Conditions: Squamous Cell Lung Cancer
Keywords: Neoadjuvant Chemotherapy; NSCLC; nacitumumab
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This will be a single-arm study to primarily evaluate the feasibility of administering necitumumab added to gemcitabine and cisplatin as neoadjuvant treatment in treatment-naïve patients with stage IB (tumor size \>4cm), II or IIIA squamous NSCLC. Feasibility will be assessed by the proportion of patients able to proceed to surgery after administering necitumumab in the neoadjuvant setting. These patients would otherwise be offered standard adjuvant chemotherapy (without necitumumab) for squamous cell lung cancer. Determination of surgical resectability will be reviewed at a multidisciplinary thoracic tumor board, attended by surgical oncology, medical oncology, radiation oncology, radiology, and pathology.

Detailed description:
The goal of this study is to explore whether it is possible to add a drug called necitumumab to standard treatment for patients with squamous cell lung cancer that can be surgically removed. This study is important because it will determine whether there is added benefit to giving necitumumab with chemotherapy before surgery. It is currently already known that chemotherapy given before or after surgery has better outcomes compared to only receiving surgery. Results from this study may help to develop more effective treatments for patients with squamous cell lung cancer.

The U.S. Food and Drug Administration (FDA) has approved necitumumab in combination with chemotherapy drugs called gemcitabine and cisplatin to treat stage IV or metastatic squamous cell lung cancer, but the FDA has not approved necitumumab to treat squamous cell lung cancer that can be surgically removed.

Analyzing the tumor cells from many cases of squamous cell lung cancer has shown that this cancer often has a special protein called EGFR. Necitumumab is a drug that targets EGFR.

Results from a recent medical study showed that patients with stage IV or metastatic squamous cell lung cancer who received necitumumab with gemcitabine and cisplatin showed a small, but significant, improvement in survival. We believe trying to gather more information about the way necitumumab interacts with cancer cells will help to learn how to use necitumumab more effectively.

This study will allow to see the effects of treating an earlier stage of squamous cell lung cancer using necitumumab with gemcitabine and cisplatin. It will also allow us to better analyze tumor cells after they have been treated with necitumumab and chemotherapy that are obtained after surgical resection. Other blood samples that will be drawn during the treatment will also allow to see the effect of necitumumab on both the body and the tumor cells and to observe any side effects that may result from this treatment.

Arms:
arm 1: Chemotherapy and Necitumumab Regimen Gemcitabine 1250mg/m2 IV over 30 minutes, days 1 and 8 following necitumumab, Cisplatin 75mg/m2 IV over 60 minutes, day 1, immediately following gemcitabine,each cycle is 3 weeks (21 days).

Necitumumab 800mg absolute dose IV over a minimum of 60 minutes, days 1 and 8 prior to chemotherapy regimen Each cycle is 3 weeks (21 days).

The regimen will be given for a total of 3 cycles.

The regimen will be given for a total of 3 cycles.

Interventions: intervention 1: Necitumumab-Gemcitabine-Cisplatin intervention 2: Evaluation to determine if patient is a candidate to proceeed with surgical resection or not
Intervention descriptions: intervention 1: * Gemcitabine 1250mg/m2 IV on D1, D8
* Cisplatin 75mg / m2 IV on D1
* Necitumumab 800mg IV on D1, D8 (peripheral blood for effector cells and cytokine measurements prior to each cycle) Repeat cycle every 21 days up to 3 cycles. intervention 2: Patients will be evaluated with repeat imaging studies (PET/CT or CT Chest, Abdomen, Pelvis) and will be re-evaluated for surgical resection. Patients who had progressive disease or are NOT a surgical candidate will come off the study and will be treated according to standard therapies. All patients will be followed up for 2-year disease-free survival and overall survival

Protocol document:
Prot_SAP_ICF_000.pdf: 
IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
1 
Local Protocol #: 
TBD 
ClinicalTrials.gov Identifier: TBD 
TITLE: 
A Feasibility and Biomarker Study to Evaluate Necitumumab in the Neoadjuvant 
Setting with Gemcitabine and Cisplatin in Surgically Resectable Squamous Lung 
Cancer 
Coordinating Center: 
Montefiore Medical Center, Albert Einstein College of 
Medicine 
Co-Principal Investigators: 
Missak Haigentz, Jr., M.D. 
Morristown Medical Center/Atlantic Health System 
Carol G. Simon Cancer Center 
100 Madison Avenue, Second Floor 
Morristown, NJ 07960 
973-971-7960
Fax: 973-397-2901
missak.haigentz@atlantichealth.org
Balazs Halmos, M.D. 
Montefiore Medical Center, Albert Einstein College of 
Medicine 
1695 Eastchester Road, 2nd Floor
Bronx, NY 10461 
718-405-8404
Fax: 718-405-8433
bahalmos@montefiore.org
Statistician: 
Dr. Xiaonan (Nan) Xue 
1300 Morris Park Avenue 
Belfer Room 1303C  
Bronx, NY 10461  
(718) 430-2431
Fax: (718) 430-8780
xiaonan.xue@einstein.yu.edu
NCI-Supplied Agent(s): N/A 
Other Agent(s): Necitumumab, Eli Lilly; Gemcitabine, commercial; Cisplatin, commercial 
Protocol Type / Version # / Version Date: 
Original / Version #7 / April 21, 2017


