the Principal Investigator’s staff 
office. The term of study approval will not exceed one year. A progress report will be submitted 
annually to the IRB and re-approval obtained to continue the study. The IRB will also approve any 
significant changes to the protocol as well as a change of PI. The PI will report to the IRB any changes 
in the research protocol and all unanticipated problems involving risks to human subjects and others. No 
changes will be made in the research activity without IRB approval Records of all study review and 
approval documents will be kept on file by the PI and/or his/her staff. Adverse events will be reported to 
the IRB per institutional reporting guidelines. The IRB will receive notification of the completion of the 
study and final report within 3 months of study completion or termination. The PI will maintain an 
accurate and complete record of all submissions made to the IRB, including a list of all reports and 
documents. 


96 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
23.0 Informed Consent/Informed Consent Process 
    
 
The PI or designee will fully explain the purpose and potential risks and benefits of the study to the 
patient prior to enrollment, and address any questions posed by the patient. In accordance with federal 
guidelines, all patients will sign a statement of informed consent, which has been approved by the IRB. 
The patient will receive a copy of the executed consent document. The signed consent will be retained at 
the investigative site for each patient. The informed consent document serves as authorization as deemed 
under HIPAA and contains the appropriate statements regarding privacy and confidentiality of protected 
health information (PHI) as well as information on withdrawal from the study. The investigator or 
designee will explain to each patient (or legally authorized representative) the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits, and any 
discomfort the study may entail. Each patient will be informed that participation in the study is 
voluntary and that he/she may withdraw from the study at any time and that withdrawal of consent will 
not affect his/her subsequent medical treatment or relationship with the treating physician. The patient 
will have as much time as he/she may need to make an informed decision about the study and all 
treatment related questions will be answered. The consent discussion should occur in an exam room or a 
private area where it is just the research staff, the patient and his/her family/significant other(s) if 
desired. 
The informed consent will be given by means of a standard written statement, written in non-technical 
language. For those that cannot read, or are blind, the consenter will read the consent form verbatim in 
the presence of a witness. The patient will read and consider the statement before signing and dating the 
document, and should be given a copy of the signed document. If the patient is unable to sign, make 
another kind of mark (like an X) to indicate consent. The person obtaining consent will document at the 
bottom of the consent form that the consent was read out loud to the patient by (name of person 
obtaining consent).  If an X or mark is used instead of a signature, the person obtaining consent will note 
on the consent form that the subject wrote a mark or X instead of a signature.   The witness will sign the 
consent form. Subjects who do not read/understand English may be potentially enrolled following 
DUHS HRPP policy, including obtaining IRB approval of either a short form or long form consent 
translation. No patient will enter the study before his/her informed consent document has been obtained. 
Before, during, and after the consent is signed, the research team and investigators will be available in 


97 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
person and by phone to answer any questions the participants may have.  Any and all other available 
treatment options are offered to the patient in order to avoid undue influence.  Participants are not 
offered compensation for this study in order to avoid any monetary coercion/influence. The PI is 
responsible for ensuring that appropriate signatures have been obtained prior to the performance of any 
protocol procedures and prior to the administration of study drug. 
 
 
24.0 Data Collection and Maintenance 
 
24.1   Study Documentation 
 
Study documentation includes but is not limited to source documents, case report forms, monitoring 
logs, appointment schedules, study team correspondence with sponsors or regulatory bodies/committees, 
and regulatory documents that can be found in the DCI-mandated “Regulatory Binder”, which includes 
but is not limited to signed protocol and amendments, approved and signed informed consent forms, 
FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies receipts and distribution 
records. 
 
Source documents are original records that contain source data, which is all information in original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents include but are not limited to hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories 
and at medico-technical departments involved in the clinical trial.  When possible, the original record 
should be retained as the source document.  However, a photocopy is acceptable provided that it is a 
clear, legible, and an exact duplication of the original document. 
 
 
The research nurse, data manager and PI are responsible for ensuring that data extraction (information 
required by the protocol) is completed in a timely manner for every patient enrolled on study. The 
following forms are an integral part of the study data and will be maintained in the patient’s clinical 


98 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
chart. Any errors on the form should be lined through, but not obliterated with the correction inserted, 
initialed and dated by the person making the correction: 
 
 On-study Eligibility Checklist 
 
 DUHS Adverse Event Form (if applicable) 
 
 DUHS Protocol Deviation Form (if applicable) 
 
24.2   Case Report Forms 
 
An electronic CRF (eCRF) will be the primary data collection document for the study. The electronic 
records of subject data will be maintained using a dedicated database (Oracle Clinical or Redcap) which 
is housed in an encrypted and password-protected DCI file server).  Access to electronic databases will 
be limited to the PI and designated study staff listed on key personnel.  Subject data may be stored 
temporarily on encrypted and password-protected portable memory devices such as flash drives and 
external hard drives, but only when absolutely necessary.  Data stored on portable memory devices will 
be de-identified.  Subject data will be deleted from the portable memory device at the earliest 
opportunity.  The security and viability of the IT infrastructure will be managed by the DCI and/or Duke 
Medicine.   
The CRFs will be updated in a timely manner following acquisition of new source data.  Only the PI and 
designated staff (as listed on key personnel), will be permitted to make entries, changes, or corrections 
in the eCRF. 
An audit trail will be maintained automatically by the eCRF management system. (RedCap or Oracle 
Clinical database).  All users of this system will complete user training as required or appropriate per 
regulations. 
 
Users of the electronic CRF will have access based on their specific roles in the protocol.   
 
Completeness of entered data will be checked automatically by the eCRF system, and users will be 
alerted to the presence of data inconsistencies.  Additionally, the data manager and/or designess (per key 
personnel) will cross-reference the data to verify accuracy.  Missing or implausible data will be 
highlighted for the PI requiring appropriate responses (i.e. confirmation of data, correction of data, 
completion or confirmation that data is not available, etc.). 
 
The database will be reviewed and discussed prior to database closure, and will be closed only after 
resolution of all remaining queries.  An audit trail will be kept of all subsequent changes to the data. 
 
All medical terms will be coded with MedDRA(Medical Dictionary for Regulatory Activities).  
Medication will coded according to the World Health Organization Drug Dictionary. 


99 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
24.3   Study Closure 
 
Following completion of the studies, the PI will be responsible for ensuring the following activities have 
been completed if applicable for the study: 
 Date Clarification and/or resolution 
 Accounting, reconciliation, and destruction/return of used and unused study drugs 
 Review of site study records for completeness 
 Shipment of all remaining laboratory samples to designated laboratories. 
 
Upon completion of the study, research records will be archived and handled per DUHS HRPP policy.     
 
 
25.0 Appropriateness of Measurements 
There are no surrogate endpoints used in this study. All efficacy and safety assessments used in this 
study are standard and appropriate for an oncology study. 
 
