Conditions: Non Small Cell Lung Cancer Stage IIIB
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
Metastatic non small cell lung cancer can be treated with cytotoxic chemotherapy or using recently approved immunotherapy with antibody, Nivolumab. Both the therapies have limitation due to development of tolerance or immunosuppression. This trial combines one drug from each category, immunotherapeutic Nivolumab and chemotherapeutic gemcitabine as it was reported that gemcitabine reduces immunosuppression by killing myeloid derived suppressor cells, thereby increasing the efficacy of Nivolumab.

Detailed description:
Primary Objective

• The primary objective of this proposal is to evaluate gemcitabine as a method of MDSC depletion.

Secondary Objectives

* Evaluate whether these measures result in enhanced T-cell activity and/or NK cell function and number.
* Determine the tolerability and clinical activity (including response rate and survival) of this approach.
* Correlate MDSC number with tumor PD-L1 expression

Arms:
arm 1: Nivolumab infusion on day 1 and 15 with the addition of gencitabine on day 1, 8 and 15 of 28 day cycle

Interventions: intervention 1: Nivolumab intervention 2: Nivolumab+Gemcitabine
Intervention descriptions: intervention 1: Monoclonal antibody against non small cell lung cancer intervention 2: Gemcitabine is added to the Nivolumab treatment

Protocol document:
Prot_SAP_000.pdf: 
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Martin J Edelman, MD 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone: 215-728-5682 
Fax: 215-728-5336 
Email: martin.edelman.fccc.edu 
Hossein Borghaei, DO 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone: 215-728-2937 
Email:hossein.borghaei@fccc.edu 
Jessica Bauman, MD 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone: 215-214-4297 
Email:jessica.bauman@fccc.edu 
Joseph Treat, MD 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone: 215-214-4297 
Email:joseph.treat@fccc.edu 
 
 
Depletion of Myeloid Derived Suppressor Cells to Enhance anti PD-1 Therapy 
 
Supported by: Bristol-Myers Squibb 
 
Sponsor Investigator:   
 
 
 
 
 
 
 
 
Co-Investigators:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Yanis Boumber, MD, PhD 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone: 215-214-4297 
Email:yanis.boumber@fccc.edu   
Eric Ross, PhD 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone: 215-728-2891 
Email: eric.ross@fccc.edu  
Anthony J Olszanski, MD 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111 
Phone: 215-214-1676 
Email:anthony.olszanski@fccc.edu   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Statistician:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
IND Number: 135730 
 
 
Version Date (Amendment #2):   03/27/2018  
 
 
 


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                                                       Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Population 
10 advanced NSCLC patients who had at least one prior platinum based 
chemotherapy regimen and do not have any curative therapy available. If 
EGFR or ALK mutation present, must have received at least one TKI, normal 
organ function, PS 0-1, no active autoimmune disease, archival tumor 
specimen available  
MDSC Assessment 
Days 1, 8, 15 of cycle 1, Day 1 of cycles 2, 3 
Disease Assessment 
Evaluation by CT scan every 8 weeks 
 
Continue treatment until 
Disease progression 
Unacceptable toxicity 
Patient preference 
Follow up 
Follow up for 2 years or until death 
whichever occurs earlier  
Treatment 
 
Nivolumab 240mg, IV on day 1, 15 + Gemcitabine 1000mg/m2, IV on day 1, 
8, 15 of 28 days cycle 
 


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Contents 
Schema 
3 
1.0 
Introduction 
7 
1.1. 
Non-small cell lung cancer 
7 
1.2. 
Immunotherapy in NSCLC 
8 
1.3. 
Study Hypothesis 
10 
1.4. 
Correlative Testing 
10 
T-cell activation assay 
10 
2.0 
Objectives 
11 
2.1. 
Primary Objective 
11 
2.2. 
Secondary Objectives 
11 
3.0 
Study Plan 
11 
3.1. 
Description of Study Design, Population and Duration of Study Therapy 
11 
3.2. 
MDSC Enumeration Method 
11 
3.3. 
PD-L1 expression 
11 
4.0 
Patient Selection Inclusion & Exclusion 
12 
4.1. 
Inclusion Criteria 
12 
4.2. 
Exclusion Criteria 
13 
4.3. 
Inclusion of Women and Minorities 
15 
4.4. 
Pregnancy 
15 
4.5. 
Patient Registration 
16 
5.0 
Treatment Plan 
17 
5.1. 
Treatment Administration 
17 
5.1.1. 
Nivolumab 
17 
5.1.2. 
Gemcitabine 
18 
5.2. 
Concomitant Medications, Supportive Care, Excluded Therapies and Restrictions 
18 
5.3. 
Duration of Therapy 
18 
5.4. 
Duration of Follow up 
19 
5.5. 
Criteria for Discontinuation 
19 
6.0 
Dose Modifications 
19 
6.1. 
General Principles 
19 
6.1.1. 
Nivolumab administration should be delayed for the following: 
19 
6.1.2. 
Criteria to Resume Treatment 
20 
6.1.3. 
Management Algorithms 
21 
6.1.4. 
Discontinuation Criteria 
21 
6.1.5. 
Treatment of Nivolumab Related Infusion Reactions 
22 


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6.2. 
Gemcitabine 
24 
6.2.1. 
General guidelines 
24 
6.2.2. 
Dose Modifications 
24 
6.2.3. 
Hematologic Toxicity 
24 
6.2.4. 
Nephrotoxicity 
24 
6.2.5. 
Pulmonary Toxicity 
25 
6.2.6. 
Skin Toxicity attributed to gemcitabine 
25 
6.2.7. 
Hypersensitivity Reactions attributed to gemcitabine 
25 
6.2.8. 
Other Non-Hematologic 
25 
7.0 
Study Agent Information 
25 
7.1. 
Nivolumab 
25 
7.1.1. 
Product description 
25 
7.1.2. 
Storage 
26 
7.1.3. 
Route of administration 
26 
7.2. 
Gemcitabine 
26 
7.2.1. 
Product description 
26 
7.2.2. 
Availability 
26 
7.2.3. 
Solution preparation 
27 
7.2.4. 
Storage requirements 
27 
7.2.5. 
Route of administration 
27 
7.2.6. 
Toxicity 
27 
7.3. 
Drug Ordering, Storage and Handling 
27 
7.4. 
Destruction of Drug 
27 
7.5. 
Records to be kept at Site; Dispensing and Accountability 
28 
8.0 
Correlative /Special Studies 
28 
8.1. 
T- cell activation assay 
28 
8.1.1. 
Outcome measure 
28 
8.1.2. 
Collection and handling of specimen 
28 
8.1.3. 
Shipping of specimen 
Error! Bookmark not defined. 
8.1.4. 
Site(s) performing correlative study 
28 
8.2. 
Optional Blood and tissue for future research and Banking 
28 
9.0 
Study Calendar 
29 
Footnotes 
30 
10.0 
Adverse Events 
31 
10.1. 
Definitions 
31 
Potential Drug Induced Liver Injury (DILI) 
31 
10.1.1. 
Severity Rating 
32 
10.1.2. 
Attribution/Relationship to study drug 
32 
10.1.3. 
Expectedness 
32 
10.2. 
Recording and Reporting Responsibilities 
33 
10.2.1. 
Investigative Site Recording Responsibilities: 
33 
10.2.2. 
Investigative Site Reporting Responsibilities: 
33 
10.2.3. 
Sponsor Reporting Responsibilities: 
34 
10.3. 
Pregnancy 
35 


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10.4. 
Overdose 
36 
10.5. 
Secondary Malignancy 
36 
10.6. 
Second Malignancy 
37 
10.7. 
Other Safety Considerations 
37 
11.0 
Measures of Effect 
37 
11.1. 
Treatment beyond disease progression 
37 
11.2. 
Definitions 
38 
11.3. 
Disease Parameters 
38 
11.4. 
Methods for Evaluation of Measurable Disease 
40 
11.5. 
Response Criteria 
41 
11.5.1. 
Evaluation of Target Lesions 
41 
11.5.2. 
Evaluation of Non-Target Lesions 
42 
11.5.3. 
Evaluation of Best Overall Response 
42 
11.6. 
Duration of Response 
43 
11.7. 
Progression-Free Survival 
44 
12.0 
Statistical Considerations 
44 
12.1. 
Analysis of Secondary and Exploratory Endpoints 
44 
12.2. 
Sample Size/Accrual Rate 
45 
13.0 
Data and Safety Monitoring Plan 
45 
13.1. 
Monitoring Plan 
45 
13.2. 
Data & Safety Monitoring Board 
45 
14.0 
Administrative 
46 
14.1. 
Data Reporting 
46 
14.2. 
Retention of Records 
46 
14.3. 
Study Agents 
46 
14.4. 
Informed Consent 
46 
15.0 References 
48 
Appendix I: 
51 
Appendix II 
60 
Appendix III 
62 
 
 


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1.0 Introduction  
1.1. Non-small cell lung cancer 
Lung cancer is the most common form of cancer worldwide. In the United States in 2015, 
there will be an estimated 213,380 new cases of lung cancer and 160,390 deaths (Jemal et 
al. 2015). Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancer 
diagnoses.  Most patients with NSCLC will present with metastatic disease or develop 
metastases 
after 
initial, 
potentially 
curative, 
treatment 
with 
surgery 
or 
chemoradiotherapy. 
 
Treatment of advanced NSCLC has become increasingly complex in the past 10 years. 
Approximately 15% of patients have “activating mutations” that can be targeted with 
specific agents, usually tyrosine kinase inhibitors (TKI).  These mutations include EGFR 
activating mutations, ALK and ROS translocations amongst others.  Though such 
patients usually have excellent initial responses to therapy, the overwhelming majority 
eventually develops progressive disease and will be candidates for additional therapy.  
The median survival for these patients is approximately 30 months.  Patients with 
advanced disease that is not characterized by activating mutations or in which there is no 
targeted therapy for the mutation is not available (e.g. k-ras, insertion 20 EGFR etc),  are 
often initially treated with a platinum-based doublet chemotherapy regimen.  The median 
survival with such regimens is typically 10-14 months with virtually all patients 
ultimately dying of disease.  Once a patient has relapsed after platinum-based 
chemotherapy, second-line therapy is considered. There are 3 approved second-line 
treatment options for NSCLC in patients with prior platinum-based chemotherapy: 
docetaxel , pemetrexed, and erlotinib. A randomized, phase 3 trial of second-line therapy 
with docetaxel produced a statistically significant improvement in survival compared 
with best supportive care. (Fossella et al. 2000, Shepherd et al. 2000). A phase 3 trial of 
pemetrexed compared with docetaxel demonstrated similar response rates (RR), 
progression-free survival (PFS), and overall survival (OS) for the 2 treatments. (Hanna et 
al. 2004). While a formal proof of non-inferiority was not achieved, the efficacy and 
toxicity data were sufficient to support full approval of pemetrexed in this setting. 
Erlotinib, which is also approved for use in second-line NSCLC, was studied in patients 
with NSCLC previously treated with at least 1 chemotherapy; this study demonstrated a 
survival advantage compared with placebo (Shepherd et al. 2005) and led to approval of 
erlotinib as a second- and third-line therapy. In the second-line setting, RR and survival 
continue to be low (Shepherd et al. 2000, Hanna et al. 2004). Docetaxel has demonstrated 
phase 3 RR of 5% to 11% and a median survival of 5 to 8 months in second-line NSCLC 
patients. Pemetrexed is comparable, with a RR of 9.1% and a median survival of 8.3 
months in a similar population. In a large phase 3, placebo-controlled trial, erlotinib and 
placebo demonstrated RR of 8.9% and <1% and median survival of 6.7 and 4.7 months, 
respectively (Shepherd et al. 2005).  In 2014 the anti-VEGF-receptor agent ramacirumab 
was approved in combination with docetaxel for the second line treatment of NSCLC, 
though the degree of benefit is quite modest.  
 
 


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1.2. Immunotherapy in NSCLC 
Immunotherapy, specifically targeting of T-cell checkpoints has emerged as an important 
therapeutic approach in non-small cell lung cancer.    The CTLA-4 inhibitor ipilumamab, 
approved for therapy in melanoma, appeared to provide some benefit in addition to 
standard chemotherapy in a randomized phase II study.1  More remarkably, are the 
reports of activity of anti-PD1 and PD-L1 antibodies with significant and occasional 
durable responses in heavily pretreated disease. 2 3 Nivolumab is a fully humanized, IgG4 
(kappa) isotype monoclonal antibody (mAb) that binds the programmed death receptor-1 
(PD-1). PD-1 is a transmembrane protein primarily expressed on activated immune cells.  
In its usual function, the binding of PD-1 (found on activated T-cells) to its ligands PD-
L1 (B7-H1) and PD-L2 (B7-DC) inhibits T-cell proliferation and activation.  
Upregulation of PD-1 ligands can occur in tumors and is thought to serve as a means of 
immune evasion by the tumor. Nivolumab blocks the interaction of the PD-1 T-cell 
receptor with its ligands, potentially enabling the reactivation of immunosurveillance and 
cancer eradication. 
Nivolumab was approved by the US Food and Drug Administration in March 2015 for 
the treatment of patients with metastatic squamous non-small cell lung cancer with 
progression on or after platinum-based chemotherapy. A Phase II (NCT01721759) study 
evaluated nivolumab in patients refractory squamous lung cancer, progressive after 2 or 
more lines of chemotherapy. This study demonstrated an objective response rate of 15%, 
stable disease rate of 26% with median duration of response  for stable disease patients of 
6 months. Median overall survival was 8.2 months (95% CI 6.1-10.9 months) and overall 
survival was 41% at 1 year. A phase III trial  evaluating patients with squamous cell 
carcinoma of the lung (NCT01642004) has been reported. In interim analysis, patients 
randomized to nivolumab demonstrated an improvement in median overall survival of 9.2 
months compared to those treated with docetaxel (p-0.00025).4  Similar results have been 
reported for non-squamous carcinoma, leading to approval in that group of patients as 
well. More recently, the dosing schedule has been changed from 3 mg/kg to a flat dose of 
240 mg every 3 weeks.  
 
In most studies, response rates have been higher for patients with strong PD-L1 
expression by immunohistochemistry.  For example in a pooled analysis of responses to 
pembroluzimab, patients with high levels of expression of PD-L1 had response rates of 
39%, though responses were seen for patients who were negative (16%).5 While these 
results are encouraging, it is clear that current immunotherapeutics only benefit a 
minority of patients.  A logical approach to improving efficacy is to combine anti-PD-1 
therapy with other agents that can enhance immune function. This has already been done 
with possible benefit with the combination of anti-PD-1 therapies with anti-CTLA4 
agents. However, this approach is likely to be ultimately limited by toxicity and expense. 
Another approach is to target other aspects of immunity that may lead to suppression of 
the tumor immune response.  
 
Tumor initiation and progression are associated with inflammation and immune 
dysfunction. A link between these two areas is the myeloid derived suppressor cell 
(MDSC).6 It has been demonstrated that patients with non-small cell lung cancer 


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(NSCLC) show elevated levels of MDSCs that act as powerful immune suppressors via 
multiple pathways.  These include preventing activation of CD4+ and CD8+ T-cells, 
inducing T-regulatory cells, polarizing immunity towards a type-2 tumor-promoting 
phenotype, and blocking natural killer cell cytotoxicity.7 MDSCs originate in the bone 
marrow as Gr1+CD11b+CD31+ hematopoietic precursor cells that under normal 
conditions differentiate into mature dendritic cells, macrophages, or granulocytes.  In the 
presence of tumor-derived and host-produced factors, differentiation is blocked and 
MDSCs accumulate.8 These cells have been shown to inhibit T-cell proliferation and 
cytotoxic lymphocytes in an MHC- and antigen-independent manner. 9   Myeloid cells 
expressing similar markers in humans have been found to be increased fivefold in 
patients with head and neck squamous cell cancer, renal cell cancer, breast cancer, and 
NSCLC.10 Observations that pro-inflammatory cytokines both induce MDSCs and 
promote tumor progression suggest that chronic inflammation increases the number of 
MDSCs, inhibiting anti-tumor immunity, and promoting tumor growth.1     Depletion of 
MDSCs has been shown to reduce tumor progression and to improve immune-based 
cancer therapies.12 13 
 
We have evaluated peripheral blood mononuclear cells (PBMCs) of 10 patients with 
NSCLC and 5 normal controls.  These studies show that CD11b+CD33+ (MDSC) levels 
were quantified at 26.5±13% of PBMCs from NSCLC patients as compared to 11±6% of 
PBMCs from healthy patients.  To determine if the MDSC population is suppressive, 
PBMCs from patients 3, 8, and 11 were activated in vitro with anti-CD3 and anti-CD28 
mAbs.  T-cell proliferation was assessed by 3H-thymidine uptake.  Depletion of MDSCs 
significantly increased T-cell proliferation. 
 