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
2 
 
 
SCHEMA 
 
 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
3 
 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. OBJECTIVES ...........................................................................................................................5 
1.1 Primary Objectives......................................................................................................5 
1.2 Secondary Objectives..................................................................................................5 
1.3 Exploratory Objectives ...............................................................................................5 
2. BACKGROUND ......................................................................................................................6 
2.1 Squamous Cell Lung Cancer ......................................................................................6 
2.2 Neoadjuvant Chemotherapy for NSCLC ....................................................................6 
2.3 Squamous Cell Lung Cancer and EGFR Antagonists ................................................7 
2.4 Necitumumab ..............................................................................................................7 
2.5 Gemcitabine/Cisplatin.................................................................................................7 
2.6 Rationale .....................................................................................................................8 
2.7 Correlative Studies Background .................................................................................8 
3. PATIENT SELECTION .........................................................................................................10 
3.1 Eligibility Criteria .....................................................................................................10 
3.2 Exclusion Criteria .....................................................................................................12 
3.3 Inclusion of Women and Minorities .........................................................................13 
4. REGISTRATION PROCEDURES ........................................................................................13 
4.1 Patient Registration ...................................................................................................13 
4.2 General Guidelines....................................................................................................13 
5. TREATMENT PLAN .............................................................................................................14 
5.1 Chemotherapy and Necitumumab Administration Schedule ....................................15 
5.2 Surgical Resection ....................................................................................................17 
5.3 Supportive Care Guidelines ......................................................................................18 
5.4 Duration of Therapy ..................................................................................................20 
5.5 Duration of Follow Up ..............................................................................................20 
6. DOSING DELAYS/DOSE MODIFICATIONS ....................................................................20 
6.1 Gemcitabine/Cisplatin...............................................................................................20 
6.2 Necitumumab ............................................................................................................24 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ..................................26 
7.1 Adverse Events .........................................................................................................26 
7.2 Adverse Event Characteristics ..................................................................................28 
7.3 Reporting requirements .............................................................................................29 
8. PHARMACEUTICAL INFORMATION ...............................................................................32 
8.1 Necitumumab ............................................................................................................32 
8.2 Gemcitabine ..............................................................................................................33 
8.3 Cisplatin ....................................................................................................................35 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
4 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .............................................36 
9.1 Exploratory Correlative Studies ................................................................................36 
10. STUDY CALENDAR ..........................................................................................................40 
11. MEASUREMENT OF EFFECT...........................................................................................41 
11.1 Antitumor Effect – Solid Tumors ...........................................................................41 
11.2 Other Response Parameters ....................................................................................46 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................46 
12.1 Study Oversight ......................................................................................................46 
12.2 Data Management ...................................................................................................47 
12.3 Collaborative Agreements Language ......................................................................47 
13. STATISTICAL CONSIDERATIONS..................................................................................47 
13.1 Study Design ...........................................................................................................47 
13.2 Primary Endpoint ....................................................................................................47 
13.3 Secondary Endpoints ..............................................................................................48 
13.4 Sample Size/Accrual Rate .......................................................................................48 
13.5 Correlative Studies ..................................................................................................49 
REFERENCES ..............................................................................................................................50 
APPENDIX A PERFORMANCE STATUS CRITERIA ...........................................................52 
APPENDIX B INFORMED CONSENT ......................................................................................0 
APPENDIX C STUDY SCHEMA FOR PARTICIPANT ...........................................................0 
APPENDIX D STUDY CALENDAR FOR THE PARTICIPANT .............................................0 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
5 
 
 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
To assess the proportion of patients able to proceed to surgery after administering 
necitumumab in the neoadjuvant setting with gemcitabine and cisplatin in surgically 
resectable patients with stage IB with tumor size >4cm, II and potentially resectable IIIA 
squamous cell lung cancer. 
 
1.2 
Secondary Objectives 
 
1.2.1 To evaluate the response rate of neoadjuvant chemotherapy with necitumumab, 
gemcitabine, and cisplatin. 
 
1.2.2 To evaluate the frequency and severity of toxicities in patients while receiving 
neoadjuvant chemotherapy with necitumumab, gemcitabine and cisplatin. 
 
1.2.3 To evaluate the pathologic complete response (pCR) rate in patients receiving 
neoadjuvant chemotherapy with necitumumab, gemcitabine, and cisplatin followed by 
surgical resection. 
 
1.2.4 To determine the 2-year disease-free survival (DFS) in patients receiving neoadjuvant 
chemotherapy with necitumumab, gemcitabine, and cisplatin followed by surgical 
resection. 
 
1.2.5 To determine the overall survival at 2 years in patients receiving neoadjuvant 
chemotherapy with necitumumab, gemcitabine, and cisplatin followed by surgical 
resection. 
 
1.3 
Exploratory Objectives 
 
1.3.1 To evaluate EGFR expression on pre-chemotherapy diagnostic tissue biopsy (if adequate 
tissue is available) and tissue specimens obtained from post-chemotherapy surgical 
resection. 
 