 
26.0 Statistical Methods and Analytical Plans 
 
26.1. General Considerations 
 
STATISTICAL CONSIDERATIONS: 
 
Sample size justification 
The primary objective of the phase II trial is to determine the proportion of early stage lung cancer patients 
with detectable circulating T cells specific against TAA after receiving platinum based neoadjuvant 
chemotherapy plus ipilimumab before surgery.  Based on Duke ICS assessments over the past 8 years, 
“detectable” circulating T cells with specificity against TAA are defined as a CD8, CD4, and DP 
(CD4+CD8+) lymphocyte percentage of ≥ 0.05% with each value also being at least twice that of the 
background unstimulated control value (see Appendix B of the correlative science measures for additional 
details). It was found that the proportion of patients before or without the treatment with “detectable” 
circulating T cells specific against TAA is 0-1%. Let p be the true proportion of patients with “detectable” 


100 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
circulating T cells at Collection 3 after receiving the protocol treatment ipilimumab of any dose. For the 
purpose of sample size determination, we assume that the null hypothesis H0: p<0.01 is tested against the 
alternative hypothesis H1: p>0.20. With a sample size of 25 evaluable patients treated with the ipilimumab, 
we have approximately 90% power to test the above hypothesis using a one-sided binomial test at a 
significance level of 0.010. The null hypothesis H0 will be rejected if 3 or more patients are found with 
detectable circulating T cells specific against TAA after the treatment.  Assuming a 5% screening failure 
rate, the study will enroll a total of 30 patients. A patient is deemed “evaluable” if the patient meets 
eligibility criteria, receives the protocol treatment ipilimumab of any dose before Collection 3, and the 
levels of circulating T cells against TAA are measurable at Collection 3. All treated patients will be 
evaluated for treatment related adverse events and followed for tumor response and disease free survival.  
 
Futility Analysis 
Futility analysis is often used for assessing clinical efficacy before the trial reaches target accrual and stops 
the trial early if the therapy clearly performs worse than control. The primary objective of this one-arm 
phase II trial is not to evaluate the efficacy of ipilimumab in this population. Since it is unlikely that the 
therapy will harm the patients, a futility analysis on the percentage of patients with detectable T-cells is 
unnecessary. 
   
Adverse event monitoring 
The first 12 treated patients will be evaluated for AE’s attributable to the preoperative treatment. Overall, if 
3 or more of the first 12 treated patients (>25%) experience grade3-5 non-hematologic adverse events 
(excluding diarrhea and rash) that are probably, possibly, or definitely related to the preoperative treatment, 
OR if the number of treatment-related deaths from the first treatment until  30 days after surgery is 2 or 
more among the first 12 patients (>17%), accrual to the study will be suspended to allow for 
investigation. After consideration by the study team and the IRB, a decision will be made as to whether 
accrual can be resumed, potentially with modifications to entry criteria and/or study conduct.  In addition, 
all toxicity patterns will be monitored by the DCI Safety Oversight Committee. Postoperative ipilimumab 
will not be included in toxicity monitoring to determine continued accrual.  
 
Evaluation of Investigational Therapy Feasibility 


101 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Adverse events in the first 10 patients with computerized data were analyzed according to the guidelines in 
the above section. It became apparent that it was difficult to accurately attribute adverse events to standard 
chemotherapy, ipilimumab, or other causes. Further it seemed that analysis of treatment toxicities as 
isolated events did not best represent whether or not the combination of chemotherapy plus ipilimumab 
follow by surgery is safe and feasible. As of June 28, 2014, a total of 15 patients were registered and 
treated. Therefore, safety and feasibility for the remainder of the trial will be evaluated whenever additional 
5 patients have been treated by assessing: 1) whether the cumulative percentage of deaths among all treated 
patients related to any of the study treatments from the first ipilimumab treatment until 30 days after surgery 
exceeds 17%, and 2) if the cumulative percentage of all treated patients deemed unable to go to surgery due 
to adverse events attributed to neoadjuvant therapy exceeds 20%.  The percentage of patients unable to go 
to surgery after chemotherapy is a conservative estimate based on data reported for a SWOG trial that 
studied neoadjuvant chemotherapy in early state lung cancer (22).  The trial will be stopped for accrual 
whenever a total of 30 patients are registered or at least one of the thresholds of the safety and feasibility 
criteria is exceeded. In the event either of these two thresholds is exceeded, the investigational therapy will 
be considered “infeasible” in this setting. 
 
 
 
 
Analytic methods 
The primary outcome will be analyzed using the evaluable patients as defined in the sample size 
justification section.  The exact binominal test will be used to test the increase in the proportion of patients 
with detectable circulating T cells specific against TAA after the treatment. The proportion will be 
estimated and its 2-sided 98% confidence interval will be given to be consistent with the nominal 1-sided 
significance level of 0. 01 used in the sample size justification.  All secondary objectives are considered 
exploratory in nature, and type I error will not be controlled for multiplicity. P-values for these statistical 
tests will be provided for descriptive purposes.  . All treated patients will be included in the analysis of 
adverse events. 
 
The following statistical analyses will be conducted on the secondary objectives:  
(1) Feasibility/tolerability of neoadjuvant chemotherapy plus ipilimumab and surgery.  Based on data 
provided by Pisters et al (Pisters et al. J Clin Oncol. 2010 April 10; 28 (11): 1843-1849), the following 


102 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
criteria would be considered evidence of not feasible/tolerable: less than 75% of subjects receive 3 
cycles of preoperative therapy (i.e. receive some amount of the expected study medications each cycle), 
“less than 80% of subjects undergo surgical exploration within 42 days of day 1 of the last cycle of 
neoadjuvant chemotherapy”, more than 10% of subjects undergoing lobectomy have surgery-related 
mortality, or more than 20% of subjects experience dose-limiting toxicity during neoadjuvant therapy. 
Dose-limiting toxicity will be defined as possibly, probably or definitely treatment-related:  ≥ Grade 4 
hematologic toxicity (excluding Grade 4 neutropenia without fever or infection), or ≥ Grade 3 non-
hematologic toxicity (excluding grade 3 fatigue, nausea, vomiting, peripheral neuropathy, chemotherapy 
infusion reaction to carboplatin or paclitaxel).  
 
(2) Evaluate disease-free survival and patterns of metastases after neoadjuvant chemotherapy plus 
ipilimumab in early stage NSCLC. Disease-free survival (DFS) is defined as the time from surgical 
resection to disease recurrence (first disease recurrence or death, whichever comes first) after surgery. The 
Kaplan-Meier estimator will be used to estimate median DFS and its 95% confidence interval. The 
frequencies of metastases by site will be tabulated. 
 