       A.                                                                              B.                                               
Fig. 1:  Lung cancer patients have immunosuppressive CD11b+CD33+ (MDSCs) in their peripheral 
blood.  Panel A:  PBMC from healthy donor BC123104 and from NSCLC patients 3 and 11 were 
stained with mAbs for CD11b, CD33, and CD15, CD3, CD68, CD11c, DEC205, CD56, CD80, or 
isotype control mAbs (data not shown).  Viable cells were gated and analyzed by flow cytometry.  
Panel B:PBMCs from lung cancer patient 6 were either depleted or not depleted for CD11b+CD33+ 
(MDSC) cells and activated with anti-CD3 and anti-CD28 mAbs.  T-cell proliferation was assessed by 
3H-thymidine uptake. These data are representative of two to three independent experiments with 
PBMC from 5 healthy donors and 10 NSCLC patients. 
                                              
Cytotoxic chemotherapy has traditionally been thought to suppress antitumor 
immunity. Most cytotoxics kill through apoptosis, typically thought to be 


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immunologically “bland” or to result in tolerance. However, several agents, most 
notably gemcitabine, can in fact selectively enhance anti-tumor immunity, in 
particular, T-cell mediated immunity. 14 Cytotoxic chemotherapy also has the 
potential to both increase and decrease MDSC numbers.  A recent paper has 
demonstrated that cyclophosphamide and doxorubicin can increase MDSC and 
potentially decrease the efficacy of immune checkpoint inhibitors.15  However, 
gemcitabine has reduced some MDSC in animal models.16 17  Gemcitabine has 
demonstrated benefit in a number of common malignancies, including NSCLC, 
breast, ovarian and pancreatic cancers. Given the activity of the drug as both a single 
agent and its potential to enhance immunotherapy, it is logical to explore its 
interaction with immunotherapeutics.  
 
1.3. Study Hypothesis       
We hypothesize that gemcitabine can deplete MDSCs in lung cancer patients and 
depletion of MDSCs will enhance T-cell activity and consequently the activity of PD-1 
inhibitors. 
 
1.4. Correlative Testing 
T-cell activation assay 
Since the hallmark of MDSC is their ability to suppress T cell activation, we will 
determine the effects by comparing the level of T cell activation using patient samples 
obtained before and after treatment. T cell activation studies will be performed in vitro 
with PBMC at specified time points.  
 
These assays will be conducted as previously described.21 Briefly, PBMC from each 
patient at each time point will be divided into two aliquots.  One aliquot will be depleted 
for CD11b+CD33+ cells (MDSC) using Miltenyi magnetic beads.  The number of T cells 
in each aliquot will then be determined by flow cytometry staining with antibodies to 
CD3.  Both aliquots will then be activated by placing 105 T-cells/well in a 96 well round-
bottom plates previously coated with antibodies to CD3 and CD28. These cultures will be 
incubated for 72 hrs and then pulsed with tritiated thymidine.  Sixteen to 18 hrs later the 
cells will be harvested and counted in a scintillation counter.  Since tritiated thymidine 
uptake is a direct measure of T cell activation, we anticipate that there will be minimal 
uptake of the radiolabeled thymidine in the total PBMC and higher levels of radiolabel in 
the MDSC depleted cultures.  Since we will initially plate out the same number of T cells 
in each well, we can directly compare the level of T cell activation between the different 
treatments.  As an alternative to assessing T cell proliferation by tritiated thymidine 
uptake, we could assess T cell proliferation by CFSE dilution assay, or measure IFNγ 
production by either ELISA or Elispot assay 
 
  
 


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2.0 Objectives 
2.1. Primary Objective 
 The primary objective of this proposal is to evaluate gemcitabine as a method of 
MDSC depletion. 
 
2.2. Secondary Objectives  
 Evaluate whether these measures result in enhanced T-cell activity and/or NK cell 
function and number. 
 Determine the tolerability and clinical activity (including response rate and 
survival) of this approach.  
 Correlate MDSC number with tumor PD-L1 expression.  
 
3.0 Study Plan  
3.1. Description of Study Design, Population and Duration of Study Therapy  
This is a phase II trial with primary endpoint of evaluating the ability of gemcitabine to 
deplete MDSC number prior to administration of nivolumab. Patients who meet 
eligibility criteria (see section 4) will be enrolled. Patients will receive nivolumab 240 mg 
on days 1, 15 and gemcitabine 1000 mg/m2 on days 1, 8, 15 days.  Every 28 days will be 
considered one cycle.  
 
3.2. MDSC Enumeration Method 
Blood will be collected for PBMC isolation on day 1, 8, 15 of cycle 1 and day 1 of cycles 
2, and 3 before drug administration.  Granulocytic and monocytic MDSC in the blood 
will be quantified by flow cytometry using fluorescently tagged antibodies to the 
following markers of monocytic and granulocytic MDSC.  All human MDSC express 
CD33 and CD11b and are either negative or very low expressers of HLA-DR.  They are 
also negative for the lineage markers CD3, CD16, CD19, CD20, and CD56 18, 19, 20, 21 22, 
23, 24. Monocytic MDSC also express IL-4Rα and CD14, 22, 27, 25 while granulocytic (or 
polymorphonuclear) MDSC express CD15 26, 27. The staining protocol will be as 
previously described28, 21.This will be done by the Ostrand-Rosenberg lab at the 
University of Maryland Baltimore County. The blood samples will be handled and 
shipped by the Fox Chase Cancer Center Protocol Support Lab (PSL) according to the 
procedures described in the lab manual. The amount of blood to be shipped along with 
the procedures to be followed are specified in section 8.1 
 
3.3. PD-L1 expression  
Fresh or archival specimens of formalin fix tissue samples will be required for study 
entry (See Appendix III for details). Specimens may be from tumor material obtained 
from the primary or metastatic sites. They will be analyzed for PD-L1 expression to 
correlate with response and MDSC changes. Given the small sample numbers, this would 
be an exploratory analysis. The commercially available and FDA approved 
complementary diagnostic analysis for PD-L1 expression using the DAKO 28-8 antibody 


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will be performed.  We will analyze by employing the previously used cutoff points of 
>1%, 5% and 10% tumor cell staining.  In addition, we will also evaluate staining of 
tumor infiltrating lymphocytes.  
 
4.0 Patient Selection Inclusion & Exclusion 
4.1. Inclusion Criteria   
4.1.1 Histologically confirmed diagnosis of non-small cell lung cancer 
(NSCLC). Patients should have stage IV disease (AJCC 7th 
edition), stage IIIb disease that is not amenable to potentially 
curative treatment (e.g. chemoradiotherapy) or unequivocal 
progression in a prior irradiated field.  Measurable or evaluable 
disease is required. 
4.1.2 Fresh/ archived tumor tissue available for molecular marker testing 
is required for entry.  A tumor block or at least 5 unstained slides 
must be available. As an alternative FFPE cell block that is 
sufficient for histologic analysis is acceptable. . If a patient has had 
PD-L1 status previously determined with and FDA approved 
assay, they have met this requirement. Tissue is still requested (but 
not required) for further analysis. 
4.1.3 Age > 18 years. 
4.1.4 ECOG performance status 0 or 1 
4.1.5 Patients must have normal organ and marrow function as defined 
below 
 White Blood Cells (WBC) 
 
 
> 2,000/mcL 
 Absolute neutrophil count(ANC) 
            > 1,500/mcL 
 Platelets 
 
 
                        > 100,000/mcL 
 Hb                                                                   ≥ 9g/dl 
 Serum creatinine                                          ≤ 1.5 x ULN  
                                             or  
 creatinine clearance (CrCl) ≥ 50 mL/min (if using the Cockcroft-
Gault formula below): 
 
o Female CrCl = {(140 - age in years) x weight in kg/  
                           (72 x serum creatinine in mg/dL)} x 0.85  
o Male CrCl = {(140 - age in years) x weight in kg/  
                           (72 x serum creatinine in mg/dL)}x1.0 
 AST/SGOT              ≤ 3 x ULN 
 Total bilirubin,  
o If no known liver metastases: 
Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)    
(except subjects with Gilbert Syndrome, who may have total 
bilirubin <3.0 mg/dl) 


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o If known metastasis: 
Total bilirubin ≤ 5 ULN 
 
4.1.6 Negative serum pregnancy test result in Women of Child-bearing 
Potential (WOCBP) 
4.1.7 Prior therapies: 
 Patients without activating mutations and gene rearrangements 
should have received at least one prior chemotherapy regimen. 
Any number of prior therapies is    allowed except for 
immunotherapy (e.g. anti PD-1, PD-L1, vaccines, CTLA-4 etc.),  
 Patients with activating mutations and gene rearrangements with 
known documented benefit from tyrosine kinase inhibitors should 
have received and demonstrated progression with that inhibitor 
(e.g. EGFR del 19 mutation should have been treated with 
gefitinib, erlotinib or afatanib etc). ALK rearrangements should 
have been treated with an ALK inhibitor. Patients who have 
progressed on these agents should be assessed, if appropriate, for 
resistance mutations susceptible to approved agents and treated 
with that agent.  
 No prior gemcitabine treatment 
4.1.8 Ability to understand and willingness to sign a written informed 
consent and HIPAA consent document 
 
4.2. Exclusion Criteria   
4.2.1 Patients with active, known or suspected autoimmune disease. 
Subjects are permitted to enroll if they have vitiligo, type I diabetes 
mellitus, residual hypothyroidism due to autoimmune condition 
only requiring hormone replacement, psoriasis not requiring 
systemic treatment, or conditions not expected to recur in the 
absence of an external trigger 
4.2.2 Patients requiring systemic treatment with either corticosteroids (> 
10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of study drug administration. Inhaled 
or topical steroids and adrenal replacement doses > 10 mg daily 
prednisone equivalents are permitted in the absence of active 
autoimmune disease.  Subjects are permitted to use topical, ocular, 
intra-articular, intranasal, and inhalational corticosteroids (with 
minimal systemic absorption). Physiologic replacement doses of 
systemic corticosteroids are permitted, even if > 10 mg/day 
prednisone equivalents. A brief course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-
autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by contact allergen) is permitted. 


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4.2.3 As there is a potential for hepatic toxicity with nivolumab, drugs 
with predisposition to hepatotoxicity should be used with caution 
in patients treated with nivolumab-containing regimen.  
4.2.4 Patients are excluded if they have active brain metastases or 
leptomeningeal metastases. Subjects with brain metastases are 
eligible if metastases have been treated and without clinical or 
radiologic evidence of progression for 14 days prior to initiation of 
treatment. An MRI within 14 days of commencing therapy is 
required for patients with a history of brain metastases. 
4.2.5 There must be no requirement for immunosuppressive doses of 
systemic corticosteroids (> 10 mg/day prednisone equivalents) for 
at least 2 weeks prior to study drug administration. 
4.2.6 History of allergic reactions attributed to compounds of similar 
chemical or biologic composition to nivolumab. 
4.2.7 Uncontrolled intercurrent illness that would increase the risk of 
toxicity or limit compliance with study requirements.  This 
includes but is not limited to, uncontrolled infection, symptomatic 
congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
4.2.8 Known HIV-positive patients on combination antiretroviral 
therapy are ineligible because of the abnormal immune response 
that results from HIV disease.  
4.2.9 Patients should be excluded if they are positive test for hepatitis B 
virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic 
acid (HCV antibody) indicating acute or chronic infection 
4.2.10 Patients who have had systemic (IV) cytotoxic chemotherapy or 
any other investigational agents within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those 
who have not recovered from adverse events due to agents 
administered more than 4 weeks earlier. If a patient received an 
oral agent, treatment on study cannot commence at least five half-
lives of the agent have elapsed. 
4.2.11 Subjects with previous malignancies (except non-melanoma skin 
cancers, and in situ cancers such as the following: bladder, gastric, 
colon, cervical/dysplasia, melanoma, or breast) are excluded unless 
a complete remission was achieved at least 2 years prior to study 
entry and no additional therapy is required or anticipated to be 
required during the study period. 
4.2.12 Other active malignancy requiring concurrent intervention. 


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4.2.13 Subjects with any history of interstitial lung disease or a history of 
> or = to grade 2 radiation pneumonitis.  
4.2.14 Pregnant or breast feeding. Refer to section 4.4 for further details. 
 
4.3. Inclusion of Women and Minorities 
Men and women, regardless of race, ethnic group or sexual orientation are eligible for 
this study.   
 
4.4. Pregnancy 
The effects of nivolumab and gemcitabine on the developing human fetus at the 
recommended therapeutic dose are unknown.  For this reason and because nivolumab and 
gemcitabine agents are known to be teratogenic, women of child-bearing potential 
(WOCBP) and men must agree to use adequate contraception prior to study entry, and for 
the duration of treatment.   
 
WOCBP is defined as follows: Any female who has experienced menarche and who has 
not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or a 
bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 
consecutive months, or women on hormone replacement therapy (HRT) with documented 
plasma follicle-stimulating hormone (FSH) level > 35 mIU/ml).  Even women who are 
using oral, implanted, or injectable contraceptive hormones or mechanical products 
(diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or 
where partner is sterile (e.g. vasectomy), should be considered to be WOCBP. 
 
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she must inform her treating physician immediately. 
 
Prior to study enrollment, WOBCP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  In addition, men enrolled on this study should understand the risks to any 
sexual partner of childbearing potential. Women of childbearing potential (WOCBP) 
receiving nivolumab will be instructed to adhere to contraception for a period of 23 
weeks after the last dose of investigational product 
 
All WOCBP must have a negative pregnancy test within 24 hours prior to receiving the 
first dose of the investigational agent(s).  If the pregnancy test is positive, the patient 
must not receive protocol treatment and must not be enrolled in the study. 
 
Men who are sexually active with WOCBP must use any contraceptive method with a 
failure rate of less than 1% per year. Men receiving nivolumab and who are sexually 
active with WOCBP will be instructed to adhere to contraception for a period of 31 
weeks after the last dose of investigational product. Women who are not of childbearing 


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potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do 
not require contraception 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
 Male condoms with spermicide 
 Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants and intrauterine devices (IUDs) such as 
Mirena by WOCBP subject or male subject’s WOCBP partners participating in 
the study may use hormone based contraceptives as one of the acceptable methods 
of contraception since they will not be receiving study drug 
 Nonhormonal IUDs, such as ParaGard 
 Tubal ligation  
 Vasectomy 
 Complete Abstinence* 
 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and 
is an acceptable form of contraception for all study drugs. Subjects who choose complete 
abstinence are not required to use a second method of contraception, but female subjects 
must continue to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to forego complete 
abstinence. 
 
Less effective Methods of Contraception 
 
 Diaphragm with spermicide 
 Cervical cap with spermicide 
 Vaginal Sponge 
 Male condom without spermicide 
 Progestin only pills by WOCBP subject and male subject’s WOCBP partner 
 Female Condom* 
*A male and female condom must not be used together 
 
4.5. Patient Registration 
Participants may be registered from 8:00 am to 4:00 pm EST excluding holidays by 
emailing 
the 
Investigator-Sponsored 
Research 
Unit 
(ISRU) 
at: 
FCCC.MONITOR@fccc.edu. Eligible participants will be entered on study centrally 
once the following items have been received by email: 
 
Completed registration form  
Consent and HIPAA signature pages  
Eligibility checklist 
 


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Following registration, participants must begin protocol treatment within 7 calendar days 
of registration.  Issues that would cause treatment delays must be discussed with the 
Sponsor-Investigator.  If a registered participant does not receive protocol therapy 
following registration, the participant will be recorded as withdrawn from study.  The 
Study Monitor must be notified as soon as possible if a participant does not begin 
protocol treatment as scheduled. For additional registration questions, please email 
FCCC.MONITOR@fccc.edu or call (215) 728-5544. 
 
The FCCC ISRU will notify the site by email once registration is confirmed and the 
sequence number has been assigned.  Participants must be registered and have received a 
sequence number prior to the initiation of treatment.   
 
Exceptions to the current registration policies will not be permitted.  
  
5.0 Treatment Plan 
Treatment will be administered on an outpatient basis.  Treatment will be administered 
as described below.  Dose delays and modifications should only be done following 
protocol guidelines described in section 6.0.  Missed days will not be made up.  
Gemcitabine should be administered first followed by nivolumab. The day1 of the 
treatment should be scheduled in such a way that blood sample collection day for 
MDSC enumeration does not fall on a Friday. 
 
5.1. Treatment Administration 
 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
Gemcitabine 
1000mg/m2 
IV over 30 
minutes 
Day 
1,8,15 
 
4 weeks 
(28 days) 
Nivolumab 
240 mg  
30 minutes IV 
infusion 
Day 1, 15  
 
5.1.1. Nivolumab 
            Nivolumab will be given every two weeks beginning day 1 at a dose of 240 mg to 
be administered as a 30 minute IV infusion. Subjects may be dosed no less than 
12 days from the previous dose of drug. There are no premedications 
recommended for nivolumab on the first treatment. There will be no dose 
modifications allowed. 
 
            Subjects should be carefully monitored for infusion reactions during nivolumab 
administration. If an acute infusion reaction is noted, subjects should be managed 
according to Protocol guidelines in section 6.1.5 Doses of nivolumab may be 


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interrupted, delayed, or discontinued depending on how well the subject tolerates 
the treatment. 
 
            Nivolumab Injection, 100 mg/10 mL (10 mg/mL Nivolumab injection is to be 
administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, low-
protein binding polyethersulfone membrane in-line filter at the protocol-specified 
doses. It is not to be administered as an IV push or bolus injection. Nivolumab 
Injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium 
Chloride Injection, USP or 5% Dextrose Injection, USP to protein concentrations 
as low as 1 mg/mL. Care must be taken to assure sterility of the prepared solution 
as the product does not contain any antimicrobial preservative or bacteriostatic 
agent.  
             