1.3.2 To evaluate EGFR gene amplification copy number on pre-chemotherapy diagnostic 
tissue biopsy (if adequate tissue is available) and tissue specimens obtained from post-
chemotherapy surgical resection. 
 
1.3.3 To evaluate markers of antibody-dependent cellular-mediated cytotoxicity (ADCC) on 
peripheral blood specimens prior to neoadjuvant chemotherapy, during neoadjuvant 
chemotherapy and following neoadjuvant chemotherapy. 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
6 
 
1.3.4 To evaluate markers of ADCC on pre-chemotherapy diagnostic tissue biopsy and tissue 
specimens obtained from post-chemotherapy surgical resection. 
 
1.3.5 To evaluate tumor infiltrating lymphocytes on resected surgical specimens and compare 
with historical controls obtained from the Montefiore lung cancer biorepository. 
 
1.3.6 To evaluate necitumumab-binding on tissue specimens obtained from post-chemotherapy 
surgical resection. 
 
2. BACKGROUND 
 
2.1 
Squamous Cell Lung Cancer 
 
Lung cancer is the leading cause of cancer death in the United States. Non-small cell lung 
cancer (NSCLC) can be divided into two histological classes: non-squamous  and 
squamous cell carcinoma (SCC). SCC accounts for approximately 25-30% of lung cancer 
cases.1 While the treatment of non-squamous cell carcinomas has greatly benefited from 
the identification of targetable somatic mutations such as EGFR and ALK mutations, the 
treatment of SCC, until the recent incorporation of immunotherapy, has remained mostly 
restricted to conventional chemotherapy. 
 
2.2 
Neoadjuvant Chemotherapy for NSCLC 
 
Standard treatment for SCC includes platinum-based therapy combined with gemcitabine, 
vinorelbine or a taxane. The use of neoadjuvant chemotherapy for all histologic classes of 
NSCLC can also be considered for selected patients based on a meta-analysis including 
13 randomized control trials showing that overall survival (OS) was significantly 
improved in patients receiving neoadjuvant chemotherapy compared to surgery alone 
(HR = 0.84, 95% CI 0.77-0.92, p=0.0001).2 
 
The use of the gemcitabine and cisplatin neoadjuvant chemotherapy regimen in patients 
with stages IB to IIIA NSCLC was reported by Scagliotti et al. In this study, patients 
were randomized to receive either three preoperative cycles of gemcitabine and cisplatin 
every 3 weeks followed by surgery, or surgery alone. In this study, 129 patients were 
randomly assigned to the chemotherapy plus surgery group, and 127 patients received at 
least one dose of chemotherapy. Of the 127 patients who received at least one dose of 
chemotherapy, 110 (87%) of patients proceeded to surgical resection. We use this data as 
our benchmark to evaluate feasibility of this study regimen. Of the 17 patients who did 
not proceed to surgical resection, the reasons were: patient decision (3), progression of 
disease (4), lost to follow-up (2), other causes (7) or no information was available (3). In 
the surgery alone group, after randomization, 96% (136 of 141) of patients received 
surgery. Of note, the pathologic complete response rate was reported as 4% in the 
chemotherapy plus surgery group.3 
 
The use of neoadjuvant chemotherapy has several advantages as opposed to 
administering adjuvant chemotherapy such as increased therapeutic compliance and 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
7 
 
ability to treat micrometastatic disease. In addition, neoadjuvant chemotherapy allows for 
analysis of the post-treatment effects on the primary tumor. 
 
2.3 
Squamous Cell Lung Cancer and EGFR Antagonists 
 
In SCC, EGFR activating mutations are rare, however EGFR overexpression has been 
reported in about 85-95% of cases.4,5 Cetuximab is an anti-EGFR monoclonal antibody 
(mAb) composed of a murine anti-EGFR antibody joined to the human IgG1 heavy and 
light chain regions, which binds to the extracellular domain of the EGF receptor. 
Competitive inhibition with cetuximab leads to decreased signaling of downstream 
pathways, EGFR internalization and degradation. In addition, antibody-dependent 
cellular-mediated cytotoxicity (ADCC), complement-mediated cytotoxicity and adaptive 
immunity-mediated by CD8+ cytotoxic T lymphocytes have also been described.6-8  
 
Several studies have studied the use of cetuximab in NSCLC. The FLEX trial reported on 
the use of cetuximab with cisplatin and vinorelbine in patients with advanced NSCLC. 
They found that the addition of cetuximab improved OS at 11.3 months compared to 
cisplatin and vinorelbine alone at 10.1 months (HR 0.871, 95% CI 0.762-0.996, p=0.04). 
There was also an improvement in response rates at 36% with cetuximab compared to 
29% with cisplatin and vinorelbine alone (p=0.01).9 However, no difference in 
progression-free survival was observed. Subgroup analysis of EGFR expression from 
FLEX study patients was conducted using immunohistochemistry. High EGFR 
expression was found in 31% of the patients, and low EGFR expression was found in 
69% of the patients. Patients in the high EGFR expression group had an increased overall 
survival in the cetuximab and chemotherapy group compared to the chemotherapy alone 
group (median OS: 12 months vs. 9.6 months, HR 0.73, 95% CI 0.58-0.93, p=0.011). No 
survival benefit was found in the low EGFR expression group. A treatment interaction 
test suggested a predictive value for EGFR expression (p=0.044).4  
 