 (3)  The relationship between pathologic response and the RECIST response will be explored by looking at 
a frequency cross-tabulation of pathologic versus RECIST response. 
 
 
The following exploratory objectives will be conducted: 
 
(1) Determine the percentage of patients with “detectable” (percentage of ≥ 0.05% with each value also 
being at least twice that of the background unstimulated control value) tumor infiltrating lymphocytes 
(TILs) after neoadjuvant chemotherapy plus ipilimumab. The percentage of patients with TILs for patients 
who have surgical resection and its 95% exact confidence interval will be estimated. See Appendix B of the 
correlative science measures for additional details on identifying TILs. 
 
(2) Estimate the  pathologic response rate for neoadjuvant chemotherapy plus ipilimumab in early stage 
NSCLC. The definition of pathologic response rate is given in section 16.3. The pathologic response rate 
along with its 95% exact confidence interval will be estimated.  


103 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
(3) Estimate the objective response rate of neoadjuvant chemotherapy plus ipilimumab in early stage 
NSCLC. Best response rate is of interest and tumor response will be evaluated from treatment initiation to 
prior to surgery. The definition of objective response will be measured by RECIST 1.1. The objective 
response rate (ORR=CR+PR) along with its 95% exact confidence interval will be estimated.  
 
(4) Determine if the immunomodulatory effects of neoadjuvant chemotherapy plus ipilimumab  impact the 
suppressive mechanisms, restoring functional reactivity to important anti-tumor effector cell populations.  
Functional TAA-specific T cell reactivities will be measured in the blood at four time points: Collection 1, 
2, 3 and 4. Changes in measures of anti-TAA reactivity (see Appendix B for details about these correlative 
science measures) across time points will be visualized using boxplots with the mean, median and 
interquartile range for each time point. For the phenotypic reactivity measures with background 
unstimulated negative control values (from the ICS panel), the percentage of patients with a positive 
response (a percentage value greater than the background unstimulated negative control value) will be 
calculated.  A Wilcoxon signed rank test will be used to test for differences from baseline, as well as for 
any association between each reactivity measure and pathologic response to neoadjuvant therapy.  
 
(5) Explore an alternative definition for detectability suitable for expression values generated using Boolean 
gating, and determine the percentage of patients with circulating T cells meeting this definition.  The 
percentage of patients with circulating T cells meeting the new definition of detectable and its 95% exact 
confidence interval will be estimated.  See Appendix B for additional details about this outcome measure.  
 
(6) Evaluate whether presence, quantity or quality of detectable TILs is associated with pathologic response 
to neoadjuvant therapy. Quality of TILs (also called relative polyfunctionality) is defined as ≥2 
functional marker values (out of 4) that meet the definition of detectable described in Objective 5. See 
Appendix B for additional details about this outcome measure. A Fisher exact test will be used to evaluate 
the association of both the presence and the quality of TILs with pathologic tumor response to neoadjuvant 
therapy. A Wilcoxon rank sum test will be used to test the association of the quantity of TILs and 
pathologic response to neoadjuvant therapy. 
 
 


104 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
27.0   References 
1. Graziano S, et al. Proc Am Soc Clin Oncol 1998;17:460a ab#1772 
2. Nesbitt JC,et al..  Ann Thorac Surg 1995; 60:466-472. 
3.  NSCLC Collaborative Group, et al. BMJ 1995,311:899-909. 
4.  Herbst R, et al. Clin Lung Cancer 2009,10:20-27. 
5.  Klastersky J, et al. Lung Cancer 2001, 34 (suppl 4) S95-S101. 
6.  Schiller JH et al. N Engl J Med 2002: 346, 92-96. 
7.  Scagliotti GV, et al. J Clin Oncol 2008,26:3543-3551.   
8.  Sandler A, et al. N Eng J Med 2006, 355:2542-2550.   
9.  Mok TS, et al. N Engl J Med 2009, 361:947-957.  
10. Kwak EL, et al. N Engl J Med 2010, 363:1693-1703. 
11.Winton et al. NEJM 2005;352:2589 
12.  Strauss et al, J Clin Oncol 2008;26:5043). 
13. Arriagada R, et al. N Engl J Med 2004,350:351-360. 
14. Winton TL, et al. J Clin Oncol 2004, 22;621s (suppl 14;abst 7018). 


105 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
15. Strauss GM, et al. J Clin Oncol 2004 22; 621s (suppl 14; abst 7018). 
16. Auperin et al. Ann Oncol 17:473-483, 2006).  
17. Rosell R, et al. NEJM 1994;330:153-158. 
18. Roth JA, et al. J Natl Cancer Inst 1994, 86:673-680. 
19. Roth JA, et al Lung Cancer 1998, 12:1-8.  
20. Rosell R, et al. Lung Cancer 1999, 26:7-14. 
21. Depierre A, et al. J Clin Oncol 2002, 20:247-253) 
22. Pisters KM, et al. J Clin Oncol 2010, 28:1843-1849.  
23. Felip E, et al. J Clin Oncol 2010, 28: 3138-3145). 
24. Gilligan D, et al. Lancet 2007, 368:1929-1937).   
25. Scagliotti GV, et al. J Clin Oncol 2012, 30:172-178. 
26. Lim E, et al. J Thorac Oncol. 2009;4:1380-1388. 
27. Patel A, et al. J Clin Oncol 26:408s, 2008 (suppl; abstr 7546).   
28.  Brudett S, et al. J Thorac Oncol 2006, 1: 611-621.  
29.  Song WA, et al. J Thorac Oncol 2010, 5:510-516.). 
30.  Hodi FS, et al, N Engl J Med 2010;363:711-23.  
31.  Lynch et al, abstr 701, 14th World Conf on Lung Cancer, July, 2011;  
32. Grossi et al, abstr M004, 14th World Conf on Lung Cancer, July, 2011).  
33. Lenschow D.J., et al., Ann Rev Immunol, 1996.  14:233-258. 
34. Schwartz R.H.. Cell, 1992. 71(7): 1065-1068. 
35. Chen L.S., et al. Cell, 1992. 71(7):1093-1102. (Protocol CA184004). Bristol-Myers Squibb 
Research and Development; 2010. Document Control No. 930043855. 
36. Townsend S.E., et al Science, 1993. 259(5093):368-370. 
37. Townsend S.E., et al.  Cancer Res, 1994. 54(24):6477-6483. 
38. Allison J.P., et al.Curr Opin Immunol, 1995. 7(5):682-686. 
39. Linsley P.S., et al.. J Exp Med, 1991. 174(3):561-569. 
40. Thompson C.B., and Allison J.P. Immunity, 1997. 7(4): p.445-450. 
41. Walunas T.L., et al. Immunity, 1994. 1(5): p. 405-413. 
42. Kearney E.R., et al J Immunol, 1995. 155(3): 1032-1036. 