5.1.2. Gemcitabine 
Gemcitabine 1000 mg/m2 IV over 30 minutes on day 1, 8 and 15 every 28 days. 
The dosing calculations should be based on the actual body weight at baseline. If 
the subject’s weight on the day of dosing differs by > 10% from the weight used 
to calculate the original dose, the dose must be recalculated. All doses should be 
rounded to the nearest milligram.  
 
5.2. Concomitant Medications, Supportive Care, Excluded Therapies and 
Restrictions 
Active prophylaxis and therapy, when available, should be considered per 
standard clinical indications.  Examples include gastritis and nausea prophylaxis 
and therapy for acute esophagitis, enteritis and cystitis. Palliative local therapy, 
including palliative radiation therapy- and palliative surgical resection, to 
symptomatic non-target bone lesions, skin lesions, or CNS lesions is permitted 
prior to discontinuation of study treatment for subjects who do not have evidence 
of overall clinical or radiographic progression per RECIST 1.1. 
 
Prohibited and/or Restricted Treatments 
The following medications are prohibited during the study (unless utilized to treat 
a drug related adverse event): 
 Immunosuppressive agents. 
 Immunosuppressive doses of systemic corticosteroids  
 
5.3. Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment will continue as 
long as the patient is benefitting (absence of progression and good tolerance of therapy) 
or until one of the following criteria applies: 
 
 Unequivocal disease progression 
 Intercurrent illness that prevents further administration of treatment 


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 Unacceptable adverse events 
 Patient becomes pregnant 
 Patient decides to withdraw from the study ( In this event sponsor-investigator 
must be notified, reason for withdrawal should be documented and patient must 
be followed for disease progression and survival for the duration specified in the 
protocol) 
 General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator. 
5.4. Duration of Follow up 
A safety follow-up will be performed 30 days after discontinuation from study treatment. 
Patients removed from study for unacceptable adverse events that are related to the study 
treatment will be followed until resolution or stabilization of the adverse event. All 
patients who discontinue the study treatment due to reasons other than disease 
progression will be followed every 2 months for response and survival (secondary 
endpoints) until disease progression or death or 2 years whichever occurs first. 
Reasonable effort should be made to evaluate their disease by scan to determine disease 
progression by a clinic visit.  Patients who undergo disease progression or start a new 
anti-cancer therapy will directly move into survival follow-up and will be followed once 
every 3 months by phone call for survival status until death or 2 years whichever occurs 
first. 
 
5.5. Criteria for Discontinuation 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies. 
The reason for study removal and the date the patient was removed must be documented 
in the medical record and case report form. 
 
6.0 Dose Modifications 
6.1. General Principles  
Because of the potential for clinically meaningful nivolumab-related AEs requiring 
early recognition and prompt intervention, management algorithms have been 
developed for suspected AEs of selected categories (see current Investigator Brochure 
and Appendix I for citation examples). 
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not 
the event is attributed to nivolumab). Nivolumab must be delayed until treatment can 
resume.  
 
6.1.1. Nivolumab administration should be delayed for the following: 
 
1. Any Grade ≥ 2 non-skin, drug-related AE, with the following exceptions: 
 Grade 2 drug-related fatigue or laboratory abnormalities do not require a 
treatment delay 


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2. Any Grade ≥3 skin, drug-related AE 
3. Any Grade 3 drug-related laboratory abnormality, with the following exceptions 
for lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic 
amylase or lipase: 
 Grade 3 lymphopenia or leukopenia does not require dose delay. 
 If a subject has a baseline AST, ALT, or total bilirubin that is within normal 
limits, delay dosing for drug-related Grade ≥ 2 toxicity. 
 If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 
toxicity range, delay dosing for drug-related Grade ≥ 3 toxicity. 
 Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not 
associated with symptoms or clinical manifestations of pancreatitis does not 
require dose delay. The Sponsor-Investigator should be consulted for such 
Grade ≥ 3 amylase or lipase abnormalities. 
4. Any AE, laboratory abnormality, or intercurrent illness that in the judgment of the 
investigator, warrants delaying the dose of study medication. 
 
Subjects who require delay of nivolumab should be re-evaluated weekly or more 
frequently if clinically indicated and resume nivolumab dosing when re-treatment 
criteria are met. 
 
6.1.2. Criteria to Resume Treatment 
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions: 
 
 Subjects may resume treatment in the presence of Grade 2 fatigue  
 Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity  
 Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose 
delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may 
resume treatment in the presence of Grade 2 AST/ALT or total bilirubin 
 Any drug-related liver function test (LFT) abnormality that meets the following 
criteria requires discontinuation (also see Hepatic Adverse Event Management 
Algorithm): 
o AST or ALT > 5-10x ULN for > 2 weeks 
o AST or ALT > 10x ULN 
o Total bilirubin > 5 x ULN 
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
 
 Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to 
baseline before treatment is resumed. Subjects with persistent Grade 1 
pneumonitis after completion of a steroid taper over at least 1 month may be 
eligible for retreatment after discussion with the Sponsor-Investigator.  
 Drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment if Sponsor-Investigator allows. 


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 Patients who received systemic corticosteroids for the management of any drug-
related toxicity must be off corticosteroids or have tapered down to an equivalent 
dose of prednisone ≤ 10 mg/day. 
  
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled time-point per protocol. However, if the treatment is delayed past the next 
scheduled time-point per protocol, the next scheduled time-point will be delayed until 
dosing resumes. 
If treatment is delayed or interrupted for > 6 weeks, the subject must be permanently 
discontinued from study therapy, except as specified in discontinuation section (6.1.4).  
 
6.1.3. Management Algorithms 
Guidelines for the management of immune related events can be found in the current 
Investigator Brochure, in the approved United States Package Insert and Appendix I. 
Immuno-oncology agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab is considered an immuno-
oncology agent in this protocol. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management algorithms 
have been developed to assist investigators in assessing and managing the following 
groups of AEs: 
Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, Neurological. 
 
For subjects expected to require more than 4 weeks of corticosteroids or other 
immunosuppressants to manage an AE, consider recommendations provided in the 
algorithms. These algorithms are found in the Nivolumab IB [and in Appendix I] of this 
protocol. The guidance provided in these algorithms should not replace the Investigator’s 
medical judgment but should complement it. 
 
6.1.4. Discontinuation Criteria 
Treatment should be permanently discontinued for the following: 
 Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within the re-
treatment period (section 6.1.2) OR requires systemic treatment  
 Any Grade ≥ 2 drug-related pneumonitis or interstitial lung disease that does not 
resolve to dose delay and systemic steroids (also see Pulmonary Adverse Event 
Management Algorithm) 
 Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the 
following exceptions for drug-related laboratory abnormalities, uveitis, 
pneumonitis, bronchospasm, diarrhea, colitis, neurologic toxicity, hypersensitivity 
reactions, and infusion reactions, and endocrinopathies: 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation 
o Grade 3 drug-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 


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o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below 
- 
Grade 3 drug-related thrombocytopenia > 7 days or associated with 
bleeding requires discontinuation 
- 
Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation:  
 
 
Total bilirubin > 5 x ULN 
 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
 Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
o Isolated Grade 4 amylase or lipase abnormalities that are not associated 
with symptoms or clinical manifestations of pancreatitis and decrease to < 
Grade 4 within 1 week of onset.  
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not 
associated 
with 
clinical 
sequelae 
and 
are 
corrected 
with 
supplementation/appropriate management within 72 hours of their onset 
o Grade 4 lymphopenia or leucopenia 
o Grade 4 neutropenia 7 days 
o Grade 4 drug-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose 
intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-
controlling agents, respectively, may not require discontinuation after 
discussion with and approval from the Sponsor-Investigator [as allowed 
by protocol] 
 Any dosing interruption lasting > 6 weeks with the following exceptions: 
o Dosing delays or interruptions to allow for prolonged steroid tapers to 
manage drug-related adverse events are allowed. Prior to re-initiating 
treatment in a subject with a dosing interruption lasting > 6 weeks, the 
Sponsor-Investigator must be consulted. Tumor assessments should 
continue as per protocol even if dosing is interrupted or delayed 
o Dosing interruptions or delays lasting > 6 weeks that occur for non-drug-
related reasons may be allowed if approved by the Sponsor-Investigator. 
Prior to re-initiating treatment in a subject with a dosing interruption 
lasting > 6 weeks, the Principal-Investigator must be consulted. Tumor 
assessments should continue as per protocol even if dosing is interrupted 
 Any adverse event, laboratory abnormality, or intercurrent illness that in the 
judgment of the Sponsor-Investigator, presents a substantial clinical risk to the 
subject with continued nivolumab dosing. 
 
6.1.5. Treatment of Nivolumab Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely 
to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 


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pruritis, arthralgia, hypo- or hypertension, bronchospasm, or other symptoms of allergic-
like reactions.  
 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. 
Infusion reactions should be graded according to NCI CTCAE version 4.0 guidelines. 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as appropriate: 
 
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention 
not indicated) - Remain at bedside and monitor subject until recovery from symptoms. 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) at least 30 minutes before additional nivolumab administrations. 
 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours) - Stop the nivolumab infusion, begin an IV infusion 
of normal saline, and treat the subject with diphenhydramine 50 mg IV (or equivalent) 
and/or paracetamol 325 to 1000 mg (acetaminophen); remain at bedside and monitor 
subject until resolution of symptoms. Corticosteroid or bronchodilator therapy may also 
be administered as appropriate. If the infusion is interrupted, then restart the infusion at 
50% of the original infusion rate when symptoms resolve; if no further complications 
ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. 
Monitor subject closely. If symptoms recur then no further nivolumab will be 
administered at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside 
and monitor the subject until resolution of symptoms. The amount of study drug infused 
must be recorded on the electronic case report form (eCRF). The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50 mg (or 
equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) should be administered 
at least 30 minutes before additional nivolumab administrations. If necessary, 
corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may 
be used. 
 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not 
rapidly responsive to symptomatic medication and/or brief interruption of infusion]; 
recurrence of symptoms following initial improvement; hospitalization indicated for 
other clinical sequelae [eg, renal impairment, pulmonary infiltrates]). Grade 4: (life 
threatening; pressor or ventilatory support indicated). - Immediately discontinue infusion 
of nivolumab. Begin an IV infusion of normal saline, and treat the subject as follows. 
Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10000 solution injected slowly for 
IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg 
IV (or equivalent), as needed. Subject should be monitored until the treating Physician is 
comfortable that the symptoms will not recur. Nivolumab will be permanently 


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discontinued. Investigators should follow their institutional guidelines for the treatment 
of anaphylaxis. Remain at bedside and monitor subject until recovery from symptoms.  
 
In the case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritis within 1 week after treatment), symptomatic treatment may be given 
(eg, oral antihistamine, or corticosteroids). 
 
6.2. Gemcitabine 
6.2.1. General guidelines 
If more than one of the dose modifications apply, use the most stringent (i.e., the greatest 
dose reduction). Gemcitabine will be continued when nivolumab is held for toxicities. If 
nivolumab is permanently discontinued for excessive toxicity gemcitabine will continue 
as monotherapy. All dose reductions are permanent  
 
6.2.2. Dose Modifications 
The following dose levels are used for dose modifications. If toxicity is seen at dose level 
-2, then gemcitabine will be permanently discontinued. 
 
Dose Level 
Gemcitabine 
0 
1000 mg/m2  
-1 
750 mg/m2  
-2 
500 mg/m2  
 
6.2.3. Hematologic Toxicity 
1. For ANC <1500 or platelets <100000 on day 1, delay treatment with gemcitabine 
until ANC ≥1,500 and platelets ≥100,000, then resume at the previous doses. If 
treatment is delayed for ≥ 3 weeks, discontinue gemcitabine. 
2. For platelets <25,000, decrease gemcitabine by one dose level for all subsequent 
doses. 
3. For febrile neutropenia occurring at any time during a cycle, reduce gemcitabine 
by one dose level for all subsequent doses. 
4. For ANC 500-999 or platelets 50,000 – 74,999 on day 8 or 15, decrease 
gemcitabine by one dose level for the current and all subsequent doses. 
5. For ANC <500 or platelets <50,000 on day 8 or 15, skip gemcitabine and 
decrease gemcitabine by one dose level for all subsequent doses. 
6. For a second episode of thrombocytopenia <25,000 or febrile neutropenia, 
decrease gemcitabine by one further dose level for all subsequent doses. 
 
6.2.4. Nephrotoxicity 
If creatinine clearance is < 45 ml/min, delay gemcitabine until CrCl ≥ 45 ml/min. When 
CrCl improves to ≥ 45 ml/min, resume gemcitabine at the previous dose level; if 
treatment is delayed / interrupted for ≥ 3 weeks, discontinue gemcitabine. 
 


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6.2.5. Pulmonary Toxicity 
Gemcitabine may rarely cause pulmonary toxicity characterized by dyspnea and 
interstitial pneumonitis. The pneumonitis will usually respond to steroids. Other causes of 
dyspnea should be excluded (i.e., anemia, cardiac, COPD exacerbation, etc.) before 
concluding that pulmonary toxicity is drug associated.  In addition, given the association 
of nivolumab with pulmonary toxicity, the algorithm for management of pulmonary 
toxicity due to nivolumab should be followed unless there is compelling evidence that the 
toxicity is due to gemcitabine. 
 For grade 2 pulmonary toxicity due to gemcitabine, hold protocol treatment.  
Patients may be retreated with a two level dose reduction in gemcitabine dose on 
the next and all subsequent cycles at the physician’s discretion if pulmonary 
symptoms improve to grade 0-1 within 3 weeks. 
 For grade 3 and 4 pulmonary toxicity, discontinue protocol therapy. 
 
6.2.6. Skin Toxicity attributed to gemcitabine 
 Grade 2: Decrease gemcitabine by one dose level.  
 Grade 3 or 4: Discontinue gemcitabine. 
 
6.2.7. Hypersensitivity Reactions attributed to gemcitabine 
For grade 3 allergic or anaphylaxis reactions thought to be due to gemcitabine, 
discontinue gemcitabine.  
 
6.2.8. Other Non-Hematologic  
Grade 3 Toxicity (not described above): Delay until toxicity improves to ≤ grade 2, then 
resume treatment with one dose level reduction. If treatment is delayed for > 3 weeks, 
discontinue gemcitabine. 
For recurrent other non-hematologic grade 3 toxicity: Discontinue all protocol 
therapy.  
Grade 4 Toxicity (not described above): Discontinue gemcitabine. 
 
 
 
7.0 Study Agent Information 
 
 
7.1. Nivolumab 
Nivolumab will be supplied by BMS as investigational supply. Please refer to the FDA 
approved package insert and investigational brochure for additional information. 
 
7.1.1. Product description 
Product Description:(Other names = MDX-1106, ONO-4538, anti-PD-1) 


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*Nivolumab may be labeled as BMS-936558-01 Solution for Injection 
 
7.1.2. Storage 
If stored in a glass front refrigerator, vials should be stored in the carton. 
Recommended safety measures for preparation and handling of nivolumab 
include laboratory coats and gloves. 
For additional details on prepared drug storage and use time of nivolumab under 
room temperature/light and refrigeration, please refer to the BMS-936558 
(nivolumab) Investigator Brochure section for “Recommended Storage and Use 
Conditions”  
 
7.1.3. Route of administration  
       Intra-venous 
 
7.2. Gemcitabine 
7.2.1. Product description 
Gemcitabine HCl (2’2’-difluorodeoxicytidine) is a nucleoside analogue that 
exhibits antitumor activity. It is commercially available and supplied as a 
lyophilized powder in sterile glass vials containing 200 mg or 1000 mg of active 
drug as the hydrochloride salt (expressed as the free base), mannitol, and sodium 
acetate. 
 
7.2.2. Availability  
Gemcitabine is available commercially. Please refer to the FDA approved 
package insert for additional information. 
 
Product Description 
and Dosage Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label 
Type 
Secondary 
Packaging 
(Qty) 
/Label Type 
Appearance 
Storage Conditions 
(per label) 
Nivolumab (BMS-
936558-01)* Injection 
drug product is a sterile, 
non-pyrogenic, single-
use, isotonic aqueous 
solution formulated at 10 
mg/mL   
100 
mg/Vial 
(10 
mg/mL). 
 
 
Carton of 5 
or 10 vials 
10cc Type 1 
flint glass 
vials 
stoppered 
with butyl 
stoppers and 
sealed with 
aluminum 
seals. 
 
Clear to 
opalescent, 
colorless to 
pale yellow 
liquid.  May 
contain 
particles 
BMS-936558-01 
Injection must be 
stored at 2 to 8 
degrees C (36 to 46 
degrees F) and 
protected from light 
and  freezing  


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7.2.3. Solution preparation 
The appropriate dose of gemcitabine should be diluted in 250 mL of normal saline 
(maximum concentration of 40 mg/mL) and administered intravenously as a 
constant infusion over 30 minutes. Normal saline is the only diluent approved; do 
not use other diluents. Nothing else should be added to the bag. Since gemcitabine 
is NOT a vesicant, extravasation should be handled according to local hospital 
policy concerning extravasation of drugs. 
 
7.2.4. Storage requirements 
The intact vials should be stored at controlled room temperature between 
59°-86°F (15°-30°C). The intact vials are stable for 3 years at controlled room 
temperature. Reconstituted solutions should be used within 24 hours; unused 
portions should be discarded.  
 
7.2.5. Route of administration  
Intra-venous 
 
7.2.6. Toxicity 
The DLT is myelosuppression. Other possible clinical toxicities include fever, 
chills, nausea, vomiting, diarrhea, constipation, skin rash or confluent erythema, 
edema, paresthesia, fatigue, anorexia, headache, muscle aches, cough, rhinitis, 
insomnia, sweating, drowsiness, hypotension, and mucositis.  
 