2.4 
Necitumumab 
 
Necitumumab is a recombinant human IgG1 monoclonal antibody that binds to the 
extracellular domain of EGFR. Results from the SQUIRE study recently led to the FDA 
approval of necitumumab in combination with gemcitabine and cisplatin in advanced 
SCC. In this study, 1093 patients were randomly assigned to either necitumumab with 
gemcitabine and cisplatin or gemcitabine and cisplatin alone. Although a median overall 
survival benefit of 1.6 months was observed with the necitumumab containing regimen 
(median OS: 11.5 vs. 9.9 months, stratified HR 0.84, 95% CI 0.74-0.96), the 
improvement in median progression free survival appeared more modest (median PFS: 
5.7 vs. 5.5 months, stratified HR 0.85, 95%CI 0.74-0.98) and no improvement in overall 
response was observed (ORR 31% for the combination with necitumumab vs. 29% with 
chemotherapy alone, p=0.40).10 
 
2.5 
Gemcitabine/Cisplatin 
 
Several chemotherapy regimens have been used in adjuvant chemotherapy trials with 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
8 
 
positive results. As a result, these regimens have also been used in the neoadjuvant 
setting.2,3 Because gemcitabine and cisplatin in combination with necitumumab were 
used in the SQUIRE trial in the metastatic setting, we propose to use these agents in this 
trial. In addition, gemcitabine and cisplatin were used in the neoadjuvant setting by 
Scagliotti et al. This regimen has shown to have reduced neuropathy, alopecia and 
hypersensitivity reactions compared to taxane regimens. 
 
2.6 
Rationale 
 
SCC is a challenging and difficult subtype of lung cancer to treat due to the lack of 
targetable mutations. The results of the SQUIRE trial led to the FDA approval of 
necitumumab for metastatic SCC with an overall survival benefit of 1.6 months, however 
there was a lack of effect of necitumumab on ORR and had a modest effect on PFS. The 
mechanism of action of necitumumab, similar to cetuximab, likely involves both 
inhibition of EGFR leading to the targeting of downstream pathways affecting cell 
growth and proliferation, and ADCC. As a result, a class effect of anti-EGFR therapies 
may be present as suggested by the SQUIRE trial for necitumumab and the FLEX trial 
for cetuximab where a survival benefit was seen, but either a modest effect or no effect 
on PFS. We propose that pathological response is a more reliable measure of anti-cancer 
activity than is observed in a radiographic evaluation of response. The use of 
necitumumab in the neoadjuvant setting would also allow for assessment of treatment-
related responses in the tumor, as well as providing better understanding and perhaps 
identification of predictive biomarkers to necitumumab. In addition, the benefits of 
preoperative chemotherapy including improved therapeutic compliance, and the potential 
to treat micrometastatic disease may also be an advantage. 
 
As necitumumab has not yet been used in the neoadjuvant or adjuvant settings, we 
propose this study to assess the feasibility of administering necitumumab in combination 
with cisplatin and gemcitabine neoadjuvant chemotherapy and the ability to proceed with 
surgical resection. Additional information regarding response rate and possible 
biomarkers will also be obtained. Results of this study may serve as a platform for the 
development of future studies in using necitumumab in the neoadjuvant setting. Further 
understanding of the immunological mechanisms of necitumumab may also identify 
potential advantages of its use in combination with immunotherapy. 
 
2.7 
Correlative Studies Background 
 
2.7.1 EGFR Expression by Immunohistochemistry 
 
A recent subpopulation analysis of EGFR protein expression was recently reported. In 
this study, 982 patients from the SQUIRE trial had evaluable immunohistochemistry 
results which represented approximately 90% of the SQUIRE study participants. They 
found that 95% of tumor samples expressed EGFR protein. The EGFR >0 patients 
demonstrated a significantly longer median overall survival in the necitumumab with 
gemcitabine and cisplatin group of 11.7 months compared to gemcitabine and cisplatin 
alone of 10.0 months (stratified HR 0.79, 95% CI 0.69-0.92, p=0.002). The patients with 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
9 
 
EGFR = 0 did not appear to show a benefit from the addition of necitumumab with 
gemcitabine and cisplatin with an overall survival hazard ratio of 1.52. Despite this, the 
number of patients with EGFR = 0 was small and the lack of benefit of necitumumab in 
this population is not yet conclusive.5 This study will evaluate EGFR expression on pre-
chemotherapy diagnostic tissue biopsies and post-chemotherapy tissue specimens and 
correlate it with necitumumab-treatment response. 
 