106 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
43. Krummel M.F. and Allison J.P. J Exp Med 1995; 182(2): 459-465. 
44. Krummel M.F., et al. Int Immunol, 1996. 8(4): 519-523. 
45. Tivol E.A., et al. Immunity, 1995. 3(5): 541-547. 
46. Waterhouse P. et al.  Science, 1995. 270(5238): 985-988. 
47. Chambers C.A., et al.  Immunity, 1997, 7(6): 885-895. 
48. (Protocol MDX0102). Bristol-Myers Squibb Research and Development; 2010. Document 
Control No. 930043837. 
49. (Protocol CA184004). Bristol-Myers Squibb Research and Development; 2010. Document 
Control No. 930043855 
50. (Protocol CA184007). Bristol-Myers Squibb Research and Development; 2010. Document 
Control No. 930043852. 
51. (Protocol CA184008). Bristol-Myers Squibb Research and Development; 2010. Document 
Control No. 930043858. 
52. (Protocol CA184022). Bristol-Myers Squibb Research and Development; 2010. Document 
Control No. 9.0043860. 
53. (Protocol MDX01008). Bristol-Myers Squibb Research and Development; 3008. Document 
Control No. 930023182. 
54. (Protocol CA184042). Bristol-Myers Squibb Research and Development.  
55. (Protocol MDX01028). Bristol-Myers Squibb Research and Development; 2009. Document 
Control No. 9300038451. 
56. Ipilimumab Summary of Clinical Safety. Bristol-Myers Squibb Research and Development. 
2010; Document Control No. 930043848. 
57. Honkoop AH et al. British Journal of Cancer 1998;77(4): 621-626. 
58. Fong L, et al. Cancer Res 2009; 69(2): 609-6 
59. Lynch et al. J Clin Oncol 2012, 30: 2046-2054. 
 
 
 
 
 


107 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                    Appendix A 
         Study Schedule 
 
Examination 
Baseline 
(screen)a 
Days 
-30-0 
Cycle 
1  
Cycle 
 2  
Cycle 
 3  
Eval 
post 
chemon 
Surgery 
Adjuvant  
q 3 wk  
x2 and 
Maintenance 
 q 12 wk x2 
 
End 
of 
study 
 
EOSΧ 
Follow
-upf 
Relapsei 
Day of Cycle 
 
1 
1 
1 
 
 
1 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
 
 
Medical History/Demo- 
Graphics/Smoking Hx 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
(temp, B/P, pulse) 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Weight/BSAa,β 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Physical Exama,β,f 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Performance Statusa,β 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Hematologya,β,c,g,f 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Chemistriesa,β,g,h,f 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Calculated Creatinine 
Clearance β,d 
X 
X 
X 
X 
 
 
 
 
 
 
Serum Beta HCGe 
X 
 
X 
X 
 
 
X 
 
 
 
Radiologic Evaluation b,f 
X 
 
 
 
X 
 
X  
 
X 
X 


108 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
EKG 
X 
 
 
 
 
 
 
 
 
 
Tumor Histology 
X 
 
 
 
 
 
 
 
 
 
Adverse Eventsf 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Chemotherapy  
 
X 
X 
X 
 
 
 
 
 
 
Ipilimumabk 
 
 
X 
X 
 
 
X 
 
 
 
Thyroid Functions β,L 
X 
 
 
X 
 
 
X 
 
 
 
Blood Sampling j 
X 
 
X 
 
X 
 
X 
 
 
 
Surgical Specimenp 
 
 
 
 
 
X 
 
 
 
 
 
To allow for patient and investigator schedules, holidays, weather or other emergencies requiring facilities to be closed, , 
visits can be performed  ±3 days of scheduled visit 
β May be obtained within 3 days of dosing chemo/ipilimumab 
a  Pre-enrollment baseline (screen) assessments  are to be performed within -30  to 0 days unless otherwise specified . 
b  Radiologic evaluation: pre-treatment clinical staging PET/CT of chest/abdomen and brain MRI or CT as per standard of care  
(these may be performed up to 42 days); 3-4 weeks after completing cycle#3 neoadjuvant therapy (prior to surgery) chest CT;  post-
surgery recommend chest CT prior to each of two doses maintenance Ipilimumab; then every 3-4 months (or per institutional 
standard of care) for 2 years (this can be timed with follow-up, see footnote f). 
c Hematology values to include Hgb/Hct, WBC with auto or manual differential, platelets. 
d Calculated creatinine clearance (see appendix D to be performed at baseline and prior to every dose of cisplatin or carboplatin. 
e For women of childbearing potential only. All WOCBP MUST test negative for pregnancy within48 hours prior to any initial 
study procedure based on a serum pregnancy test.  If subject uses appropriate contraceptive methods (the use of two form at the 
same time) from the time of the initial serum pregnancy test, then the subsequent pregnancy test can be done within 72 hours before 
receiving ipilimumab. If appropriate contraceptive methods are not begun immediately with the first serum pregnancy test, then 
subsequent serum pregnancy tests must be done within 48 hours prior to the study drug administration. The minimum sensitivity of 
the pregnancy test must be 25 IU/L or equivalent units of HCG. If the pregnancy test is positive, the subject must not receive 
ipilimumab and must not be enrolled in the study, or will be removed from treatment. 
f  Surveillance after end of study evaluation: every 3-4 months (or per institutional standard of care) for 2 years and then every 6 
months until 5 years, then yearly thereafter. These evaluations may be coordinated with visits for radiologic disease evaluation or 
occur via phone follow-up. Lab assessments will be at the discretion of treating physician. 
g  Baseline required labs to be performed within 30 days of enrollment Pre-study tests may be used for day 1, cycle 1 tests if 
obtained within 14 days of day 1 cycle 1 treatment.  
h Chemistries to include Na+, K+, Cl-, total protein, albumin, calcium, glucose, BUN, creatinine, uric acid, total bilirubin, alkaline 
phosphatase, SGOT, SGPT, LDH, Mg+. 
i Upon lung cancer relapse, subjects should have chest/abdomen and brain CT or MRI to document sites of failure. 
j Blood samples  to assess activated CD8+ T cells with specificity against tumor antigens and CD4 and CD8 functional memory. 
will be collected: Collection 1: Baseline: pretreatment. Collection 2: cycle 2 day 1 chemotherapy prior to Ipilimumab 
infusion.Collection 3: 21-36 days after completion of cycle 3 prior to surgery Collection 4: 3-6 weeks after post-op  adjuvant 
ipilimimab dose #2. 
k Total dose of ipilimumab to be calculated using weight obtained within 3 days of dosing visit, prior to infusion. Ipilimumab dosing 
will occur cycles 2 &3(day 1) neoadjuvant therapy and as single therapy post-surgery to consist of adjuvant therapy q3wk x2, 
followed by maintenance therapy q12 wk x2.  
L Blood samples for Thyroid Function Tests to include: Thyroid Stimulating Hormone, Free Thyroxine. 
m Evaluation Post Chemotherapy to occur at least 21 days after last dose of therapy 
n  Medical/Surgical Evaluation to occur at least 21 days after completion of neoadjuvant chemotherapy.  
p Surgery to occur 4-12 weeks after last dose of chemotherapy. After all tumor specimen necessary for standard pathological testing 
has been obtained by the surgical pathology staff, a specimen of surplus tumor will be acquired by the tumor immunology 
correlative science staff for isolation of tumor infiltrating lymphocytes. 
Χ EOS=End of Study.  Complete once subject has completed maintence therapy( approximately 12 wks after dose #2)  or 30 days 
after  subject comes off treatment for progression of disease, intolerance to protocol therapy, or patient withdraws consent. 
 