Dyspnea on exertion or at rest has occasionally been reported after gemcitabine 
therapy. Non-progressive liver function abnormalities and dip-stick-positive 
proteinuria, or hematuria may occur. Episodes of hemolytic uremic syndrome 
have been reported in patients treated with gemcitabine. There were no reports of 
injection site necrosis with gemcitabine in US trials. There may be some local 
irritation and injection site pain due to the low pH of the solution (pH3). 
 
 
7.3. Drug Ordering, Storage and Handling 
Following submission and approval of the required regulatory documents, 
participation in the study initiation meeting and receipt of the site activation letter 
from the FCCC ISRU, the initial order may be placed.  Drug order forms and 
ordering procedure will be presented at the site initiation meeting. 
 
7.4. Destruction of Drug   
At the time of study closure, the unused and expired study drug will be destroyed at 
the site per Institutional SOPs unless otherwise specified. Expired drugs may be 
destroyed during the study as per institutional SOP. 
 


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7.5. Records to be kept at Site; Dispensing and Accountability 
It is the responsibility of the Site Principal Investigator to ensure that a current 
record of investigational product disposition is maintained at each study site where 
investigational product 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. 
 Dates and initials of person responsible for each investigational 
product inventory entry/movement. 
 Amount dispensed to and returned by each patient, including unique 
patient identifiers. 
 Amount transferred to another area for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted, broken). 
 
8.0 Correlative /Special Studies 
8.1. T- cell activation assay 
8.1.1. Outcome measure 
T-cell activation assay will be performed as explained in section 1.4. 
 
8.1.2. Collection and handling of specimen 
The blood samples will be collected and handled by Protocol Support Lab 
(PSL) according to the instructions specified in their lab manual 
 
8.1.3. Specimen 
At the time of registration, the investigator will contact the Immune Monitoring 
Facility (Dr. Kerry Campbell) lab to confirm dates that they can receive 
specimen for analysis. A minimum of 7ml green top tube of blood will be drawn 
and kept at room temperature.  
 
8.1.4. Site(s) performing correlative study 
Immune Monitoring Facility, Fox Chase Cancer Center 
 
8.2. Optional Blood and tissue for future research and Banking 
Archival tissue will be collected and used for genetic testing in consenting patients. 
Blood specimen will be collected from consenting patients to isolate plasma and 
sera for banking for future research by PSL according to the instructions specified 
in the lab manual. Blood will be drawn on cycle 1 day 1 pre-treatment, every 2 
cycles (at the start of cycle 3, 5 and so on), and at the time of discontinuation. 


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9.0 Study Calendar 
  
 
 
Beyond Cycle 3, Cycle 2 and 3 will be 
repeated in the same order (except blood 
for MDSCs)  
 
 
 
 
 
CycleK 1 
Cycle 2 
Cycle 3 
Safety 
Follow-
upL 
 
Follow-
up M 
Survival 
Follow-
upN 
 
Pre-treatment 
Day 
1 
Day 
8  
Day 
15 
Day 
1 
Day 
8  
Day 
15 
Day 
1 
Day 
8  
Day 
15 
 
 
 
Informed Consent 
And HIPAAA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
Concurrent Medications 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Physical Examination 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Vital SignsB 
XC 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Performance Status 
XC 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/differential, plts 
XC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum chemistryD 
XC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Thyroid (TFT)P 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Serum Pregnancy testE 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
EKG (as clinically 
indicated)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Radiologic Tumor 
assessmentF 
XJ 
 
 
 
 
 
 
X 
 
 
 
X 
 
Other imagingG 
XJ 
 
 
 
 
 
 
X 
 
 
 
X 
 
Archival or fresh biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Nivolumab  
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Gemcitabine 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Event  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for MDSC 
quantificationH 
 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Sera and plasma for 
banking 
 
XI 
 
 
 
 
 
X 
 
 
X 
 
 


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Footnotes 
A. Informed consent must be signed within 30 days of registration.  If signature is outside that window the patient must 
sign a new consent. Following registration treatment must begin within 7 calendar days.    
B. 
Temperature, Pulse, Respiratory rate, Blood Pressure 
C.     Should be done within a week of C1D1 
D.     Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
E.    Only for Women of Child Bearing Potential. Should be done within 24 hours of day 1 of every cycle. 
F.    CT scan of chest. Must be done before treating the patient and disease status must be determined before 
treatment. 
G.   As clinically indicated other imaging may be done, for example CT of abdomen if abdominal disease is indicated 
H.    Should be collected prior to drug administration on day 1, 8, 15 of cycle 1, and day 1 of cycles 2 and 3 only.  
I.    Sera and plasma to be collected before treatment on C1D1 for banking for future research  
J.    Must be done 28 days before C1D1 
K.    Each cycle is 28 days. All treatment visits have +/1 day window. Day 1 of each treatment cycle should be 
scheduled such that blood sample collection for MDSC quantification should not fall on a Friday.    
L.    30 days after study discontinuation 
M.   Patients who discontinue without disease progression will be followed every 2 months until 2 years or disease 
progression or death whichever occurs earlier. Once disease progression is documented the patients will move to 
survival follow-up 
N.    Survival follow-up once in 3 months via phone call. 
O.   To be performed every other cycle i.e. on cycle 1,3,5 and so on. 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.0 
Adverse Events 
10.1. Definitions 
Adverse Events (AE) is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with 
the use of a medicinal (investigational) product, treatment or procedure 
regardless of whether it is considered related to the medical treatment or 
procedure (NCI CTEP Guidelines March 28, 2011) 
 
Serious Adverse Event (SAE) is an AE that is fatal or life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization (for > 24 
hours), persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, or is a congenital anomaly/ birth defect. 
Important medical event that may not result in death, be life threatening, or 
require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the above outcomes.  A “life-
threatening” adverse event places the patient at immediate risk of death in the 
judgment of the investigator or sponsor. 
 
Although pregnancy, overdose, potential drug-induced liver injury (DILI) and 
cancer are not always serious by regulatory definition, these events must be 
handled as SAEs. 
Potential Drug Induced Liver Injury (DILI)  
Wherever possible, timely confirmation of initial liver-related laboratory 
abnormalities should occur prior to the reporting of a potential DILI event. All 
occurrences of potential DILIs, meeting the defined criteria, must be reported as 
SAEs. 
Potential drug induced liver injury is defined as:  
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
                            AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase), 
                           AND 
3) No other immediately apparent possible causes of AT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to 
be hepatotoxic. 
 


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10.1.1. Severity Rating  
The investigator will evaluate the severity of each adverse event.  NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.0) or study specific 
toxicity tables provided in the protocol define severity.  If not included in 
CTCAE v.4.0, severity is expressed in numerical grade using the following 
definitions: 
 Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
 Grade 2: Moderate-minimal, local or noninvasive intervention indicated; 
limiting age appropriate instrumental ADL. 
 Grade 3: Severe-severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL. 
 Grade 4: Life-threatening consequences; urgent intervention indicated.  
 Grade 5: Death related to AE 
 
10.1.2. Attribution/Relationship to study drug  
 Definite – clearly related 
 Probable – likely related 
 Possible – may be related 
 Unlikely – doubtfully related 
 Unrelated – clearly not related 
 
10.1.3. Expectedness 
An Expected Adverse Event is one where the specificity or severity is consistent 
with the current information available from the resources. 
 
An Unexpected Adverse Event is one where the nature, severity, or frequency 
of the event is related to participation in the research is not consistent with 
either: 
 
1. The known or foreseeable risk of adverse events associated with the 
procedures involved in the research that are described in (a) the 
protocol-related documents, such as the IRB-approved research protocol, 
any applicable investigator brochure, and the current IRB-approved 
informed consent document, and (b) other relevant sources of 
information, such as product labeling and package inserts: or 
 
2. The expected natural progression of any underlying disease, disorder, or 
condition of the subject (s) experiencing the adverse event and the 
subjects(s) predisposing risk factor profile for the adverse event. 
 


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10.2. Recording and Reporting Responsibilities 
10.2.1. Investigative Site Recording Responsibilities: 
1. Upon identification of an AE or SAE, the site investigator will utilize the 
above definitions to properly classify the event.  Each category listed 
above must be recorded for each event. 
 
2. All AEs and SAEs will be recorded in the “AE case report forms” (CRF) 
and in progress reports with details about the grade and attribution of 
each episode, action taken with respect to the study drug, and the 
patient’s outcome will be recorded in the CRF.  All events will be 
recorded on case report forms for the duration of the study until they 
resolve. 
 
3. All reportable SAEs will be recorded on the FDA MedWatch form 
3500a.  After submitting the initial report it may be necessary to submit 
follow up reports to the Sponsor should the event require further 
investigation. 
 
10.2.2. Investigative Site Reporting Responsibilities: 
1.  The investigator/ site is responsible to report all SAEs that occur on or 
after the first day of study treatment to the sponsor within 24 hours of 
becoming aware of the event.  All subsequent SAEs must be reported 
for up to 30 days after the last treatment. 
 
 
Each investigator is responsible to report all AEs/SAEs to their local 
IRB following guidelines set by that IRB.  The FCCC OCR reserves 
the right to request an event be reported to the IRB at their discretion.  
Copies of events reviewed by the IRB must be sent by email to 
SAE.FCCC@fccc.edu. 
      
2. If the investigator or IRB feels the event warrants a revision to the 
informed consent that was not already initiated by the OCR, draft 
revisions will be made in track changes and submitted to the OCR for 
consideration.  Any consent revisions must receive OCR approval 
prior to submission to the IRB. 
 
3. Any investigator who is in doubt of whether a particular AE needs to 
be reported is directed to call the Study Monitor for confirmation with 
the Sponsor-Investigator 
 
4. If the results of an investigator or OCR investigation show an adverse 
event not initially determined to be reportable is so reportable, the 
investigator will report the event following the above guidelines 
based on the date the determination is made. 


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5. Copies of all related correspondence and reporting documents must 
be submitted to the ISRU and will be maintained in the trial master 
file.  
 
Participating sites should report events to: 
 
Investigator-Sponsored Research Unit 
Office of Clinical Research 
  
           Fox Chase Cancer Center 
SAE.FCCC@fccc.edu 
 
10.2.3. Sponsor Reporting Responsibilities: 
1. Adverse events which meet all of the following criteria must be reported 
to all participating institutions for IRB submission within 2 weeks of 
notification of the event.   
a. Unexpected (in terms of nature, severity, or frequency) given  
i. (a) the research procedures that are described in the 
protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and  
ii. (b) the characteristics of the subject population being 
studied; 
b. Possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures 
involved in the research); and 
c. Serious (refer to above definition) or otherwise one that suggests 
that the research places subjects or others at a greater risk of 
physical or psychological harm than was previously known or 
recognized. 
2. If the adverse event requires modification of the study protocol and 
informed consent, these changes will be provided to all participating 
institutions in the form of an amendment from the OCR for each site’s 
IRB of record along with the report of the adverse event.   
3. Copies of all related correspondence and reporting documents will be 
maintained in a centralized regulatory file for this study at OCR. 
4. SAEs that are related, unexpected, fatal, or life-threatening are 
reportable through the Food and Drug Administration (FDA) MedWatch 
program by telephone or fax no later than 7 calendar days after initial 
receipt of the information.  Further information on the timing of 
submissions are as directed by FDA guidelines 
(http://www.fda.gov/medwatch/index.html).  Serious, unexpected events 
that suggest significant clinical risk will be submitted to within 15 
calendar days after initial receipt of this information. 
 


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Food and Drug Administration: 
Telephone 1-800-FDA-1088 
Fax 1-332-FDA-0178 
http://www.fda.gov/medwatch/report.htm 
 
SAE and pregnancies must be reported to BMS within 24 hours. SAEs must be 
recorded on BMS or an approved form; pregnancies must be reported on a 
Pregnancy Surveillance Form (Appendix II). 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports should include the same investigator term(s) 
initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 
hours to BMS (or designee) using the same procedure used for transmitting the 
initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 An SAE report should be completed for any event where doubt exists regarding 
its seriousness.  
 If the investigator believes that an SAE is not related to study drug, but is 
potentially related to the conditions of the study (such as withdrawal of previous 
therapy or a complication of a study procedure), the relationship should be 
specified in the narrative section of the SAE Report Form. 
 
10.3. 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. 
 
In the event of a confirmed pregnancy in a patient participating in the study, the site 
Investigator must immediately notify the Fox Chase Cancer Center Study Monitor 
who will notify Dr. Martin J Edelman and BMS. 
 


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If, following initiation of the investigational product, it is subsequently discovered 
that a study participant is pregnant or may have been pregnant at the time of 
investigational product exposure, including during at least 5 half-lives after product 
administration, the investigational product will be permanently discontinued in an 
appropriate manner (eg, dose tapering if necessary for participant).  
The sponsor-investigator must immediately notify Worldwide.Safety@bms.com of 
this event via the Pregnancy Surveillance Form in accordance with SAE reporting 
procedures.  
Protocol-required procedures for study discontinuation and follow-up must be 
performed on the participant. 
Follow-up information regarding the course of the pregnancy, including perinatal 
and neonatal outcome and, where applicable, offspring information must be 
reported on the Pregnancy Surveillance Form [provided upon request from BMS] 
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. In order for Sponsor or designee to collect any pregnancy 
surveillance information from the female partner, the female partner must sign an 
informed consent form for disclosure of this information.  
10.4. Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. 
 
10.5. Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., treatment with investigational agent/intervention, radiation or chemotherapy).  
A secondary malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an 
agent under an NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three 
options are available to describe the event:  
 
 Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia ([AML])  
 Myelodysplastic syndrome (MDS)  
 Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should 
also be reported via the routine reporting mechanisms outlined in each protocol.  
 


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10.6. Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine AE reporting unless otherwise specified. 
 
10.7. Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded as a nonserious 
or serious AE, as appropriate, and reported accordingly.  
11.0 
Measures of Effect 
The patients will be re-evaluated every 8 weeks. In addition to a baseline scan, 
confirmatory scans should also be obtained ≥ 4 weeks following initial 
documentation of objective response.  Assessment of response is based upon 
RECIST 1.1 with the modifications described by Nishino et al. Though 
“pseudoprogression” in lung cancer is uncommon, it has been documented. 
Therefore, patients may continue on therapy if they are felt to be clinically 
benefitting and will be withdrawn if there is clinical deterioration. Additionally, 
new lesions will be added to the sum of the prior lesions and will not automatically 
be considered disease progression. 
 
11.1. Treatment beyond disease progression 
Accumulating evidence indicates a minority of subjects treated with immunotherapy 
may derive clinical benefit despite initial evidence of PD. Subjects will be permitted 
to continue treatment beyond initial RECIST 1.1 defined PD as long as they meet the 
following criteria determined by the investigator: 
 
• 
Investigator-assessed clinical benefit 
• 
Tolerance of study drug 
• 
Stable performance status 
 
The assessment of clinical benefit should take into account whether the subject is 
clinically deteriorating and unlikely to receive further benefit from continued 
treatment.  
 
Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (eg, CNS metastases).  
 
A radiographic assessment/ scan should be performed within 6 weeks of initial 
investigator-assessed progression to determine whether there has been a decrease in 
the tumor size or continued PD. The assessment of clinical benefit should be balanced 


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by clinical judgment as to whether the subject is clinically deteriorating and unlikely 
to receive any benefit from continued treatment with nivolumab. 
 
For the subjects who continue nivolumab study therapy beyond progression, further 
progression is defined as an additional 10% increase in tumor burden from time of 
initial PD. This includes an increase in the sum of diameters of all target lesions and/ 
or the diameters of new measurable lesions compared to the time of initial PD. 
Nivolumab treatment should be discontinued permanently upon documentation of 
further progression. 
 
New lesions are considered measureable at the time of initial progression if the 
longest diameter is at least 10 mm (except for pathological lymph nodes which must 
have a short axis of at least15 mm). Any new lesion considered non-measureable at 
the time of initial progression may become measureable and therefore included in the 
tumor burden if the longest diameter increases to at least 10 mm (except for 
pathological lymph nodes which must have a short axis of at least 15 mm). In 
situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions that become measurable, these new lesions must demonstrate 
an absolute increase of at least 5 mm. 
 
 
11.2. Definitions 
Evaluable for adverse events.  All patients will be evaluable for adverse events from 
the time of their first treatment 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for response.  These patients will 
have their response classified according to the definitions stated below.  
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target disease.  The response assessment is 
based on the presence, absence, or unequivocal progression of the lesions.  
 
11.3. Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by 
chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might 
not be considered measurable.   


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Malignant lymph nodes.  To be considered pathologically enlarged and measurable, 
a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum.  The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of these lesions are 
not required, but the presence, absence, or in rare cases unequivocal progression of 
each should be noted throughout follow-up.  
 


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11.4. Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm 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:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
 
MRI has excellent contrast, spatial, and temporal resolution; however, there are 
many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI 
is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality 
used at follow-up should be the same as was used at baseline and the lesions should 
be measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used 
and the image acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types, such as germ cell tumors, where known residual benign tumors can 
remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response 


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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. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement 
CT scanning in assessment of progression (particularly possible 'new' disease).  
New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm:  
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
  
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation corrected 
image. 
 
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. 
 