2.7.2 EGFR Gene Copy Number by FISH 
 
The SWOG S0819 trial was conducted to determine if cetuximab improved outcome in 
combination with chemotherapy in patients with stage IV NSCLC. A subgroup analysis 
of this trial on was recently presented reporting on the use of EGFR gene amplification 
positivity in squamous NSCLC and found an improved median overall survival of 11.8 
months in the cetuximab and chemotherapy group, compared to 6.4 months who received 
chemotherapy alone (HR 0.56, p=0.006). EGFR gene amplification was measured by 
fluorescence in situ hybridization (FISH) testing and determined by the Colorado Scoring 
System, defined as EGFR FISH-positive if >40% of cells displaying >4 copies of the 
EGFR signal, or EGFR to CEP7 ratio >2 over all scored nuclei, or gene clusters (>4 
spots) or >15 copies of the EGFR signals in >10% of tumor cells.11 
 
EGFR FISH analysis was also done on patient samples from the SWOG0342 trial. This 
study compared sequential versus concurrent cetuximab and paclitaxel-carboplatin 
chemotherapy. In a subgroup analysis, they reported 59.2% of patients with available 
tumor tissue to be EGFR FISH-positive. Disease control rate, median PFS, and median 
OS were all found to have statistically significant improvements over EGFR FISH-
negative patients.12 This study will evaluate EGFR gene copy number on pre-
chemotherapy diagnostic tissue biopsies and post-chemotherapy tissue specimens and 
correlate it with necitumumab-treatment response. 
 
2.7.3 Antibody-Dependent Cellular-Mediated Cytotoxicity (ADCC) 
 
ADCC is an immunologic mechanism triggered by the binding of a monoclonal antibody 
to the surface of tumor cells. This mechanism has been well described with trastuzumab 
for breast cancer and rituximab for B-cell lymphoma.13 Preclinical studies have compared 
the level of ADCC activity in necitumumab, cetuximab and panitumumab. Necitumumab 
and cetuximab both belong to the IgG1 class allowing them to activate ADCC, whereas 
panitumumab of the IgG2 class could not.14 The Fc fragment of the mAb interacts with 
the Fc-gamma receptors (FcR) of immune cells such as macrophages and NK cells, 
leading to the activation of these immune cells and resulting in lysis of the antibody-
coated tumor cells. Various cytokines have been shown to enhance cetuximab-mediated 
ADCC reactions, such as IL-12 and IL-2. Interestingly, various genotypes of the FcRs 
have been described, some of which may be relevant to ADCC. For example, in 
colorectal cancer, the FcRIIIa VV or FF genotypes have shown improved clinical 
response to cetuximab.15  
 
Kurai et al. evaluated the relationship of EGFR expression and cetuximab-mediated 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
10 
 
ADCC activity in in vitro lung cancer cell lines. To test for induction of ADCC activity 
by cetuximab, they used a 4-hour 51Cr release assay against various lung cancer cell lines 
with various EGFR expression levels using healthy human peripheral blood mononuclear 
cells (PBMC). They found that cetuximab-mediated ADCC activity was capable even at 
low levels of EGFR, but had no linear correlation with the EGFR expression. They 
further evaluated cetuximab-mediated ADCC activity by collecting PBMCs and 
determined that the cell type likely responsible for ADCC activity were CD3-CD56+ NK 
cells. Because cytotoxic drug have been previously reported to deplete NK cell function, 
this study also investigated whether ADCC activity was affected by chemotherapy and 
found that cetuximab-mediated ADCC activity was less susceptible to 
immunosuppression than NK activity by cytotoxic drugs.13 
 
Tregs are increased in the tumor microenvironment and increased Tregs often correlated 
with a poor prognosis in epithelial cancer types such as lung cancer. Pircher et al. 
investigated the correlation of regulatory T cells (Treg CD4+CD25high+FoxP3+) on NK-
mediated cetuximab-mediated ADCC. In an in vitro setting, they showed that human 
Tregs potently inhibited cetuximab-mediated and NK-cell mediated ADCC against 
EGFR-expression target cells. The study also evaluated the impact of neoadjuvant 
chemotherapy and cetuximab on the immune cells. They showed that after neoadjuvant 
chemotherapy, decreasing Treg counts in the peripheral blood correlated significantly 
with clinical response. Using immunohistochemistry on tumor tissue, the study also 
compared the Treg levels in peripheral blood to levels in the tumor tissue, but found there 
was no correlation between the two. Due to insufficient tissue from pre-chemotherapy 
specimens, they were unable to compare the Treg levels before and after therapy.16 This 
study will compare the levels of Treg levels prior to each administration of necitumumab 
therapy and evaluate for any changes between doses. 
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed squamous cell non-small cell 
lung cancer with any of the following stage groupings: IB with tumor size >4cm, II or 
potentially resectable IIIA. 
 
3.1.2 Patients who have been evaluated by thoracic surgery and eligible for resection. 
 
3.1.3 Patients must have adequate fresh frozen paraffin embedded (FFPE) tumor tissue 
available to perform pre-treatment biomarker testing. 
 