 
 
 


109 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix B     Correlative Science Measures 
 
Primary Objective 
 
The primary endpoint is the proportion of early stage lung cancer patients with detectable 
circulating T cells specific against TAA after receiving platinum based chemotherapy plus 
ipilimumab before surgery.  Detectable circulating T cells with specificity against TAA will be 
identified using the following process: 
 
Whenever individual patient tumor tissue is available for analysis, the expression of 10 highly 
conserved TAA’s (see Table I below) will be assessed using standard Real-Time (RT) PCR 
technology. Peptide pools representing the three most highly expressed TAA’s by each tumor 
will serve as antigen-specific stimulators for PBMC isolated from the same patient at the 4 
specified time points. If no tumor tissue is available for TAA expression analysis, peptide pools 
representing the three most commonly expressed TAA’s on NSCLC, namely Survivin, PRAME, 
and MAGE-A3, will be chosen as antigen-specific stimulators. 
 
The percentage of CD4, CD8, and double positive (DP=CD4+/CD8+) lymphocytes with 
specificity against the three selected TAA’s,  will be calculated for each of 4 individual 
functional markers (IL-2, TNF-α, IFN-γ, and CD107 underlined below).  For each peripheral 
blood collection, the lab will generate a total of 12 lymphocyte values (4 values each for CD4, 
CD8 and DP) for each of the three TAA’s and for CD3/CD28 (used as a positive control), as 
well as generating 12 background unstimulated negative control values.  All values will be 


110 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
expressed as percentages.  A patient will be considered to have detectable circulating T cells if 
≥1 of the 36 percentage values (12 values * 3 TAA’s) satisfies the definition of “detectable” as 
described in section 26.0 (a lymphocyte percentage of ≥0.05% at the pre-surgical peripheral 
blood collection (Collection 3) with each value also being at least twice that of the background 
unstimulated negative control value).  
 
Table I          
 
TAA Peptide Pools 
 
 
      (15-mers, overlapping by 11 amino acids) 
 
 Survivin (33 peptides) 
 PRAME/OIP4 (125 peptides) 
 MAGE-A3 (76 peptides) 
 Melan A/MART-1 (27 peptides) 
 Gp100 (163 peptides) 
 Tyrosinase (117 peptides) 
 NY-ESO-1 (43 peptides) 
 MAGE-A1 (75 peptides) 
 MAGE-A4 (77 peptides) 
 CEA (173 peptides) 
 
 
 
 
Assessing detectable circulating T cells specific against three TAA’s (individually 
selected from the Table I list of TAA’s using the process outlined above) in the following 
combinations of T cells and functional markers:  
* %CD4+/CD69+/IL-2+ 
 
*%CD4+/CD69+/TNF-α+ 
 
*%CD4+/CD69+/ IFN-γ+ 
 
*%CD4+/CD69+/ CD107+ 
 
* %CD8+/CD69+/IL-2+ 
 
*%CD8+/CD69+/TNF-α+ 
 
*%CD8+/CD69+/IFN-γ+ 
 
*%CD8+/CD69+/CD107+ 
 
* %DP+/CD69+/IL-2+ 
 
*%DP+/CD69+/TNF-α+ 
 
*%DP+/CD69+/IFN-γ+ 
 
*%DP+/CD69+/CD107+ 
 
 
Exploratory Objectives 
 


111 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Using the same methods noted above, 12 lymphocyte percentage values (functional markers) for 
the 3 selected TAA’s will also be generated from tumor tissue collected at surgery, and in this 
context are called tumor infiltrating lymphocytes (TILs).  These values will be used to determine 
the percentage of patients with any detectable TILs (exploratory objective 1).  Expression 
percentage values for each T cell (CD4, CD8, and DP) will also be collected corresponding to 
each combination of the 4 functional markers (excluding the combination where all four markers 
are negative) using Boolean gating. These 135 values (15 values * 3 T cells * 3 TAA’s) will be 
used to determine a definition of detectability suitable for these measures to avoid missing 
potential positive values, and to determine the percentage of patients with ≥1 of the 135 values 
satisfying the new definition of detectable circulating T cells (exploratory objective 5).  In 
addition, this definition will also be used to explore whether the presence, quantity or quality of 
TILs is associated with pathologic response (exploratory objective 6).   
 
* Boolean gating will be performed to calculate percentage values corresponding to the 
following combinations of T cells and functional markers (excluding the combination 
where all 4 markers are negative): 
 
* %CD4+/CD69+/-IL-2+ or -TNF-α+ or -IFN-γ+ or -CD107+ or -  
* %CD8+/CD69+-IL-2+ or -TNF-α+ or -IFN-γ+ or -CD107+ or - 
* %DP+/CD69+/-IL-2+ or -TNF-α+ or -IFN-γ+ or -CD107+ or - 
 
For exploratory outcome 4, changes in all  measures of anti-TAA reactivity listed below across time 
points will be analyzed, as well as how these values relate to pathologic response.   In addition, for 
the  phenotypic reactivity measures with background unstimulated negative control values (those 
from the ICS panel), the percentage of patients with a positive response (a percentage value 
greater than the background unstimulated negative control value) will be calculated.  The 
distribution of the changes will be estimated with a boxplot and the median (mean) change will 
be calculated by pathologic response status (yes/no). 
 