11.5. Response Criteria 
11.5.1. Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. 
 Any 
pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to <10 mm. 


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Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
11.5.2. Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
11.5.3. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria. 
 


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For Patients with Measurable Disease (i.e., Target Disease) 
 
F
o
r
  
F
o
F
o
r
 
P
a
t
i
e
n
t
s
 
N
 Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so 
to assign this category when no lesions can be measured is not advised 
 
11.6. Duration of Response 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR: measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD /not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD /not 
evaluated 
No 
SD 
documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 


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measurements recorded since the treatment started, including the baseline 
measurements.  
 
11.7. Progression-Free Survival 
PFS is defined as the duration of time from first dose of the study drug to time of 
progression or death, whichever occurs first. 
 
12.0 
Statistical Considerations 
 The primary goal is to evaluate the efficacy of the combination therapy in suppressing 
MDSCs by comparing day 1 (baseline- prior to any treatment) with  samples collected on 
day 1 of cycle 2, with each patient serving as his/her own control.  Ten (10) patients will 
be treated with the combination therapy beginning in the first four week cycle (two 
administrations of nivolumab).  A paired t-test, (one-sided; α = 0.05) or Wilcoxon signed 
rank test will be used in this small pilot study to compare baseline to day 1 of cycle 2 
changes in MDSC measurements. MDSC data may be transformed before analysis if 
appropriate. Efficacy analyses will be conducted using data from evaluable patients. It is 
anticipated that the addition of gemcitabine will produce at least a 50% reduction in the 
number of MDSCs circulating in the blood. Table 1 displays the detectable mean pre- to 
post-treatment reductions in MDSC values with 10 paired samples over a range of 
potential within-subject correlations. 
 
Table 1.  Detectable mean pre- to post-treatment reduction in MDSC measurements with 
80% power using a paired t-test (1-sided; α=0.05) assuming unit standard deviation for 
individual measurements and 10 paired samples over a range of potential within-subject 
correlations. 
Within-Subject 
Correlation 
Standard deviation 
of change over time 
Detectable mean pre- to post-treatment 
reduction in MDSC values 
0.5 
1.00 
0.85 
0.6 
0.89 
0.76 
0.7 
0.77 
0.66 
0.8 
0.63 
0.54 
0.9 
0.45 
0.38 
    
12.1. Analysis of Secondary and Exploratory Endpoints 
Patient characteristics and biomarker measurements at baseline and day 1 of subsequent 
cycles will be summarized using standard methods (e.g., binomial proportions, means, 
medians, 95% confidence intervals). Secondary and exploratory endpoints will include 
response rate (determined with RECIST 1.1 and with modified immune RECIST, as 
described by Nishino), progression free and overall survival. Response rates will be 
computed and reported with 2-sided 95% confidence intervals. Overall survival (OS) is 
defined as the time between the date of first dose of experimental therapy and death from 
all causes. Progression-free survival (PFS) is defined as the time between the date of first 
dose of experimental therapy and disease progression or death from any cause, whichever 
comes first. Overall survival and progression-free survival will be characterized by the 


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Kaplan-Meier method. For calculation of OS, patients alive at last follow-up will be 
censored. For PFS analyses, patients alive and progression free at last follow-up will be 
censored. Adverse events will be tabulated by type, severity. 
 
Since the hallmark of MDSC is their ability to suppress T cell activation, we will 
determine the effects of the treatment by comparing the level of T cell activation using 
patient samples obtained before and after treatment. These assays will be conducted as 
previously described. 21 T cell proliferation will be assessed by tritiated thymidine uptake 
or CFSE dilution assay; T cell function will be measured by IFNγ production by either 
ELISA or Elispot assay. Baseline to day 1 of subsequent cycles changes in the level of T 
cell proliferation and T cell function will be compared using one-sided Wilcoxon signed 
rank tests (=0.05). 
 
A series of correlative analyses will be conducted between pairs of biomarkers (e.g., 
MDSC number and tumor PD-L1 expression) measured at specific time points as well as 
baseline to follow-up changes in biomarker values. We will use Spearman’s rank 
correlation coefficient to quantify these associations.  With a two-tailed test (=0.05) we 
will have 80% power to detect true correlations of > 0.76 (or<-0.76). Correlations much 
weaker than these are unlikely to be biologically and clinically useful. 
 
12.2. Sample Size/Accrual Rate 
Ten (10) patients with paired samples will be required. Therefore, a total of 10 evaluable 
patients will be enrolled. If a patient is not evaluable (i.e. there is not an adequate paired 
sample, that patient will be replaced and not considered in the final primary analysis. It is 
anticipated that there will be a 10% inevaluable rate, therefore, up to 11 patients may be 
enrolled. Accrual rate for this study is estimated to be 1-2 patients per month. 
 
 
13.0 
Data and Safety Monitoring Plan 
13.1. Monitoring Plan  
FCCC ISRU will monitor the medical and study records of each participant accrued 
throughout the course of the study.  In addition, the ISRU will collect and report 
data to the study Sponsor-Investigator who will review the data on a regular basis at 
a rate dependent on subject accrual.  All serious adverse events (SAEs) will be 
reviewed on a real time basis first by the study site PI and subsequently by the 
ISRU and Sponsor-Investigator as applicable. 
 
13.2. Data & Safety Monitoring Board   
Interim analysis of toxicity, outcome and ongoing scientific investigations will be 
performed by the Fox Chase Cancer Center Data & Safety Monitoring Board 
(FCCC DSMB).  In this capacity the FCCC DSMB will serve as an advisory 
committee to the Sponsor-Investigator.  The FCCC DSMB will review those 
aspects of this trial that are outlined in the responsibilities section of the Data & 
Safety Monitoring Plan (DSMP).  If the committee decides that changes should be 


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made to this trial, it will make recommendations in writing to the Sponsor-
Investigator, the Associate Director of Clinical Research, and the Protocol 
Management Executive Committee, which, in turn, have the authority to approve or 
disapprove these recommendations.  These changes will be discussed with the 
Sponsor-Investigator before they are implemented.  These changes may include 
early termination of accrual.  Other changes might include altering the accrual goals 
or changing the eligibility criteria for the trial. 
 
14.0 
Administrative   
This study will be conducted in accordance with local, state and Federal regulations and 
according to accepted good clinical practice guidelines. 
 
14.1. Data Reporting 
The FCCC Study Monitor will request case report forms to be completed within 2 
weeks of the protocol visit.  Participating sites are responsible to respond to queries 
prior to the next scheduled monitoring visit 
 
The ISRU is responsible for compiling and submitting data to the Sponsor-
Investigator and statistician on an ongoing basis for monitoring as described in the 
DSMP and reporting to the Data and Safety Monitoring Board. 
 
All patient information will be stored in an EDC system accessible only to the study 
team members for the purpose of entering, reviewing and analyzing data.  Any 
paper records, such as case report files, produced will be stored in a secure location.  
 
The ISRU is responsible for distributing and tracking review of all IND Action 
Letters, Safety Reports, study specific Serious Adverse Events 
 
14.2. Retention of Records   
Time points for the retention of records are described in detail in the contract 
between the grantor and the OCR and passed on to the participating site.  Please 
refer to the study specific terms for specific time points.  In all cases the Study 
Monitor must be notified of any plans to move records to an offsite location prior to 
doing so. 
 
14.3. Study Agents 
Any study agent supplied through the OCR from the manufacturer or a third party 
distributor may not be used for any purpose outside the scope of this protocol.  The 
agent may not be transferred to any party not participating in the clinical trial. 
 
14.4. Informed Consent 
The IRB approved informed consent documents must be signed by the patient, or 
the patient’s legally authorized representative, before his or her participation in the 


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study.  The case history for each patient shall document that informed consent was 
obtained prior to participation in the study.  A copy of the informed consent 
documents must be provided to the patient or the patient’s legally authorized 
representative.  If applicable, they will be provided in a certified translation of the 
local language. 
 
Original signed consent forms must be filed in each patient’s study file or medical 
record with a copy in the study file. 
 
At the time of disease progression patient must sign “treatment beyond disease 
progression” informed consent before next treatment with nivolumab 
 
 
 


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15.0 References 
 
1Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-
Small-Cell Lung Cancer.N Engl J Med. 2015 Jul 9;373(2):123-35. PMID: 26028407 
 
2 Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-
Small-Cell Lung Cancer.N Engl J Med. 2015 Oct 22;373(17):1627-39.PMID: 26412456 
 
3 Rizvi NA, Hellmann MD, Snyder A et al. Cancer immunology. Mutational landscape determines 
sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015 Apr 3;348(6230):124-8. PMID: 
25765070 
 
4 Marx J.  Cancer’s bulwark against immune attack: MDS cells.  Science 2008 319:154-156. 
 
5 Gabrilovich, D., S. Ostrand-Rosenberg, and V. Bronte, 2012.  Coordinated regulation of myeloid cells by 
tumors.  Nat. Rev. Immunol. 12:253-268. PMCID 3587148 
 
6 Parker, K.H., D.W. Beury, and S. Ostrand-Rosenberg, 2015.  Myeloid-derived suppressor cells: critical 
cells driving immune suppression in the tumor microenvironment.    Advances in Cancer Research 128:95-
139. 
 
7 Srivastava, M.K., J.J. Bosch, J. A. Thompson, B.K. Ksander, M.J. Edelman, and S. Ostrand-Rosenberg, 
2008.  Lung cancer patients' CD4+ T cells are activated in vitro by MHC II cell-based vaccines despite the 
presence of myeloid-derived suppressor cells. Cancer Immunol Immunother. 57:1493-1504.  
PMCID: PMC2805175 
 
8 Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S.  (2007).  Prostaglandin E2 promotes tumor 
progression by inducing myeloid derived suppressor cells.  Cancer Res.  67, 4507-13. 
 
9 Breyer RM, Bagdassarian CK, Myers SA, Breyer MD.  Prostanoid receptors: subtypes and signaling. 
Annu Rev Pharmacol Toxicol  2001, 41: 661–690. 
 
10 Konya V, Marsche G, Schuligoi R, Heinemann A.E-type prostanoid receptor 4 (EP4) in disease and 
therapy. 
Pharmacol Ther. 2013 Jun;138(3):485-502. PMID: 23523686 
 
11Kundu N1, Ma X, Holt D, Goloubeva O, Ostrand-Rosenberg S, Fulton AM Antagonism of the 
prostaglandin E receptor EP4 inhibits metastasis and enhances NK function. Breast Cancer Res Treat. 2009 
Sep;117(2):235-42 
 
12 Bhoosahn N, Staats P, Fulton A,  Feliciano J, Edelman MJ. Prostaglandin E Receptor EP4  expression, 
survival and pattern of recurrence in locally advanced NSCLC Lung Cancer, in press, 2016.  
 
13 Bao X, Albu D, Huang K-C, Wu J, Twine, N, Nomoto K, Woodall-Jappe M .: Combination of EP4 
antagonist and checkpoint inhibitors promotes anti-tumor effector T cells in preclinical tumor models. 
Journal for ImmunoTherapy of Cancer 2015 3(Suppl 2):P350. 
 
14 Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V, Chouaib S. PD-L1 is a 
novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation.J 
Exp Med. 2014 May 5;211(5):781-90. doi: 10.1084/jem.20131916. Epub 2014 Apr 28.PMID: 24778419 
 
15  Murphey LJ, Williams MK, Sanchez SC et al. Quantification of the major urinary metabolite of PGE2 
by a liquid chromatographic/mass spectrometric assay: determination of cyclooxygease-specific PGE2 
synthesis in healthy humans and those with lung cancer.  Analytical Biochem  2004  334:266-275. 


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16 Csiki I, Morrow JD, Sandler A. et al. Targeting cyclooygenase-2 in recurrent non-small cell lung cancer: 
a phase II trial of celecoxib and docetaxel. Clin Ca Res 2005:11; 6634-6640. 
 
17  Reckamp KL, Krysan K, Morrow JD et al.  A phase I trial to determine the optimal biological dose of 
celecoxib when combined with erlotinib in advanced non-small cell lung cancer.  Clin Cancer Res. 2006 
Jun 1;12(11 Pt 1):3381-8 
 
18 Edelman MJ, Wang X-F,Hodgson L, Cheney RT, Baggstrom M,  Sachdev T, Gajra A, Bertino E, 
Reckamp K, Molina J, Schiller J,  Mitchell-Richards K,  Friedman P, Ritter J,  Vokes E.   Phase III 
randomized, placebo controlled trial of COX-2 inhibition in addition to standard chemotherapy for 
advanced non-small cell lung cancer (NSCLC):CALGB 30801 (Alliance). Proceedings AACR 2014 
1Almand, B, J I Clark, E Nikitina, J van Beynen, N R English, S C Knight, D P Carbone & D I Gabrilovich. 
Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in 
cancer. J Immunol 166, 678-689 (2001). 
 
19Diaz-Montero, C M, M L Salem, M I Nishimura, E Garrett-Mayer, D J Cole & A J Montero. Increased 
circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, 
and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58, 49-59 (2009). 
PMCID:PMC3401888 
 
20Srivastava, M K, J J Bosch, J A Thompson, B R Ksander, M J Edelman & S Ostrand-Rosenberg. Lung 
cancer patients' CD4(+) T cells are activated in vitro by MHC II cell-based vaccines despite the presence of 
myeloid-derived 
suppressor 
cells. 
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Immunol 
Immunother 
57, 
1493-1504 
(2008). 
PMCID:PMC2805175 
 
21Filipazzi, P, R Valenti, V Huber, L Pilla, P Canese, M Iero, C Castelli, L Mariani, G Parmiani & L 
Rivoltini. Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma 
patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. 
J Clin Oncol 25, 2546-2553 (2007). 
 
22Finke, J, J Ko, B Rini, P Rayman, J Ireland & P Cohen. MDSC as a mechanism of tumor escape from 
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(2011). 
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23Lechner, M G, D J Liebertz & A L Epstein. Characterization of cytokine-induced myeloid-derived 
suppressor cells from normal human peripheral blood mononuclear cells. J Immunol 185, 2273-2284 
(2010). PMCID:PMC2923483 
 
24Lechner, M G, C Megiel, S M Russell, B Bingham, N Arger, T Woo & A L Epstein. Functional 
characterization of human Cd33+ and Cd11b+ myeloid-derived suppressor cell subsets induced from 
peripheral blood mononuclear cells co-cultured with a diverse set of human tumor cell lines. Journal of 
translational medicine 9, 90 (2011). PMCID:PMC3128058 
 
25Mandruzzato, S, S Solito, E Falisi, S Francescato, V Chiarion-Sileni, S Mocellin, A Zanon, C R Rossi, D 
Nitti, V Bronte & P Zanovello. IL4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients. J 
Immunol 182, 6562-6568 (2009). 
 
26Montero, A J, C M Diaz-Montero, C E Kyriakopoulos, V Bronte & S Mandruzzato. Myeloid-derived 
Suppressor Cells in Cancer Patients: A Clinical Perspective. Journal of immunotherapy 35, 107-115 (2012). 
 
27Zea, A H, P C Rodriguez, M B Atkins, C Hernandez, S Signoretti, J Zabaleta, D McDermott, D Quiceno, 
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28 Srivastava, M K, J J Bosch, A L Wilson, M J Edelman & S Ostrand-Rosenberg. MHC II lung cancer 
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Appendix I:  
 
MANAGEMENT ALGORITHMS 
 
Management for immune related Adverse Events 
 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and 
duration than AEs caused by other therapeutic classes. Nivolumab is considered an 
immuno-oncology agent in this protocol. Early recognition and management of AEs 
associated with immuno-oncology agents may mitigate severe toxicity. 
 
Pulmonary Adverse Events 
Pulmonary AEs have been observed following treatment with nivolumab. The 
frequency of pulmonary AEs may be greater with nivolumab combination therapies 
than with nivolumab monotherapy. The majority of cases reported were Grade 1 or 2, 
and subjects presented with either asymptomatic radiographic changes (eg. focal 
ground glass opacities and patchy infiltrates) or with symptoms of dyspnea, cough, or 
fever. Subjects with reported Grade 3 or 4 pulmonary AEs were noted to have more 
severe symptoms, more extensive radiographic findings, and hypoxia. 
 
Pulmonary Adverse Event Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. Evaluate with imaging and pulmonary consultation. 
 
Grade of 
Pneumonitis 
Management 
Follow-up 
Grade 1 
Radiographic changes 
only 
• Consider delay of I-O therapy 
• Monitor for symptoms every 2-3 
days 
• Consider Pulmonary and 
Infectious Disease (ID) consults 
• Re-image at least every 3 
weeks 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2 
Mild to moderate new 
symptoms 
• Delay I-O therapy per protocol 
• Pulmonary and ID consults 
• Monitor symptoms daily, 
consider hospitalization 
• 1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent 
• Consider bronchoscopy , lung 
• Re-image every 1-3 days 
If improves: 
• When symptoms return to 
near baseline, taper steroids 
over at least 1 month and then 
resume I-O therapy per 
protocol and consider 
prophylactic antibiotics 


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biopsy 
If not improving after 2 weeks 
or worsening: 
• Treat as Grade 3-4 
Grade 3-4 
Severe new 
symptoms; 
New/worsening 
hypoxia; Life-
threatening 
• Discontinue I-O therapy per 
protocol 
• Hospitalize 
• Pulmonary and ID consults 
• 2-4 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider bronchoscopy, lung 
sy 
If improves to baseline: 
• Taper steroids over at least 6 
weeks 
If not improving after 48 hours 
or worsening: 
• Add additional 
immunosuppression (e.g. 
infliximab, cyclophosphamide, 
intravenous immunoglobulin 
(IVIG), or mycophenolate 
mofetil) 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Gastrointestinal Adverse Events 
Gastrointestinal AEs have been observed following treatment with nivolumab. 
Most cases of diarrhea were of low grade (Grade 1-2). Colitis occurred less frequently 
than diarrhea. High-grade cases of diarrhea and colitis were managed with 
corticosteroids and, in all cases, the events resolved. 
 