3.1.4 No prior systemic treatment for squamous cell non-small cell lung cancer. 
 
3.1.5 Age ≥18 years. 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
11 
 
3.1.6 ECOG performance status 0-1 (Karnofsky ≥70%, see Appendix A). 
 
3.1.7 Patients must have hematologic function as defined by: 
 
 absolute neutrophil count 
≥1.5 x 109/L 
 hemoglobin 
 
≥9.0 g/dL 
 platelets 
 
≥100 x 109/L 
 
3.1.8 Patients must have organ function as defined below: 
 
 bilirubin ≤1.5 × the upper limit of normal (ULN), alkaline phosphatase (ALP), 
alanine aminotransferase (ALT) and asparate transaminase (AST) ≤3.0 times 
ULN.  For patients with hepatic metastases, ALT and AST equaling ≤5.0 times 
ULN are acceptable.  
 If a patient experiences elevated ALT >5 × ULN and elevated total bilirubin >2 × 
ULN, clinical and laboratory monitoring should be initiated by the investigator. 
For patients entering the study with ALT >3 × ULN, monitoring should be 
triggered at ALT >2 × baseline. 
 calculated creatinine clearance >50mL/min (per the Cockcroft-Gault formula). 
 serum albumin ≥2.5 g/dL 
 
3.1.9 Patients may be on a stable regimen of therapeutic anticoagulation or may be receiving 
prophylactic anticoagulation of venous access devices. 
 
3.1.10 The patient is a woman of child-bearing potential who tests negative for pregnancy 
within 14 days prior to receiving first dose of study medication based on serum 
pregnancy test and agrees to use 2 methods of birth control or abstain from heterosexual 
activity during the study and for 6 months following the last dose of the study drug(s) or 
country requirements, whichever is longer or be of non-child bearing potential.  
 
Non-childbearing potential is defined as (by other than medical reasons): 
 
 ≥45 years of age and has not had menses for greater than 2 years, 
 amenorrheic for < 2 years without a hysterectomy and oophorectomy and a 
follicle-stimulating hormone value in the postmenopausal range upon pretrial 
(screening) evaluation, or 
 post hysterectomy, oophorectomy or tubal ligation.  Documented hysterectomy or 
oophorectomy must be confirmed with medical records of the actual procedure or 
confirmed by an ultrasound.  Tubal ligation must be confirmed with medical 
records of the actual procedure otherwise the patient must be willing to use 
2 adequate barrier methods throughout the study, starting with the screening visit 
through 6 months after the last dose of study therapy. 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent document. 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
12 
 
3.1.12 The patient is willing to comply with protocol schedules and testing. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients with histologically or cytologically confirmed non-squamous cell, small cell or 
mixed histology lung carcinoma. 
 
3.2.2 Patients with stage IIIB or stage IV disease. 
 
3.2.3 Prior history of other malignancy, provided that he/she has been free of disease for ≥3 
years, with the exception of in-situ carcinoma of the cervix or completely resected basal 
cell carcinoma of the skin. 
 
3.2.4 Patients who are receiving any other investigational agents. 
 
3.2.5 The patient has a known allergy / history of hypersensitivity reaction to any of the 
treatment components, including any ingredient used in the formulation of necitumumab, 
or any other contraindication to one of the administered treatments. 
 
3.2.6 History or evidence of current clinically relevant coronary artery disease ≥ Grade III by 
the Canadian Cardiovascular Society Angina Grading Scale or uncontrolled congestive 
heart failure of current > Class III as defined by the New York Heart Association. 
 
3.2.7 The patient has experienced myocardial infarction within 6 months prior to study 
enrollment. 
 
3.2.8 The patient has any ongoing or active infection, including active tuberculosis or known 
infection with the human immunodeficiency virus. 
 
3.2.9 Recent (within 30 days before enrollment) or concurrent yellow fever vaccination. 
 
3.2.10 The patient is pregnant or breastfeeding, or expecting to conceive or father children 
within the projected duration of the trial, starting with the screening visit through 6 
months after the last dose of trial treatment. 
 
3.2.11 History of arterial or venous thromboembolism within 3 months prior to study 
enrollment. Patients with a history of venous thromboembolism beyond 3 months prior to 
study enrollment can be enrolled if they are appropriately treated with low molecular 
weight heparin. 
 
3.2.12 The patient has any NCI-CTCAE Version 4.0 Grade ≥2 peripheral neuropathy. 
 
3.2.13 The patient has any other serious uncontrolled medical disorders or psychological 
conditions that would, in the opinion of the investigator, limit the patient’s ability to 
complete the study or sign an informed consent document. 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
13 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Patient Registration 
 
To register a patient, the following documents should be completed by the research nurse 
or data manager and faxed or e-mailed to the Study Coordinator at the Montefiore-
Einstein Cancer Center Clinical Trials Office, Tianfeng He, phone 718-405-8344, fax, or 
email: the@montefiore.org: 
 Copy of required laboratory tests 
 Signed patient consent form 
 HIPAA authorization form 
 
The research nurse or data manager at the participating site will then contact the CPDMU 
registration office at the Montefiore-Einstein Cancer Clinical Trials Office, phone 718-
379-6866 or email: cpdmu-registration@montefiore.org to verify eligibility. To complete 
the registration process, the Coordinator will: 
 assign a patient study number 
 register the patient on the study 
 fax or e-mail the patient study number to the participating site 
 call the research nurse or data manager at the participating site and verbally 
confirm registration. 
 
Once patients are found eligible for the study, they will be registered with the 
Montefiore-Einstein Cancer Center Coordinating Center.  
 