%CD3+CD4+CD8- (CD4 T cells) 
%CD3+CD4-CD8+ (CD8 T cells) 
%CD3+CD4+CD8+ (CD4/CD8 double positive (DP) T cells) 
 
%CD4+CD152- (CTLA-4 negative CD4 T cells) 
%CD4+CD152+ (CTLA-4+ CD4 T cells) 
 
%CD4+/CD69+ (Activated CD4 T cells) 
%CD4+CD154+ (Activated CD4 T cells) 
 
%CD4+/-HLA-DR+ (Activated CD4 cells) 
%CD4+CD28+  
%CD4+CD28-  
%CD4+/CD28+/CD152+CD279+ (Activated/Exhausted CD4 T cells) 
%CD4+CD28+CD278+ (Activated CD4 T cells/Pharmacodynamic Biomarker) 


112 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
%CD4+/CD25+FoxP3+/CD152  
%CD4+/CD25+FoxP3+/CD152 
%CD4+/CD25+FoxP3+/CD152 
%CD4+/CD25+FoxP3+/CD152  
 
%CD4+CD45RA+CCR7+ (Naïve CD4 T cells) 
%CD4+CD45RA-CCR7+ (Central memory CD4 T cells) 
%CD4+CD45RA-CCR7- (Effector memory CD4 T cells) 
%CD4+CD45RA+CCR7- (Effector CD4 T cells) 
 
%CD8+CD152- (CTLA-4 negative CD8 T cells) 
% CD8+CD152+ (CTLA-4 positive CD8 T cells) 
 
%CD8+CD69+ (Activated CD8 T cells) 
%CD8+CD152+ (Activated CD8 T cells 
 
%CD8+/-HLA-DR+ (Activated CD8 T cells) 
%CD8+CD28+  
%CD8+CD28-  
%CD8+/CD28+/CD152+CD279+ (Activated/Exhausted CD8 T cells) 
 
%CD8+CD45RA+CCR7+ (Naïve CD8 T cells) 
%CD8+CD45RA-CCR7+Central memory CD8 T cells) 
%CD8+CD45RA-CCR7- (Effector memory CD8 T cells) 
%CD8+CD45RA+CCR7- (Effector CD8 T cells) 
 
%DP CD69+ (Activated DP T cells) 
%DP CD154+ (Activated DP T cells) 
 
%DP CD45RA+CCR7+ (Naïve DP T cells) 
%DP CD45RA-CCR7+ (Central memory DP T cells) 
%DP CD45RA-CCR7- (Effector memory DP T cells) 
%DP CD45RA+CCR7- (Effector DP T cells) 
 
 
%CD3-SSChi/HLA-DRlowCD14+ (Myeloid-derived suppressor cells (MDSC)) 
 
FCSxSSC (Monocyte gate) %CD3-CD14- Lin(CD16, CD19, CD20, CD56)- HLA-DR- 
CD11b+/CD33+ (MDSC) 
 
 
 
 


113 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix C      Performance Status Criteria 


114 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
 
 
 
 
 
 
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. 


115 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Appendix D 
Standard Cockcroft and Gault Formula for Calculated Creatinine Clearance 
 
Standard Cockcroft and Gault Formula for Calculated Creatinine Clearance 
For serum creatinine concentration in mg/dL: 
Creatinine clearance (CrCl) will be calculated using the Cockroft-Gault equation as follows: 
CrCl (ml/min)= 
(140-age) X (actual weight in kg) x 0.85 for females                                                                       
72 x serum creatinine (mg/dl) 
 
 
For serum creatinine concentration in mol/L: 
CrCl = [(140 - age) x (wt in kg)] / [0.81 x serum creatinine (mol/L)] 
Females: Multiply the result x 0.85 
Units: age in years, weight in kilograms. 
 
 
Source: Cockcroft DW, Gault MH. 1976. Prediction of creatinine clearance from serum creatinine. 
Nephron 16:31-4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


116 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Appendix E    Patient Eligibility Checklist 
 
TOP 1201: Evaluation of Circulating T Cells and Tumor Infiltrating Lymphocytes with 
Specificities Against Tumor Associated Antigens During and After Neoadjuvant Chemotherapy 
and Phased in Ipilimumab in Non-small Cell Lung Cancer (NSCLC). 
 
 
 
Inclusion Criteria:  Patients are Eligible to be included in the study only if they meet ALL of the 
following criteria: 
 
 
 
 
 
 
 
 
 
 
             Yes        No 
1. 
Histological or pathologic diagnosis NSCLC.  Date obtained:______/______/____ 
 
 
2. 
Clinical stage IB (>4 cm), II or III (N0-2) NSCLC amenable to surgical resection . 
Stage: _______ (T___N____M____). 
 
 
3. 
Patient must be deemed a surgical candidate 
 
 
4. 
ECOG performance status of 0 or 1.  Status:_________  Date assessed:_____/_____/_____ 
 
 
5 
NO prior chemotherapy for current diagnosis of lung cnacer. 
 
 
6. 
Age ≥ 18 years. (DOB/age listed above). 
 
 
7. 
No active or concomitant invasive malignancy in the past 2 years other than skin or prostate cancer.   
 
8. 
Signed written informed consent including HIPAA according to institutional guidelines,.  Date 
signed:_____/_____/_____ 
 
 
9. 
Adequate Organ Funcion: 
ABC/diff:  Date obtained:_____/_____/_____ 
Platelets _____________(≥100,000 per µl) 
ANC or AGC __________________(≥1500 per µl) 
Chemistries:  Date obtained _____/_____/_____ 
Total bilirubin__________(< 1.5 mg/dL)  
Creatinine clearance ≥45 mL/min ________or  creatinine <2 mg/dL to receive 
cisplatin)__________ 
SGOT_______ SGPT_________(≤2.5 x institutional ULN ) 
 
 
10. 
Females of child-bearing potential (not surgically sterilized and between menarche and 1 year post 
menopause) must test negative for pregnancy within 48 hours prior to based on a serum pregnancy 
test. Both sexually active males and females of reproductive potential must agree to use a reliable 
method of birth control, as determined by the patient and their health care team, during the study 
and for 3 months following the last dose of study drug. If subject uses appropriate contraceptive 
methods (the use of two forms at the same time) from the time of initial serum pregnancy test, then 
the subsequent pregnancy test can be done within 72 hours of receiving study drug administration. 
If appropriate measures are not begun immediately with the first serum pregnancy test, then 
subsequent serum pregnancy tests must be done within 48 hours prior to the study drug 
administration. 
Beta HCG Result___________  Date obtained:______/______/________ 
If not applicable, please specify why:___________________________________________. 
 
 
11. 
Must agree to research blood sampling to participate. 
 
 
 
 
 
Initials: __________ Sex: M (  )  F (  ) DOB: _____/_____/_____ Age: _______ Patient ID #: __________ 
Race: _____________ Diagnosis: __________________________ Date of Diagnosis:______/_____/______ 
Physician: ______________________________  Surgeon_________________________________________ 


117 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Patient Eligibility Checklist Continued 
Exclusion Criteria: Patients will be excluded from the study if they meet ANY of the following 
criteria: 
 
 
 
 
 
 
 
 
 
 
 
 
             
YES       NO 
1. 
Treatment within the last 30 days with a drug that has not received regulatory approval for any 
indication at the time of study entry. 
 