GI Adverse Event Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat 
accordingly and continue I-O therapy. Opiates/narcotics may mask symptoms of 
perforation. Infliximab should not be used in cases of perforation or sepsis. 
  
Grade of Diarrhea/ 
Colitis 
Management 
Follow-up 
Grade 1 
Diarrhea:< 4 stools/day over 
baseline;  
Colitis: asymptomatic 
• Continue I-O therapy 
per protocol 
• Symptomatic 
treatment 
• Close monitoring for worsening 
symptoms. 
• Educate patient to report 
worsening immediately 
If worsens: 
• Treat as Grade (G) 2 or 3/4 


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Grade 2 
Diarrhea: 4-6 stools per day 
over baseline; IV fluids 
indicated <24 hours (hrs); not 
interfering with ADL 
Colitis: abdominal pain; blood 
in stool 
• Delay I-O therapy per 
protocol 
• Symptomatic 
treatment 
If improves to grade 1: 
• Resume I-O therapy per protocol 
If persists > 5-7 days or recur: 
• 0.5-1.0 mg/kg/day 
methylprednisolone or oral 
equivalent 
• When symptoms improve to grade 
1, taper steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume I-O therapy 
per protocol. 
If worsens or persists > 3-5 days 
with oral steroids: 
• Treat as grade 3/4 
Grade 3-4 
Diarrhea (G3): ≥7 stools per 
day over baseline; incontinence; 
IV fluids ≥24 hrs; interfering 
with activities of daily living 
(ADL) 
Colitis (G3): severe abdominal 
pain, medical intervention 
indicated, peritoneal signs 
G4: life-threatening, perforation 
• Discontinue I-O 
therapy per protocol 
• 1.0 to 2.0 mg/kg/day 
methylprednisolone IV 
or IV equivalent 
• Add prophylactic 
antibiotics for 
opportunistic infections 
• Consider lower 
endoscopy 
If improves: 
• Continue steroids until grade 1, 
then taper over at least 1 month 
If persists > 3-5 days, or recurs after 
improvement: 
• Add infliximab 5 mg/kg (if no 
contraindication). 
Note: Infliximab should not be used 
in cases of perforation or sepsis 
 
Hepatic Adverse Events 
Hepatic AEs, including elevated liver function tests (LFTs) and, infrequently, DILI, 
have been observed following treatment with nivolumab and nivolumab in 
combination with ipilimumab. Most cases were of low or moderate grade. Higher-
grade hepatic AEs, including DILI, were managed with corticosteroids (with or 
without mycophenolate mofetil) and, in almost all cases, the events resolved. 
 
Hepatic Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. Consider imaging for obstruction. 


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Grade of Liver 
Test Elevation 
Management 
Follow-up 
Grade 1 
AST or ALT > ULN to 
3.0 x ULN and/or Total 
bilirubin (T. bili) > ULN 
- 1.5 x ULN 
• Continue I-O therapy per 
protocol 
 
• Continue liver function tests 
(LFT) monitoring per protocol 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2 
AST or ALT > 3.0 to ≤ 5 
x ULN and/or T. bili > 
1.5 to ≤ 3 x ULN 
• Delay I-O therapy per 
protocol 
• Increase frequency of 
monitoring to every 3 days 
If returns to baseline: 
• Resume routine monitoring, 
resume I-O therapy per protocol 
If elevations persist > 5-7 days or 
worsen : 
• 0.5-1 mg/kg/day 
methylprednisolone or oral 
equivalent and when LFT returns to 
grade 1 or baseline, taper steroids 
over at least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and resume 
I-O therapy per protocol 
Grade 3-4 
AST or ALT > 5 x ULN 
and /or T.bili >3 x ULN 
• Discontinue I-O therapy* 
• Increase frequency of 
monitoring to every 1-2 days 
• 1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent** 
• Add prophylactic antibiotics 
for opportunistic infections 
• Consult gastroenterologist 
If returns to grade 2: 
• Taper steroids over at least 1 
month  
If does not improve in >3-5 days, 
worsens or rebounds: 
• Add mycophenolate mofetil 1 
gram (g) twice daily (BID) 
• If no response within an additional 
3-5 days, consider other 
immunosuppressants per local 
guidelines 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 


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*I-O therapy may be delayed rather than discontinued if AST/ALT ≤ 8 x ULN and 
T.bili ≤ 5 x ULN. 
 
**The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day 
methylprednisolone IV. 
 
Skin Adverse Events 
Rash and pruritus were the most common skin AEs observed following treatment 
with nivolumab. The rash was typically focal with a maculopapular appearance 
occurring on the trunk, back, or extremities. Most cases have been of low or moderate 
grade. In some cases, rash and pruritus resolved without intervention. Topical 
corticosteroids have been used for some cases of rash. Anti-histamines have been 
used for some cases of pruritus. More severe cases responded to systemic 
corticosteroids. 
 
Skin Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. 
 
Grade of Rash 
Management 
Follow-up 
Grade 1-2 
 
Covering ≤ 30% 
body surface area 
(BSA) 
• Symptomatic therapy (e.g. 
antihistamines, topical 
steroids) 
 
• Continue I-O therapy per 
protocol 
 
If persists > 1-2 weeks or recurs: 
• Consider skin biopsy 
• Delay I-O therapy per protocol 
• Consider 0.5-1.0 mg/kg/day 
methylprednisolone IV or oral equivalent. 
Once improving, taper steroids over at least 
1 month, consider prophylactic antibiotics 
for 
opportunistic infections, and resume I-O 
therapy per protocol 
If worsens: 
• Treat as Grade 3-4 
Grade 3-4 
 
Covering >30% 
BSA; 
Life threatening 
consequences 
• Delay or discontinue I-O 
therapy per protocol 
• Consider skin biopsy 
• Dermatology consult 
• 1.0-2.0 mg/kg/day IV 
methylprednisolone 
IV or IV equivalent 
If improves to Grade 1: 
• Taper steroids over at least 1 month and 
add 
prophylactic antibiotics for opportunistic 
infections 
• Resume I-O therapy per protocol 


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Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Renal Adverse Events 
Elevated creatinine and biopsy-confirmed tubulointerstitial nephritis and allergic 
nephritis have been infrequently observed following treatment with nivolumab. The 
frequency of renal AEs may be greater with nivolumab combination therapies than 
with nivolumab monotherapy. Most cases were Grade 2 or 3 and based on creatinine 
elevation. Subjects with a history of RCC or prior nephrectomy did not appear to be 
at higher risk. Events were managed with corticosteroids and, in all cases, renal 
function partially or fully improved. 
 
Renal Adverse Event Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy 
Grade of Creatinine 
Elevation 
Management 
Follow-up 
Grade 1 
Creatinine > upper limit 
of normal (ULN) and > 
than baseline but ≤ 1.5x 
baseline 
• Continue I-O therapy per 
protocol 
• Monitor creatinine weekly 
 
If returns to baseline: 
•Resume routine creatinine 
monitoring per protocol 
If worsens: 
•Treat as Grade 2 or 3/4 
Grade 2-3 
Creatinine > 1.5x 
baseline to ≤ 6x ULN 
• Delay I-O therapy per 
protocol 
• Monitor creatinine every 2-
3 days 
• 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent 
• Consider renal biopsy 
If returns to Grade 1: 
•Taper steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume I-O therapy 
and routine creatinine monitoring 
per protocol 
If elevations persist > 7 days or 
worsen: 
•Treat as Grade 4 
Grade 4 
Creatinine > 6x ULN 
• Discontinue I-O therapy per 
protocol 
• Monitor creatinine daily 
• 1.0-2.0 mg/kg/day 
If returns to Grade 1 : 
 Taper steroids over at least 1 month 
and add prophylactic antibiotics for 
opportunistic infections 


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methylprednisolone IV or IV 
equivalent 
• Consult nephrologist 
• Consider renal biopsy 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Neurologic Adverse Events 
Neurologic AEs have been uncommonly observed following treatment with 
nivolumab. Neurologic AEs can manifest as central abnormalities (eg, aseptic 
meningitis, encephalopathy, or encephalitis) or peripheral sensory/motor neuropathies 
(eg, Guillain-Barre Syndrome, myasthenia gravis complicated with sepsis and 
fatality). 
 
Neurological Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. 
Grade of Neurological 
Toxicity 
Management 
Follow-up 
Grade 1 
Asymptomatic or mild 
symptoms; Intervention 
not indicated 
• Continue I-O therapy per 
protocol 
 
 
Continue to monitor the patient. 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2 
Moderate symptoms; 
Limiting instrumental 
ADL 
• Delay I-O therapy per protocol 
• Treat symptoms per local 
guidelines 
• Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or PO 
equivalent 
If improves to baseline: 
•Resume I-O therapy per protocol 
when improved to baseline 
If worsens: 
• Treat as Grade 3-4 
Grade 3-4 
Severe symptoms; 
Limiting self-care ADL; 
Life-threatening 
• Discontinue I-O therapy per 
protocol 
• Obtain neurology consult 
• Treat symptoms per local 
guidelines 
• 1.0-2.0 mg/kg/day IV 
If improves to Grade 2: 
• Taper steroids over at least 1 
month 
If worsens or atypical 
presentation: 
• Consider IVIG or other 


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methylprednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics 
for opportunistic infections  
immunosuppressive therapies per 
local guidelines 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
Endocrinopathies 
Endocrinopathies have been observed following treatment with nivolumab. Most 
cases were of low or moderate grade. The events have typically been identified 
through either routine periodic monitoring of specific laboratories (eg, TSH) or as 
part of a work-up for associated symptoms (eg, fatigue). Events may occur within 
weeks of beginning treatment, but also have been noted to occur after many months 
(while still on treatment). More than 1 endocrine organ may be involved (eg, 
hypophysitis [pituitary inflammation] may need to be evaluated at the time adrenal 
insufficiency or thyroid disorder is suspected). Moderate- to high-grade cases were 
managed with hormone replacement therapy and, in some cases, with the addition of 
corticosteroids. In some cases, nivolumab treatment was held until adequate hormone 
replacement was provided. 
 
Endocrinopathy Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and 
continue I-O therapy. Consider visual field testing, endocrinology consultation, and 
imaging. 
Asymptomatic thyroid 
stimulating hormone (TSH) 
elevation 
• Continue I-O therapy per protocol 
• If TSH < 0.5 x lower limit of normal (LLN), or TSH > 2 x 
ULN, or consistently out of range in 2 subsequent 
measurements: include free thyroxine (fT4) at subsequent 
cycles as clinically indicated; consider endocrinology consult 
Symptomatic endocrinopathy 
• Evaluate endocrine function 
• Consider pituitary scan 
 
Symptomatic with abnormal 
lab/pituitary scan: 
• Delay I-O therapy per 
protocol 
If improves (with or 
without hormone 
replacement): 
• Taper steroids over at 
least 1 month and consider 
prophylactic antibiotics for 
opportunistic infections 


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• 1-2 mg/kg/day 
methylprednisolone IV or by 
mouth (PO) equivalent 
• Initiate appropriate hormone 
therapy 
No abnormal lab/pituitary MRI 
scan but symptoms persist: 
• Repeat labs in 1-3 weeks 
/MRI in 1 month 
• Resume I-O therapy per 
protocol 
• Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid 
component 
Suspicion of adrenal crisis 
(e.g. severe dehydration, 
hypotension, shock out of 
proportion to current illness 
• Delay or discontinue I-O therapy per protocol 
• Rule out sepsis 
• Stress dose of IV steroids with mineralocorticoid activity 
• IV fluids 
• Consult endocrinologist 
• If adrenal crisis ruled out, then treat as above for 
symptomatic endocrinopathy 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account 
when switching to the equivalent dose of oral corticosteroids. 
 
 
 
 


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Appendix II 
 


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Appendix III 
Tumor Tissue Specimens 
Pre-treatment tumor tissue specimens in the form of a paraffin embedded block or a 
minimum of 5 unstained slides, with a single section on positively charged slides will be 
submitted for central PD-L1 immunohistochemistry (IHC) assessment. These biopsy 
samples should be excisional, incisional, punch or core needle. Specimens that are 
obtained by needle that are sufficient for histologic analysis are appropriate.  PD-L1 
stained tissue sections will be assessed by a pathologist and scored as PD-L1 positive if 
membrane staining is observed. If the PD-L1 status has been previously assessed than the 
patient is considered to have satisfied the requirement for a tumor specimen. A tumor 
sample is still requested for further testing, but not required. 
 
These tumor samples, as well as any solitary lesions that may have been surgically 
resected from subjects following an initial response may also be assessed for the 
expression of other immune related genes, RNAs and/or proteins, as well as, the presence 
of immune cell populations using a variety of methodologies inclusive of, but not limited 
to immunohistochemistry (IHC), qRT-PCR, genetic mutation detection and fluorescent 
in-situ hybridization (FISH). These tumor tissue biomarkers include, but are not limited 
to PD-1, PD-L2, tumor infiltrating lymphocytes (TILs) or subpopulations of TILs and a 
Th1 immune mRNA expression signature. In addition, other methods of measuring tumor 
PD-L1 expression may also be assessed. Tissue from the resected solitary lesions may be 
assessed for residual tumor cells and for markers expected to accompany tumor shrinkage 
in this study, including, but not limited to TILs and subsets thereof. 
 

ICF_001.pdf: 
IRB #17-1050 
 
 
Page 1 of 20  
 
 
Protocol version date: 03/27/2018 
 
 
INFORMED CONSENT DOCUMENT 
 
TH-113: Depletion of Myeloid Derived Suppressor Cells to Enhance anti-PD-1 Therapy 
 
 
Principal Investigator:   Martin J. Edelman, MD 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to 
you.  Clinical trials include only people who choose to take part. Please take your time to make 
your decision about taking part. You should discuss your decision with your friends and family.  
You will also discuss it with your health care team. If you have any questions, you can ask your 
study doctor for more explanation.    
 
You are being asked to take part in this research study because you have non-small cell lung 
cancer. 
 
The sponsor-investigator of this study is Martin J. Edelman, MD at Fox Chase Cancer Center.  
 
The study is supported by Bristol-Myers Squibb and Fox Chase Cancer Center. 
 
Why is this research study being done? 
 
The purpose of this research study is to see if MDSCs are altered in patients receiving 
Gemcitabine in combination with Nivolumab. MDSCs are a type cells that are thought to play a 
role in suppressing immune response against cancer. Nivolumab is an antibody (a type of 
human protein) that is being tested to see if it will allow the body’s immune system to work 
against tumor cells. Gemcitabine is a drug that is already approved by FDA to treat patients with 
non-small cell lung cancer. The combination of nivolumab and gemcitabine is not yet approved 
for treating non-small cell lung cancer.  
 
We do not know if you will benefit from this research study.  It is possible that your condition will 
get better, but it is also possible that there will be no effect on your condition or that your 
condition will get worse.  We can use what we learn from this research study to help other 
people with the same disease.   
 
How many people will take part in this research study? 
 
10 people will take part in this research study.  
 
What will happen if you take part in this research study? 
 
Before you begin the research study 
You will need to have the following exams, tests or procedures to find out if you can be in the 
research study. These exams, tests or procedures are part of regular cancer care and may be 
done even if you do not join the research study. If you have had some of them recently, they 
may not need to be repeated. This will be up to your study doctor. 


IRB #17-1050 
 
 
Page 2 of 20  
 
 
Protocol version date: 03/27/2018 
 
 
We will ask you about your medical history and medicines you are taking 
 
We will do a physical exam which will include height, weight and vital signs  
 
We will ask about your ability to do your daily activities 
 
Routine blood tests (1 tablespoon) 
 
We will check your heart function by performing an EKG 
o EKG is a test to measure the electrical activity of your heart 
 
Blood for pregnancy test (2 teaspoon), if you are a female and able to become pregnant. 
 
We will evaluate your cancer by doing a CT scan  
o A CT scan is a computerized x-ray that gives your study doctor pictures of the 
inside of your body. 
 
A biopsy sample is required for entry in the study if a standard of care test for 
determining the expression of a biomarker is not already done. If you have the testing 
done we will request tissue sample from you but this is optional. A biopsy is a small 
piece of tissue from your cancer. 
 
During the research study 
 
Study Treatment 
 
 
If the screening procedures show you can take part in the study, you will receive nivolumab 
intravenously over a period of 30 minutes on day 1 and then on day 15 of the treatment cycle. In 
addition, you will also receive gemcitabine intravenously over a period of 30 minutes on day 1, 
day 8 and day 15 of the treatment cycle. Gemcitabine will be administered before nivolumab 
administration. Each treatment cycle is 28 days. Once a treatment cycle ends the next 
treatment cycle will begin. If during the treatment your study doctor determines that you are 
having unacceptable side-effects due to nivolumab, you may receive only gemcitabine for the 
rest of the study. 
 