4.2 
General Guidelines 
 
The coordinating center is:  
Montefiore-Einstein Cancer Center 
 
 
 
 
 
 
 
 
 
Clinical Trials Office Department of Oncology 
 
 
 
 
 
 
 
 
 
1695 Eastchester Road, 2nd Floor 
 
 
 
 
 
 
 
 
 
Bronx, New York 10461 
 
 
 
 
 
 
 
 
 
Phone 718-405-8344 
 
 
 
 
 
 
 
 
 
Fax 718-405-8433 
 
 
 
 
 
 
 
 
 
Coordinator: Tianfeng He 
 
 
 
 
 
 
 
 
 
Email: the@montefiore.org  
 
The eligible patients will be entered on study centrally at the Montefiore-Einstein Cancer 
Center Clinical Trials Office by the Study Coordinator. All sites should call the Study 
Coordinator Tianfeng He, phone 718-405-8344 to verify availabilities. 
 
Following registration, patients should begin protocol treatment within 14 days. Issues 
that would cause treatment delays should be discussed with the Principal Investigator. If a 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
14 
 
patient does not receive protocol therapy following registration, the patient’s registration 
on the study may be canceled. The Study Coordinator should be notified of cancellations 
as soon as possible. 
 
5. TREATMENT PLAN 
 
Following written informed consent, all subjects will undergo screening to determine eligibility 
for study interventions. All baseline procedures with the exception of translational studies are 
standard of care for subjects with stage Ib, II, and IIIA squamous cell lung cancer that are 
surgically resectable. Postoperative cancer management will be at the discretion of the 
multidisciplinary treatment team. Patients with N2 disease will have a recommendation for 
postoperative radiotherapy. 
 
Patients will be evaluated by a thoracic surgeon and medical and/or radiation oncologist and be 
determined to have potentially resectable disease. 
 
Patients, who are eligible for the study, will be treated with preoperative/neoadjuvant 
necitumumab, gemcitabine and cisplatin every 21 days for 3 cycles as outlined in section 7.1. 
 
Patients will be evaluated with repeat imaging studies (PET/CT or CT Chest, Abdomen, Pelvis) 
and will be re-evaluated for surgical resection. Patients who had progressive disease or are NOT 
a surgical candidate will come off the study and will be treated according to standard therapies. 
All patients will be followed up for 2-year disease-free survival and overall survival. 
 
To be completed within 14 days prior to first dose of study drug administration: 
 
1. Complete history and physical exam, including blood pressure, weight 
2. ECOG Performance Status 
3. CBC with differential and platelet count 
4. Serum chemistry profile to include: comprehensive panel: serum bilirubin, alkaline 
phosphatase, AST, ALT, serum creatinine, serum electrolytes, serum calcium, serum 
albumin, serum magnesium 
5. Beta HCG in women capable of becoming pregnant (defined as a sexually mature 
female), has not undergone hysterectomy (surgical removal of the uterus) or bilateral 
oophorectomy (surgical removal of both ovaries), has not been naturally postmenopausal 
for at least 24 consecutive months. 
6. PET/CT from Base of Skull to Upper Thigh if not already done 
7. MRI Brain (for patients with Stage IIIA disease only) 
 
Complete history and physical exam, including blood pressure, weight will be repeated every 3 
weeks. 
 
Repeat CBC with differential and platelet count and serum chemistry profile as included above 
will be completed prior to each dose of chemotherapy. Additional tube of peripheral blood will 
be collected for NK cell measurement and ADCC activity analysis. 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
15 
 
CT Chest, Abdomen and Pelvis will be obtained following completion of cycle 3 of 
chemotherapy and necitumumab. If a PET/CT from Base of Skull to Upper Thigh is able to be 
obtained instead, this is permissible (preferred). 
 
5.1 
Chemotherapy and Necitumumab Administration Schedule 
 
Treatment will be administered on an outpatient basis. All chemotherapy doses will be based on 
the patient’s actual weight. The actual weight at screening will be used for calculating body 
surface area (BSA). The BSA should only be recalculated if a patient’s weight changes by >10%. 
Reported adverse events and potential risks are described in Section 7. Appropriate dose 
modifications are described in Section 6. No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the patient's 
malignancy. 
 
Prior to each administration of study therapy, hematology, liver, and renal function must be 
adequate (see below) and all other toxicities must be resolved to Grade ≤2 (except for alopecia 
and skin toxicity) or baseline.  
 
Criteria for Treatment 
Neutrophils: 
≥ 1.5 x 109 / L 
Platelets: 
≥ 100 x 109 / L 
Calculated creatinine clearance: 
≥ 50 mL/min 
Bilirubin 
≤ 1.5 x ULN 
AST: 
≤ 5 x ULN in the presence of liver metastasis; 
≤ 3 x ULN in the absence of liver metastasis 
ALT: 
≤ 5 x ULN in the presence of liver metastasis; 
≤ 3 x ULN in the absence of liver metastasis 
 
 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Necitumumab 
Previous Grade 1 
or 2 infusion-
related reaction 
(IRR), pre-
medicate with 
diphenhydramine 
hydrochloride 
prior to all 
subsequent 
infusions. 
For patients who 
have experienced 
a second Grade 1 
800mg in 
250 cc NS 
IV over 60 
minutes before 
gemcitabine 
Days 1, 8, 
of 3 week 
cycle 
21 days  
(3 weeks) 
 