 
2. 
Concurrent administration of any other antitumor therapy. 
 
 
3. 
Inability to comply with protocol or study procedures. 
 
 
4. 
Active infection requiring IV antibiotics, antifungal, or antiviral agents that in the opinion of the 
investigator would compromise the patient’s ability to tolerate therapy. 
 
 
5. 
Major surgery (other than definitive lung cancer surgery) within two weeks of study or other 
serious concomitant systemic disorders, that in the opinion of the investigator, would compromise 
the safety of the patient or compromise the patient’s ability to complete the study. 
 
 
6. 
Myocardial infarction having occurred less than 6 months before inclusion, uncontrolled 
arrhythmia, symptomatic angina pectoris, no active ischemia on EKG, or cardiac failure not 
controlled by medications. 
 
 
7. 
Contraindication to corticosteroids. 
 
 
8. 
Unwillingness to stop taking herbal supplements while on study. 
 
 
9. 
Female patients that are pregnant or breast-feeding. 
 
 
10. 
Autoimmune disease. Patients with a history of inflammatory bowel disease, including  
ulcerativecolitis and Crohn’s Disease, are excluded from this study, as are patients with a history of 
symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], 
systemic lupus erythematosus, autoimmune vasculitis [eg, Wegener’s Granulomatosis]); motor 
neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome and Myasthenia 
Gravis). 
 
 
11. Any non-oncology vaccine therapy for prevention of infectious diseases (for up to 1 month be before 
after any dose of ipilimumab).  
 
 
12. 
A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4 inhibitor or 
agonist. 
 
 
13. 
Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of 
either psychiatric or physical (e.g., infectious) illness. 
 
 
 
 Patient satisfies all criteria: _______ (Yes) _______ (No) 
                            
Comments:___________________________________________________________________________ 
 
       ____________________________________________________________________________________ 
 
 
     Research Nurse/Coordinator’s Signature: _______________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
Date 
     Enrolling Physician’s Signature: ______________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
Date 


118 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
    
Appendix F   Blood Specimens for correlative sciences 
 
Blood will be collected 4 times to assess CD8+ T cells with specificity against tumor 
antigens.Blood from each of the 4 collections will also be utilized to assess the presence 
ofcirculating populations of regulatory T cells, myeloid-derived suppressor cells (MDSC), as 
well as activated and exhausted T cells. 
 
 
Blood volumes and collection time points: 
 
 At each blood collection, 4 tubes of 8.5-ml each will be collected. The tubes used will be ACD 
anti-coagulated Vacutainer (yellow tops). The following time points will  have blood collections: 
 
Collection 1: Baseline prior to treatment initiation 
Collection 2: cycle 2, day 1 chemotherapy prior to ipilimumab infusion 
Collection 3: 21-36 days after completion of cycle 3 chemotherapy prior to surgery  
Collection 4: 3-6 weeks after post-op ipilimumab dose #2.  
 
Once ACD tubes collected, Dr. Weinhold’s lab to be contacted for pick up as PBMC should 
ideally occur within 4 hours of drawn @ 919-684-3754. Tubes are to remain ambient 
(refrigeration will limit ability to recover PBMC). 
DTRI-IM Sample Transport Record form to be completed to accompany tube to Dr. Weinhold’s 
lab. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


119 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
Appendix G   Tumor Tissue Specimen for correlative sciences 
 
SURGICAL SPECIMEN 
 
Patients will be approached to participate in the “DUHS Biospecimen Repository and Processing Core 
(BRPC)” eIRB 35974 protocol prior to surgery.  Tissue will be collected and released as described in this 
protocol to ensure proper involvement of pathology to minimize the chance that a tissue collection event 
interferes with appropriate clinical tissue processing and diagnosis. 
 
 
PRINCIPLE: 
Lung tissue is harvested in the frozen section or gross dissection area of the surgical pathology suite.  The 
tissue is first examined by a certified anatomic pathologist or surrogate (resident, pathology assistant). 
Relevant margins are inked, removed and examined by frozen section analysis, if necessary. It is imperative 
that harvesting tissue for use in research trials does not impede accurate initial assessment of critical features 
of the tumor resection, most notably margin status.  After the specimen has been processed for margin 
status, the frozen section assessment of the specimen is complete, a specimen of excess tumor will be 
released and acquired by the tumor immunology correlative science staff for isolation of tumor infiltrating 
lymphocytes for purposes of this protocol.  
 
 
SPECIMEN: Lung resection specimen 
 
LOCATION: Surgical Pathology Suite 
 
QUALITY CONTROL:  
Lab guidelines for safe handling of all samples must be followed. All tubes used for specimen processing 
must be labeled with the unique patient identifier or sample number before transfer of the tissue sample. 
 
 
 
 
 
 
 
 
 
 


120 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
 
 
Appendix  H:   Hepatotoxicity Management Algorithm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
ipilimumab.   Caution: Infliximab is contraindicated in hepatic insufficiency! 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Ipilimumab may be held/delayed rather than discontinued if AST/ALT ≤ 8 x ULN and Tbili ≤ 5 x ULN. Resume ipilimumab 
when AST/ALT/ 
Tbili return to grade 2 and meet protocol specific retreatment criteria. 
**The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV. 
*** MMF, mycophenolate mofetil 
 
 
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose 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 PO corticosteroids. 
 
 
 
 
 
 
 
 
Management 
Follow-Up 
Severity of Hepatitis 
Grade 1 
AST or ALT ≤ 2.5 x ULN 
or 
Total bilirubin ≤ 1.5 x ULN 
Continue ipilimumab 
Continue monitoring LFT prior to each 
dose 
GRADE 2 
AST or ALT 
> 2.5 to ≤ 5.0 x ULN 
or 
Total bilirubin 
> 1.5 to ≤ 3.0 x ULN 
▪Increase frequency of monitoring 
(q3d) 
▪Withhold/delay ipilimumab while 
investigating alternative etiology 
Return to baseline 
▪Resume q3w monitoring 
▪Resume ipilimumab 
Elevations persist for > 5-7 days or 
worsen, and no alternative 
etiologies are identified 
Consider moderate to high dose steroids 
PO (e.g., 0.5- 1 
mg/kg/day prednisone or equivalent) 
Grade 3-4 
AST or ALT 
> 5.0 x ULN 
or 
Total bilirubin 
> 3.0 ULN 
▪Discontinue ipilimumab* 
▪Increase frequency of monitoring 
(q1-3d) 
▪High dose IV steroids (e.g., 
methylprednisolone 1-mg/kg/day**) 
AST/ALT/Tbili return to grade 2 
▪Taper steroids over at least 1 month 
Labs do not decrease over 3-5 days, 
worsen or rebound: 
▪Add MMF*** 1 g BID 
▪If no response within 3-5 days, consider 
other immunosuppressants per local 
guidelines 


121 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Appendix I:     Endocrinopathy Management Algorithm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
ipilimumab. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose 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 PO corticosteroids. 
 