Tests and Procedures 
 
If the exams, tests and procedures show that you can be in the research study, and you choose 
to take part, then you will need the following tests and procedures. They are part of regular 
cancer care. Some of these tests are being done more often because you are in this research 
study.  
 We will ask you about all the medicines you are taking 
 We will do a physical exam which will include vital signs and weight 
 We will ask about your ability to do your daily activities 
 Routine Blood tests (1 tablespoon) – once every cycle. 
 Blood for pregnancy test (2 teaspoons), if you are a female and able to get pregnant – 
once every cycle 
 We will ask you about any side effects you may be experiencing. 
 We will check your heart function by performing EKG, however this test will be performed 
only if your study doctor recommends. 
 We will assess your tumor by performing a CT scan – once every 8 weeks 
 Blood for research on day 1, 8, 15 of cycle 1, and day 1 of cycles 2, 3 (up to 1.5 
tablespoons) 
 Optional blood collection for future research and banking (1.5 tablespoon) – every other 
cycle starting from cycle 1. 
 


IRB #17-1050 
 
 
Page 3 of 20  
 
 
Protocol version date: 03/27/2018 
If you experience any changes in your body or develop any new or worsening side-effects 
during or after the infusion of the study drug/s you should inform the study doctor or nurse 
immediately. 
 
 
After you stop taking the study drug  
 
Safety Follow-up 
 
We will perform a safety follow-up 30 days after discontinuing the treatment. In this follow-up 
visit we will perform the following tests and procedures.  
 
 
We will ask you about the medicines that you are taking 
 
We will do a physical exam including weight and vital signs 
 
We will ask about your ability to do your daily activities 
 
Routine blood test ( 1 tablespoon) 
 
Optional blood for future research and banking (1.5 tablespoon). 
 
We will ask you about any side effects you may be experiencing 
 
 
Follow-up 
If you discontinued the study treatment due to reasons other than disease progression we would 
do follow-up visits to check the status of your disease. In this visit we will perform the following 
tests and procedures. 
 
 
We will ask you about the medicines that you are taking 
 
We will do a physical exam including weight and vital signs 
 
We will evaluate your cancer by doing a CT scan once every 8 weeks. 
 
We will ask you about any side effects you may be experiencing. 
 
Long-term follow-up 
We will follow-up via a phone call once every 3 months to check your overall health after it is 
confirmed that your disease has worsened (disease progression). 
 
 
Study Plan 
 
Another way to find out what will happen to you during the research study is to read the chart 
below. Start reading at the top and read down the list, following the lines and arrows.  
 
Start Here 
 
You decide to participate in the study and you sign informed consent 
 
Screening shows that you can take part in the 
study  


IRB #17-1050 
 
 
Page 4 of 20  
 
 
Protocol version date: 03/27/2018 
 
Medicines used in this study 
You will receive nivolumab on day 1, day 15, and gemcitabine on day 1, 8, 15 
 
 
 
During treatment 
 You will be monitored for any side effects you may be experiencing and your cancer 
 
                                                                             
Follow-up 
 
You will be followed for up to 2 years after discontinuing from  the study 
 
 
 
How long will you be in the research study? 
 
You will be asked to take the study drug/s as long you are benefiting from the treatment or your 
disease does not get worse. You will also be removed from the study if your doctor thinks that 
you have unacceptable toxicities due to the study drug/s and it is in your best interest that you 
stop participating in the study. 
 
Can you stop being in the research study? 
 
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks due to the 
study nivolumab and/or gemcitabine can be evaluated by your doctor. Another reason to tell 
your doctor that you are thinking about stopping is to discuss what followup care and testing 
could be most helpful for you. 
 
Can you be removed from this research study? 
 
The study doctor may stop you from taking part in this research study at any time if he/she 
believes it is in your best interest; if you do not follow the research study rules; or if the research 
study is stopped. 
 
What side effects or risks can you expect from being in the research study? 
 
You may have side effects while on the research study.  Everyone taking part in the research 
study will be watched carefully for any side effects.  However, doctors don't know all the side 
effects that may happen.  Side effects may be mild or very serious.  Your health care team may 
give you medicines to help lessen side effects.  Many side effects go away soon after you stop 
taking the nivolumab and/or gemcitabine. In some cases, side effects can be serious, long 
lasting, or may never go away. There is also a risk of death 
 
You should talk to your study doctor about any side effects that you have while taking part in the 
research study.  


IRB #17-1050 
 
 
Page 5 of 20  
 
 
Protocol version date: 03/27/2018 
 
Risks and side effects related to the nivolumab include those which are: 
 
Likely (≥ 5%) 
 
 
Fatigue – feeling tired  
 
Skin reactions – including rash, itching, hives, redness, and dry skin  
 
Hyponatremia (low sodium levels in the blood) – symptoms may include nausea and 
vomiting, loss of appetite, headache, confusion, fatigue, restlessness and irritability, 
muscle weakness, spasms or cramps, decreased consciousness, seizures or coma.  
 
Diarrhea – increased frequency of bowel movements with loose, watery stools  
 
Nausea  
 
Abdominal pain  
 
Decreased appetite  
 
Anemia (low hemoglobin, low hematocrit or low red blood cell count) – red blood cells 
carry oxygen and nutrients throughout the body. Symptoms that may be experienced as 
a result of low red blood cell counts may include feeling tired and weak, shortness of 
breath, increased heart rate, dizziness or lightheadedness, headache, chest pain and 
pale skin.  
 
Fever  
 
Joint pain or stiffness  
 
Less Likely (2-4%) 
 
 
Bowl inflammation 
 
Liver function blood test abnormalities 
 
Loss of color (pigment) from areas of skin 
 
Thyroid gland abnormalities 
 
Blood chemistry abnormalities, including low blood phosphate, magnesium, and 
potassium levels  
 
High blood uric acid level  
 
Dizziness  
 
Low white blood cells 
 
Pain in arms and legs 
 
Peripheral neuropathy – numbness and tingling in the hands and feet  
 
Allergic reaction during or between drug infusion 
 
Cough 
 
Dry Mouth 
 
Vomiting – throwing up 
 
Weight loss 
 
Headache 
 
Chills 
 
Muscle soreness, weakness, stiffness, spasms or paralysis 
 
Shortness of breath 
 
Abnormal taste 
 
Flushing 
 
High or low blood pressure 
 
Increased sensitivity of skin to sunlight 
 
Constipation 
 
Difficulty swallowing 
 
Heartburn 
 
Thrombocytopenia (low platelet count) – platelets are important in stopping bleeding. A 
low platelet count can increase the time to form a blood clot  


IRB #17-1050 
 
 
Page 6 of 20  
 
 
Protocol version date: 03/27/2018 
 
Pneumonitis (Lung inflammation – see below)  
 
Lung Inflammation: It is possible that nivolumab may cause inflammation of the tissues of 
the lung. This adverse effect has been reported infrequently in patients treated with 
nivolumab. While many patients with x-ray or CT abnormalities have not developed any 
symptoms, some patients have developed mild to severe symptoms and in rare cases, 
death has occurred as a result of their lung inflammation.   
Signs and symptoms of lung inflammation may include difficulty breathing, pain or 
discomfort while breathing, chest pain, cough, shortness of breath, increased rate of 
breathing, fever, low blood oxygen levels, or fatigue.   
Your study doctor and nurse will watch you closely for changes in your ability to breathe and 
for other signs or symptoms that might show you are developing this type of lung 
inflammation and will perform regular tests including physical exams, measurement of 
oxygen levels through non-invasive testing (i.e., pulse oximeter), blood tests, chest x-rays 
and/or CT scans. 
 
Please inform your study doctor or nurse AT ONCE if you experience any of the 
following: 
 
 
Any new or increased shortness of breath; 
 
Any new or increased chest pain; 
 
Any new or increased pain/difficulty while breathing; 
 
Any new or increased cough or any significant change in your type of cough; for 
example any new or increased mucous or blood in your cough;   
 
Any change in the amount of oxygen you require; 
 
Any fever, fatigue, or other symptoms that occur at the same time as any changes to 
your breathing or other lung symptoms.  
 
If you start to develop symptoms, your study doctor will ask you to return to the clinic for 
additional tests, which could include a physical exam, measurement of oxygen levels, blood 
tests, chest x-rays, and/or CT scans. You will be monitored very closely for changes in your 
overall lung symptoms, monitoring may require hospitalization. You may require specific 
treatment in order to control pneumonitis. You may also be seen by a special doctor called a 
pulmonologist, who has special training to be an expert in how your lungs work. 
 
Prolonged treatment with medicines that suppress inflammation, sometimes needed to manage 
the side effects of nivolumab treatment, may lower your body’s ability to fight off certain 
infections (i.e., opportunistic infections). These infections may require treatment with antibiotic 
or antifungal medications and may be fatal. 
 
 
Rare but serious (<2%) 
 
 
Low blood oxygen level 
 
Acute lung injury or failure 
 
Collection of fluid around the lungs 
 
Inflammation of the appendix 
 
Increase in inflammatory blood proteins (e.g., lipase) 
 
Adrenal gland abnormalities 
 
Pituitary gland inflammation 
 
Changes in vision (including decreased or blurry vision), inflammation of the eye, or 
bleeding into the eye 


IRB #17-1050 
 
 
Page 7 of 20  
 
 
Protocol version date: 03/27/2018 
 
Liver inflammation 
 
Acute kidney injury or failure  
 
Abnormal blood cell production 
 
Inflammation of the mouth and lining of the digestive tract  
 
Swelling of the face, arms, or legs 
 
Inflammation of the pancreas 
 
Back pain 
 
Autoimmune disorders, including Guillain-Barre syndrome (associated with progressive 
muscle weakness or paralysis)  
 
Chest discomfort 
 
Heart palpitations 
 
Inflammation of the heart or its lining 
 
Collection of fluid around the heart 
 
Increased blood sugar 
 
Dehydration 
 
Infections: including sepsis, lung infections, and skin infections.  
 
Decreased movement of the intestines 
 
Disorientation 
 
Swelling of the optic disc 
 
Inflammation of the optic nerve 
 
Inflammation or loss of the lining of the brain and spinal cord 
 
Drug reaction with rash, blood cell abnormalities, enlarged lymph nodes, and internal 
organ involvement (including liver, kidney, and lung); known as Drug Reaction with 
Eosinophilia and Systemic Symptoms (DRESS) 
 
Myasthenia gravis, a nerve disease that may cause weakness of eye, face, breathing, 
and swallowing muscles. One death in a patient who received nivolumab combined with 
ipilimumab was considered due to myasthenia gravis and severe infection (sepsis). 
 
Abnormal brain function due to brain inflammation (encephalitis), potentially life-
threatening or fatal. 
 
Toxic epidermal necrolysis, a potentially fatal disease characterized by blistering and 
peeling of the top layer of skin resembling a severe burn, has occurred in patients who 
received nivolumab treatment. 
 
Rhabdomyolysis (muscle fiber released into the blood stream which could damage your 
kidney) and polymyositis (chronic muscle inflammation with muscle weakness) has been 
reported in one patient. 
 
Risks and side effects related to the gemcitabine include those which are: 
 
Likely (≥ 20%) 
 
 
Leukopenia/Neutropenia (low white blood cell count) – a low white blood cell count 
makes it hard for you to fight infections Thrombocytopenia (low platelet count)– platelets 
are important in stopping bleeding. A low platelet count can increase the time to form a 
blood clot, causing you to bruise or bleed more easily  
 
Anemia (low hemoglobin, low hematocrit or low red blood cell count) Red blood cells 
carry oxygen and nutrients throughout the body. Symptoms that may be experienced as 
a result of low red blood cell counts may include feeling tired and weak, shortness of 
breath, increased heart rate, dizziness or lightheadedness, headache, chest pain and 
pale skin  
 
Nausea – feeling sick to your stomach  
 
Vomiting – throwing up  


IRB #17-1050 
 
 
Page 8 of 20  
 
 
Protocol version date: 03/27/2018 
 
Rash , with or without itching, usually over the legs (but can be on other parts of your 
body)  
 
Diarrhea – increased frequency of bowel movements with loose watery stools  
 
Elevated liver enzymes – liver enzymes are proteins made by the liver that are 
measured in the blood, with a blood draw. Liver enzymes indicate how well your liver is 
functioning. Elevated liver enzymes may cause no symptoms, however higher liver 
enzyme levels may cause you to feel overly tired or weak, you may bruise or bleed more 
easily, and you may experience abdominal pain or have a yellowing of the skin or eyes  
 
Hyperbilirubinemia (elevated bilirubin levels in the blood) – bilirubin is a chemical that is 
released when red blood cells are broken down. Bilirubin is used by the liver to make 
bile. Symptoms of elevated bilirubin levels include a yellowing of the skin, eyes and 
mucous membranes  
 
Flu-like symptoms including fever, chills, muscle aches and pain  
 
Fever  
 
Pain, including bone pain  
 
Fluid retention, swelling of the hands, legs or feet  
 
Shortness of breath  
 
Proteinuria – abnormal levels of protein in the urine, which may indicate kidney damage  
 
Small amounts of blood in your urine (may indicate a problem with your kidneys)  
 
Constipation – difficulty having a bowel movement  
 
Less Likely (5-19%) 
 
 
Hair loss  
 
Mucositis/stomatitis – sores in the lining of your mouth and/or throat that can be painful 
and make it hard to swallow  
 
Peripheral neuropathy – numbness and tingling in hands and feet  
 
Somnolence – feeling sleepy  
 
Radiation recall – redness, burning, shedding or peeling of the skin where you have had 
radiation  
 
Elevation in serum creatinine, an enzyme in your blood, which may or may not indicate 
damage to your kidneys  
 
Rare but serious (<5%) 
 
 
Congestive heart failure – a decrease in the heart’s strength and ability to pump blood to 
the rest of the body  
 
Heart attack – symptoms may include chest pain/tightness, shortness of breath, nausea, 
sweating and dizziness  
 
Changes in heart rhythm  
 
Stroke – symptoms may include a sudden numbness or weakness of the face, arms or 
legs (usually on one side of the body), dizziness, severe headache, confusion, difficulty 
speaking or understanding, trouble walking and a sudden loss of balance  
 
Kidney failure  
 
Liver failure  
 
Pneumonitis – inflammation of the lungs which may cause shortness of breath, chest 
pain and cough  
 
Reversible Posterior Leukoencephlopathy Syndrome (RPLS) – a neurological disorder 
which can present with a headache, confusion, seizures, vision changes  


IRB #17-1050 
 
 
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Protocol version date: 03/27/2018 
 
Tissue Necrosis – the death of body tissue which occurs when there is not enough blood 
flowing to the tissue. Necrosis is not reversible. When large areas of tissue die due to a 
lack of blood supply, the condition is called gangrene.  
 
Capillary leak syndrome – a condition in which fluid and proteins leak out of tiny blood 
vessels and flow into other tissues, resulting in dangerously low blood pressure  
 
Radiation Risk for Diagnostic Imaging 
 
 
It is unlikely that there will be any harmful effects from the radiation exposure you will 
receive from participating in this study. 
 
At high levels of exposure, scientists agree that radiation can cause cancer. 
 
At low exposure levels most scientists agree that the risk, if any, is very low.  You will 
have low levels of radiation exposure with diagnostic imaging procedures. 
 
Risks from exposure to radiation may accumulate over a lifetime. 
 
Blood Draw Risks 
 
Fainting 
 
Bleeding 
 
Bruising at the place on your arm where the blood was drawn or needle inserted 
 
Pain 
 
Swelling 
 
Infection (rare) 
 
Biopsy Risks  
 
Bleeding 
 
Pain 
 
Infection, which can be life-threatening or fatal in rare cases 
 
Reproductive Risks 
 
 
The drugs in this study may affect a baby, before or after the baby is born. 
 
You should not become pregnant or father a baby while on this research study because 
the drugs you take could possibly hurt an unborn baby. 
 
If you are pregnant now or if you are breast-feeding now, you may not take part in this 
research study. 
 
If you become pregnant while you are on the research study, you may not continue to 
take part in the research study.  Your pregnancy will be reported to Bristol Myers Squibb, 
the manufacturer of nivolumab,   and followed for outcome.  
 
For women who can become pregnant: 
 
 
You should not become pregnant while you are in this study and up to 23 weeks from 
the last dose of nivolumab. 
 
You should not breast-feed your baby while taking drugs for this research study and up 
to  23 weeks from the last dose of nivolumab. 
 
You will have a pregnancy test within first 24 hours of your first dose of nivolumab and 
then once every cycle during the course of this study. 
 
If you become pregnant, suspect pregnancy or if you missed your period or it is late, or if 
you have a change in your usual menstrual cycle (e.g., heavier bleeding during your 
period or bleeding between periods), you should immediately contact your study doctor. 


IRB #17-1050 
 
 
Page 10 of 20  
 
 
Protocol version date: 03/27/2018 
 
You are expected to use one of the highly effective methods of contraception listed 
below.  
 Progestogen only hormonal contraception associated with inhibition of ovulation 
 Hormonal methods of contraception including oral contraceptive pills 
(combination of estrogen and progesterone), vaginal ring, injectables, or implants  
 Intrauterine devices (IUDs) (hormonal or non-hormonal) 
 Intrauterine Hormone-releasing System (IUS) 
 Bilateral tubal ligation 
 Vasectomy 
 Complete abstinence (complete avoidance of heterosexual intercourse) 
 
 
For men: 
 
 
You should not make a woman pregnant while you are in this study and up to 31 weeks 
after the last dose of nivolumab. 
 