 
 
 
 
 
 
 
 
 
Management 
Follow-Up 
Severity of 
Endocrinopathy 
Asymptomatic TSH 
elevation 
Continue ipilimumab 
If TSH < 0.5 x LLN, or TSH > 2.0 x ULN, or consistently out of range in 2 
subsequent measurements: 
Include fT4 at subsequent cycles as clinically indicated; consider endocrinology 
consult 
Symptomatic 
endocrinopathy 
▪Evaluate endocrine function 
▪Consider pituitary scan 
Symptomatic with abnormal lab/pituitary scan: 
▪Withhold/delay ipilimumab 
▪High dose IV steroids (e.g., 1-2 mg/kg/day   
methylprednisolone) 
▪Initiate appropriate hormone therapy 
No abnormal lab/pituitary scan but symptoms 
persist: 
Repeat labs in 1-3 weeks / MRI in 1 month 
Symptoms resolve 
(with or 
without hormone 
substitution): 
▪Resume ipilimumab 
▪Taper steroids over at 
least 1 month* 
Suspicion of adrenal 
crisis (e.g. severe 
dehydration, 
hypotension, shock out of 
proportion to current 
illness) 
▪Rule out sepsis 
▪Stress dose of IV steroids with mineralocorticoid 
activity 
▪IV fluids 
▪Consult endocrinologist 
*Patients with adrenal 
insufficiency might need 
to continue steroids with 
mineralcorticoid 
component 


122 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Appendix J:    Neuropathy Management Algorithm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
ipilimumab. 
Discontinue ipilimumab for any grade 3-4 motor neuropathy, regardless of relationship. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose 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 PO corticosteroids. 
 
 
 
 
 
 
 
 
 
 
 
Management 
Follow-Up 
Severity of Neurologic 
Toxicity 
GRADE 1 
Continue ipilimumab 
 Continue monitoring the patient. If 
symptoms 
worsen, treat as below. 
GRADE 2 
▪ Hold/delay ipilimumab 
▪Treat symptoms per local 
guidelines 
▪Resume ipilimumab when resolved / 
grade 1 
▪If symptoms worsen, treat as below. 
Grade 3-4   MOTOR 
 Discontinue ipilimumab 
regardless of relationship 
▪Obtain neuro consult 
▪Treat symptoms per local 
guidelines 
▪High dose IV steroids (e.g., 1-2 
mg/kg/day methylprednisolone) 
Symptoms resolve / return to grade 2: 
▪Taper steroids over at least 1 month 
Symptoms do not resolve or progress; 
atypical presention: 
▪Consider IVIg or other immunosuppressive 
therapies per local guidelines 
GRADE 3-4 SENSORY 
 
▪Discontinue ipilmumab if considered 
related 
▪Obtain neuro consult 
▪Treat symptoms per local guidelines 
▪High dose IV steroids (e.g., 1-2 
mg/kg/day methylprednisolone) 
Symptoms resolve / return to grade 2: 
Taper steroids over at least 1 month 


123 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Appendix K:  Skin Toxicity Management  
 
 
 
 
 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
ipilimumab.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose 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 PO corticosteroids. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Management 
Follow-up 
Severity of Skin 
Toxicity 
 
 
Grade 1-2 
▪Symptomatic therapy, e.g. 
antihistamines, topical 
steroids 
▪ continue ipilimumab 
Symptoms resolve: continue ipilimumab 
Symptoms persist > 1-2 weeks or recur: 
▪Continue Ipilimumab 
▪Moderate to high dose steroids PO (e.g., 
prednisone 0.5-1 mg/kg/day) 
▪Once controlled, taper steroids over at 
least 1 month 
 
 
Grade 3-4 
▪Hold/delay ipilimumab(regardless 
ofrelationship) 
▪Take photos of rash 
▪Consider skin biopsy 
▪Dermatology consult 
▪High dose IV steroids (e.g., 
methylprednisolone 1-
2mg/kg/day) 
Symptoms resolve / return to grade 1: 
▪Taper steroids over at least 1 month 
▪Resume ipilimumab 
▪Discontinue if grade 4 toxicity considered 
related 


124 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016 
Appendix L:    GI Toxicity Management Algorithm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue 
ipilimumab. 
Opiates/narcotics mask symptoms of perforation! Infliximab should not be used in case of 
perforation/sepsis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients on IV steroids may be switched to oral corticosteroid (e.g., prednisone) at an equivalent dose 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 PO corticosteroids. 
 
 
 
 
 
Management 
Follow-Up 
Severity of diarrhea/ 
Colitis 
GRADE 1 
Diarrhea: < 4 stools/day 
over baseline 
Colitis:  asymptomatic 
▪Continue ipilimumab 
▪symptomatic treatment 
 ▪close monitoring for worsening 
symptoms 
▪Educate patient to report any 
worsening immediately 
GRADE 2 
Diarrhea: 4-6 stools per day 
over baseline; IV fluids 
indicated < 24 hrs; not 
interfering with ADL 
Colitis: abdominal pain; blood 
in stool 
 
 
▪ Withhold/delay ipilimumab 
▪Symptomatic treatment 
 Symptoms improve/resolve (grade 0/1): 
Resume ipilimumab 
Symptoms persist for > 5-7 days, 
worsen, or recur: 
▪Moderate to high dose steroids PO (e.g., 
prednisone 0.5 - 1 mg/kg/day) 
▪Continue to hold/delay ipilimumab until 
grade 1 
▪When symptoms are grade 1 or less 
slowly taper steroids over at least 1 month 
and resume ipilimumab. 
Symptoms worsen: Treat as grade 3/4 
Grade 3-4 
Diarrhea (G3*): ≥ 7 stools per 
day over baseline; incontinence; 
IV fluids ≥ 24 hrs; interfering 
withADL 
Colitis (G3*): fever, ileus, 
peritoneal signs 
▪ Permanently discontinue 
ipilimumab 
▪High dose IV steroids 
(e.g., methylprednisolone 
1-2 mg/kg/day) 
▪Consider endoscopy 
Symptoms improve: 
▪Continue steroids (same dose) until grade 1 
▪Then taper over at least 1 month 
Symptoms persist 3-5 days, or recur after 
improvement: 
▪1 dose* of infliximab 5 mg/kg (if no 
contraindication) 


125 
Confidential: The information contained in this document is regarded as confidential and may not be disclosed to another party unless such 
disclosure is required to initiate the study, to conduct study related activities, or to comply with national, state or local laws and regulations. 
Written authorization from the coordinating site and/or sponsor is required for disclosure.                     Version 3.0: March 10, 2016