If you are with female partners who are women of child bearing potential, you are 
expected to use condoms as the method of contraception 
 
You should immediately contact your study doctor if your female partner becomes 
pregnant while you are in this study.  If your partner does become pregnant, it will be 
reported to Bristol Myers Squibb and followed for outcome.  
 
For women and men: 
 
 
Check with the study doctor about birth control methods and how long to use them.  
Some methods might not be approved for use in this study.   
 
Are there benefits to taking part in the study? 
 
Taking part in this study may or may not make your health better.  While doctors hope that 
nivolumab in combination with gemcitabine will be more useful against cancer compared to the 
usual treatment, there is no proof of this yet.  We do know that the information from this study 
will help doctors learn more about the combination therapy as a treatment for non-small cell 
lung cancer. This information could help future cancer patients. 
 
What other choices do you have if you do not take part in this research study? 
 
Your other choices may include: 
 
Getting treatment or care for your cancer without being in a study  
 
Taking part in another study  
 
Getting no treatment  
 
Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly, but instead tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible.  
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Will your medical information be kept private?  
 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 


IRB #17-1050 
 
 
Page 11 of 20  
 
 
Protocol version date: 03/27/2018 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis include: 
 
 
Fox Chase Cancer Center and affiliated Joint Centers, The Institutional Review Boards 
of The Fox Chase Cancer Center and Temple University, Temple University, Temple 
University Health system, Inc., and its affiliates or subsidiaries and other authorized 
representatives of these organizations. 
 
Bristol Myers Squib   
 
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people  
 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
 
will include a summary of the results. You can search this Web site at any time. 
 
You will be given a separate form to review regarding the steps we will take to guard your 
privacy as part of your participation in the research study.  By signing that additional 
authorization, you will be providing your consent to use and disclose information described in 
that form connected with your participation in this research study. 
 
What are the costs? 
  
You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost 
of getting regular cancer treatment. 
 
The pharmaceutical company Bristol Myers Squib will supply nivolumab at no charge while you 
take part in this study. Bristol Myers Squib does not cover the cost of getting nivolumab ready 
and giving it to you, so you or your insurance company may have to pay for this. 
 
Even though it probably won’t happen, it is possible that the manufacturer may not continue to 
provide nivolumab for some reason. If this would occur, other possible options are: 
 
 
You might be able to get nivolumab from the manufacturer or your pharmacy but you or 
your insurance company may have to pay for it. 
 
If there is no nivolumab is available at all, no one will be able to get more and the study 
would close. 
 
If a problem with getting nivolumab occurs, your study doctor will talk to you about these 
options. 
 
You will be administered gemcitabine in addition to nivolumab. Gemcitabine is commercially 
available and will be billed to you in the same way you are usually billed for medicines.   
 
If your insurance will not pay for medicines you may need to help with side effects, you may 
have to pay for them. 
 


IRB #17-1050 
 
 
Page 12 of 20  
 
 
Protocol version date: 03/27/2018 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .    You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
Will you be compensated? 
 
You will not be paid for taking part in this study. 
 
What if you are injured while taking part in this research study? 
 
If you are injured as a result of your participation in this research study, seek immediate medical 
care.  Temple University Health System or its subsidiaries will treat the injury, though there is no 
commitment to provide monetary compensation or free medical care. Other financial 
compensation (such as lost wages or pain and suffering) for such injuries is not available.   
 
What are your rights if you take part in this research study? 
 
Taking part in this research study is your choice.  You may choose either to take part or not to 
take part in the research study.  If you decide to take part in this study, you may leave the study 
at any time.  No matter what decision you make, there will be no penalty to you and you will not 
lose any of your regular benefits. Leaving the study will not affect your medical care. You can 
still get your medical care from our institution.  
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.  
 
New findings 
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
Who can answer your questions about the research study? 
 
Important Contact Numbers 
If you are enrolled at the Fox Chase location (333 Cottman Ave) 
If you have questions about: 
Please Call: 
This study, including if you get sick or hurt 
Dr. Martin Edelman at 215-728-4300 
If you have a concern or complaint 
Risk Management Department at 215-728-2591 
Your rights as a research participant on this study  
FCCC Institutional Review Board at 215-214-3754 
Your bills or health insurance coverage 
Clinical Trial Financial Counselor at 215-214-3768 
 
Where can you get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
1-800-4-CANCER (1-800-422-6237)  


IRB #17-1050 
 
 
Page 13 of 20  
 
 
Protocol version date: 03/27/2018 
 
You may also visit the NCI website at http://cancer.gov 
 
For NCI's clinical trials information, go to: http://cancer.govclinicaltrials/  
 
For NCI's general information about cancer, go to: http://cancer.gov/cancerinfo/  
 
 
By signing below, you tell us that you have gotten all of the information you need; that you have 
received clear answers to your questions, and that you agree to take part in the research study.  
You will receive a copy of this form.  You may also request a copy of the research plan.  
 
 
___________________________   ________________________           _____________ 
Signature of Participant 
 
Print Name of Participant              Date 
 
By signing this form the Physician obtaining consent indicates that the research participant has 
been fully informed of all aspects of the research study. 
 
 
____________________________   _______________________           ____________ 
Signature of Physician 
 
Print Name of Physician  
          Date 
Obtaining Consent  
 
Obtaining Consent 
 
 
By signing this form the person obtaining consent indicates that the research participant has 
been fully informed of all aspects of the research study. 
 
 
 
____________________________   _______________________           ____________ 
Signature of Person  
 
Print Name of Person  
          Date 
Obtaining Consent  
 
Obtaining Consent 
 
 
 
____________________________________________________               _________________ 
Signature of Legally Authorized Representative (LAR)                   Date 
 
 
 
________________________________                         ________________________________ 
Print Name of LAR                                                       Relationship of LAR to Participant                                
 
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker under the 
Commonwealth of Pennsylvania) 
 
 
 


IRB #17-1050 
 
 
Page 14 of 20  
 
 
Protocol version date: 03/27/2018 
Informed Consent Document for Use of Tissue/blood for Research 
 
Please note:  This section of the informed consent form is about additional research studies that 
are being done with people who are taking part in the main study.  You may take part in these 
additional studies if you want to.  You can still be a part of the main study even if you say 'no' to 
taking part in any of these additional studies. 
 
You can say "yes" or "no" to each of the following studies. Please mark your choice for each 
study. 
 
About Using Tissue/blood for Research 
 
Tissue requirement for participating in this study is optional if you already have a biomarker 
testing done otherwise it is required for study entry. 
 
We would like to keep some of the tissue that is left over for future research. The tissue for 
future research is not mandatory. In addition we would also like to collect some blood for future 
research that is optional as well (1.5 tablespoon, every other cycle starting from cycle 1). If you 
agree, this tissue and blood will be kept and may be used in research to learn more about 
cancer and other diseases.  If you would like to read more about how tissue/ blood is used for 
research, you can visit the National Cancer Institutes’ website at 
http://www.cancer.gov/clinicaltrials/learningabout/providingtissue  
 
The research that may be done with your tissue / blood is not designed specifically to help you. 
It might help people who have cancer and other diseases in the future.  
 
Reports about research done with your tissue/blood will not be given to you or your doctor.  
These reports will not be put in your health record.  The research will not have an effect on your 
care.  
 
Things to Think About  
 
The choice to let us keep the left over tissue and blood for future research is up to you.  No 
matter what you decide to do, it will not affect your care.  
 
If you decide now that your tissue / blood can be kept for research, you can change your mind 
at any time. Just contact us and let us know that you do not want us to use your tissue/blood.  
Then any tissue/blood  that remains will no longer be used for research.  
 
In the future, people who do research may need to know more about your health.  While we 
may give them reports about your health, we will not give them your name, address, phone 
number, or any other information that will let the researchers know who you are.  
 
Sometimes tissue/blood is used for genetic research (about diseases that are passed on in 
families).  Even if your tissue is used for this kind of research, the results will not be put in your 
health records.  
 
Your tissue/blood will be used only for research and will not be sold.  The research done with 
your tissue may help to develop new products in the future.  
 
Benefits  
 


IRB #17-1050 
 
 
Page 15 of 20  
 
 
Protocol version date: 03/27/2018 
The benefits of research using tissue include learning more about what causes cancer and 
other diseases, how to prevent them, and how to treat them.  
 
Risks  
 
The greatest risk to you is the release of information from your health records.  We will do our 
best to make sure that your personal information will be kept private.  The chance that this 
information will be given to someone else is very small.  
 
Making Your Choice  
 
Please read each sentence below and think about your choice.  After reading each sentence, 
circle "Yes" or "No."  If you have any questions, please talk to your doctor or nurse, or call our 
research review board at 215-214-3754.  
 
No matter what you decide to do, it will not affect your care. 
 
1.  My tissue/blood may be kept for use in research to learn about, prevent, or treat cancer.  
YES  
NO 
2.  My tissue/blood may be kept for use in research to learn about, prevent or treat other health 
problems (for example: diabetes, Alzheimer's disease, or heart disease).  
YES  
NO 
 
3.  Someone may contact me in the future to ask me to take part in more research.  
YES  
NO 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB #17-1050 
 
 
Page 16 of 20  
 
 
Protocol version date: 03/27/2018 
By signing below, you tell us that you have gotten all of the information you need; that you have 
received clear answers to your questions, and that you agree to take part in the research study.  
You will receive a copy of this form. You may also request a copy of the research plan.  
 
___________________________   ________________________           _____________ 
Signature of Participant 
 
Print Name of Participant              Date 
 
 
By signing this form the Physician obtaining consent indicates that the research participant has 
been fully informed of all aspects of the research study. 
 
 
____________________________   _______________________           ____________ 
Signature of Physician 
 
Print Name of Physician  
          Date 
Obtaining Consent  
 
Obtaining Consent 
 
 
By signing this form the person obtaining consent indicates that the research participant has 
been fully informed of all aspects of the research study. 
 
 
____________________________   _______________________           ____________ 
Signature of Person  
            Print Name of Person  
          Date 
Obtaining Consent  
 
Obtaining Consent 
 
 
 
____________________________________________________               _________________ 
Signature of Legally Authorized Representative (LAR)                   Date 
 
 
________________________________                         ________________________________ 
Print Name of LAR                                                       Relationship of LAR to Participant                                
 
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker under the 
Commonwealth of Pennsylvania) 
 


IRB #17-1050 
 
 
Page 17 of 20  
 
 
Protocol version date: 03/27/2018 
 
 
Authorization (Permission) to Use or Disclose (Release) Protected Health Information 
(PHI) for Research 
 
IRB# and Protocol ID: 
 
17-1050:TH-113 
Study Title:  
Depletion of Myeloid Derived Suppressor Cells to Enhance 
anti-PD-1 Therapy 
 
Principal Investigator: 
Martin J. Edelman, MD 
Sponsor: 
Martin J. Edelman, MD at Fox Chase Cancer Center 
 
1. What is the purpose of this form? 
 
This form is required by the Health Insurance Portability and Accountability Act of 1996.  
Specifically the privacy regulation (HIPAA) permits the research investigators listed above to 
use and disclose health information about you for the research study identified above which has 
been approved by the Fox Chase Cancer Center Institutional Review Board. 
The sponsor is an organization/person that does research to learn about the causes of cancer, 
and how to prevent and treat cancer. Researchers would like to use your protected health 
information for research. The elements of protected health information as defined by HIPAA are: 
 
Data Elements for Protected Health Information (PHI) 
 
Names 
 
All geographic subdivisions smaller than a state (except for the first 3 digits of the zip 
code in some cases) 
 
All elements of dates (except year) for dates directly related to an individual (e.g., birth 
date, admission date, discharge date, date of death) and all ages over age 89 and dates 
indicative of that age 
 
Telephone numbers 
 
Fax numbers 
 
E-mail addresses 
 
Social security numbers 
 
Medical record numbers 
 
Health plan beneficiary numbers 
 
Account numbers 
 
Certificate/license numbers 
 
Vehicle identifiers and serial numbers, including license plate numbers 
 
Device identifiers and serial numbers 
 
Web Universal Resource Locators (URL) 
 
Internet Protocol (IP) addresses 
 
Biometric identifiers, including finger and voice prints 
 
Full face photos and any comparable images 
 
Any other unique identifying number, characteristic, or code 


IRB #17-1050 
 
 
Page 18 of 20  
 
 
Protocol version date: 03/27/2018 
 
2. What protected health information do the researchers want to use? 
The researchers want to copy and use the portions of your medical record that they will need for 
their research. If you enter a research study, medical information that will be used and/or 
released may include the following: 
 
The history and diagnosis of your disease 
 
Specific information about the treatments you received, including previous treatment(s) 
you may have had 
 
Information about other medical conditions that may affect your treatment 
 
Medical data, including laboratory test results, tumor measurements, CT scans, MRIs, x-
rays, and pathology results 
 
Long-term information about your general health status and the status of your disease 
 
Data that may be related to tissue, urine and/or blood samples that may be collected 
from you 
 
You may request a blank copy of the data forms from the study doctor or his/her research staff 
to learn what information will be shared. 
 
3. Why do the researchers want my protected health information? 
Fox Chase Cancer Center will collect your protected health information and share it with the 
sponsor, as applicable, if you enter a research study. The centers will use your information in 
their cancer research study. 
 
4. Who will be able to use my protected health information? 
Fox Chase Cancer Center, Temple University, Temple University Health System affiliates, and 
Temple University Clinical Faculty Practice Plan will use your health information for research. As 
part of this research, they may give your information to the following groups taking part in the 
research. Fox Chase Cancer Center and Temple University may also permit these groups to 
come in to review your original records that are kept by Fox Chase Cancer Center so that they 
can monitor their research study. 
 
Bristol Myers Squib 
 
The Fox Chase Cancer Center IRB 
 
Public Health agencies and other government agencies (including non-U.S.) as 
authorized or required by law 
 
Other people or organizations assisting with research efforts of the sponsor 
 
Central laboratories, central review centers, and central reviewers. The central 
laboratories and review agencies may also give your health information to those groups 
listed above 
 
5. How will information about me be kept private? 
The sponsor will keep all patient information private to the extent possible, even though the 
sponsor is not required to follow the federal privacy laws. Only researchers working with the 
sponsor will have access to your information. The sponsor will not release personal health 
information about you to others except as authorized or required by law. However, once your 
information is given to other organizations that are not required to follow federal privacy laws, 
we cannot assure that the information will remain protected. However, the laws of the 
Commonwealth of Pennsylvania or your state of residence may provide further privacy 
protection. 
 
6. What happens if I do not sign this permission form? 
If you do not sign this permission form, you will not be able to take part in the research study for 
which you are being considered. 


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Protocol version date: 03/27/2018 
7. If I sign this form, will I automatically be entered into the research study? 
No, you cannot be entered into any research study without further discussion and separate 
consent. After discussion, you may decide to take part in the research study. At that time, you 
will be asked to sign a specific research consent form. 
Treatment by your physician will not be affected by whether you provide authorization for the 
requested use or disclosure except if your treatment is related to research. 
 
8. What happens if I want to withdraw my permission? 
You can change your mind at any time and withdraw your permission to allow your protected 
health information to be used in the research. If this happens, you must withdraw your 
permission in writing.  Beginning on the date you withdraw your permission, no new protected 
health information will be used for research. However, researchers may continue to use the 
protected health information that was provided before you withdrew your permission.  If you sign 
this form and enter the research study, but later change your mind and withdraw your 
permission, you will be removed from the research study at that time. 
 
To withdraw your permission, please contact the person below. He will make sure your written 
request to withdraw your permission is processed correctly. 
 
Contact Name: 
Martin J Edelman 
Contact Address:  
333 Cottman Avenue 
Philadelphia, PA 19111 
Contact Phone and 
FAX: 
215-728-4300 and 215-728-3639 
 
9. How long will this permission last? 
If you agree by signing this form that researchers can use your protected health information, this 
permission has no expiration date. However, as stated above, you can change your mind and 
withdraw your permission at any time. 
 
10. What are my rights regarding access to my personal health information? 
You have the right to refuse to sign this permission form. You have the right to review and/or 
copy records of your protected health information kept by Fox Chase Cancer Center and 
Temple University affiliates. However, while the research study is in progress, you may not be 
able to access your protected health information in order to preserve the integrity of the 
research.  You will be able to access this information when the study is completed. You do not 
have the right to review and/or copy records kept by the sponsor or other researchers 
associated with the research study. 
 


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Protocol version date: 03/27/2018 
************************************************************************************************************* 
 
 
 
 
 
 
Signatures 
I agree that my protected health information may be used for the research purposes described 
in this form. 
 
 
 
 
___________________________   ________________________           _____________ 
Signature of Participant 
 
Print Name of Participant              Date 
 
By signing this form the physician indicates that the research participant has been fully informed 
of all aspects of the research study. 
 
 
 
_______________________       _______________________ 
         ____________ 
Signature of Physician               Print Name of Physician                         Date 
 
 
 
 
____________________________   _______________________           ____________ 
Signature of Person  
 
Print Name of Person  
               Date 
Obtaining Consent  
 
Obtaining Consent 
 
 
 
      __________________________                                                    _________________ 
Signature of Legally Authorized Representative (LAR)                              Date 
 
 
 
_______________________                              ________________________________ 
Print Name of LAR                                               Relationship of LAR to Participant                                        
 
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker under the 
Commonwealth of Pennsylvania) 
*************************************************************************************************************