 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
16 
 
or 2 occurrence of 
IRR, pre-medicate 
for all subsequent 
infusions with 
diphenhydramine 
hydrochloride, 
acetaminophen, 
and 
dexamethasone 
prior to each 
infusion. (or 
equivalent of each 
of above) 
Gemcitabine 
Dexamethasone 
10mg IV on Day 
1, 8 
1250mg/m2 
in 250 cc 
NS 
IV given 60 
minutes after 
necitumumab, 
given over 30 
minutes 
Days 1, 8, 
week 1-3 
Cisplatin 
Pre- and post-
hydration 
75mg/m2 in 
500 cc NS 
IV following 
gemcitabine 
over 120 
minutes  
Day 1, 
week 1-3 
 
 
5.1.1 Chemotherapy Regimen 
 
Gemcitabine 1250mg/m2 IV over 30 minutes, days 1 and 8 following necitumumab 
 
Cisplatin 75mg/m2 IV over 60 minutes, day 1, immediately following gemcitabine  
 
Each cycle is 3 weeks (21 days). 
 
The regimen will be given for a total of 3 cycles. 
 
5.1.1.1 
Antiemetics 
 
It is strongly recommended that all patients receive adequate anti-emetics 
with cisplatin- based chemotherapy. The specifics of the regimen are at the 
discretion of the treating physician, provided adequate control is achieved. 
One potential regimen consists of 20 mg of oral dexamethasone and a high 
dose of oral or IV 5HT3 antagonist (such as 2 mg oral or 10 mcg/kg IV 
granisetron, or 32 mg oral or IV ondansetron) on the day of cisplatin 
administration. Followed by additional anti-emetics consisting of 4 days of 
oral dexamethasone (8 mg PO bid for 2 days (days 2, 3) then 4 mg PO bid 
for 2 days (days 4, 5) and scheduled metoclopramide or 5HT3 antagonist 
for days 2-5 for delayed emesis (see supportive care Section 5.2.7).  
NOTE: Dexamethasone dose should be reduced by 50% when 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
17 
 
administered with aprepitant.  
 
5.1.1.2 
Hydration Requirements 
 
Hydration guidelines may be modified at the discretion of the treating 
physician provided adequate pre and post cisplatin hydration is achieved 
and renal function remains adequate. One suggested regimen consists of 
administering cisplatin in 500 cc to 1000 cc of IV fluids following 
adequate hydration and the establishment of adequate urinary output. It is 
suggested the pre-cisplatin hydration consist of NS at 500 cc/hr x 1 liter 
and post-cisplatin hydration consist of 1/2 NS + 10 meq KCl/liter + 1 
gram magnesium sulfate/liter + 25 grams mannitol/liter at 500 cc/hr for at 
least one hour, followed by additional hydration at the discretion of the 
investigator.  
 
5.1.2 Necitumumab 
 
Necitumumab 800mg absolute dose IV over a minimum of 60 minutes, days 1 and 8 prior 
to chemotherapy regimen 
 
Each cycle is 3 weeks (21 days). 
 
The regimen will be given for a total of 3 cycles. 
 
5.1.2.1 
Premedication 
 
 
For patients who have experienced a previous Grade 1 or 2 infusion-
related reaction (IRR), pre-medicate with diphenhydramine hydrochloride 
(or equivalent) prior to all subsequent necitumumab infusions. 
 
For patients who have experienced a second Grade 1 or 2 occurrence of 
IRR, pre-medicate for all subsequent infusions, with diphenhydramine 
hydrochloride (or equivalent), acetaminophen (or equivalent), and 
dexamethasone (or equivalent) prior to each necitumumab infusion. 
 
 
5.2 
Surgical Resection 
 
Patients who had significant clinical down staging and deemed medically fit to tolerate surgery 
will have surgical resection within 4 weeks after last staging imaging studies.  
 
Patients with non-progressive disease who are not going for surgery should have mediastinal 
restaging done by either EUS/EBUS or mediastinoscopy. 
 
5.2.1 
Mediastinoscopy 
 
A mediastinoscopy is highly recommended for all patients prior to neoadjuvant 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
18 
 
therapy for confirmation of mediastinal disease. 
 
5.2.2 
Pulmonary resection 
 
Thoracotomy or video-assisted thoracoscopic surgery (VATS) may be performed 4-6 
weeks after neoadjuvant therapy. Surgery is performed if post neoadjuvant induction 
CT scan shows no significant progression of disease. Patients must be medically fit to 
tolerate surgery as deemed by the operative surgeon (post operative predicted FEV1> 
40% predicted, no severe active comorbidity-see section 3). Complete surgical 
resection is the goal. This may entail pneumonectomy, bilobectomy, or lobectomy. 
Any procedure less than lobectomy is not recommended. Intraoperative frozen 
sections are performed at the discretion of the surgeon (bronchial resection margin is 
recommended). Reasons for incomplete resection will be documented. Bronchial 
stump coverage with local vascularized tissue is recommended. 
 
5.2.3 
Handling of mediastinal lymph nodes at thoracotomy 
 
At the time of thoracotomy or VATS, mediastinal lymph node dissection is 
performed at the nodal station biopsied positive on prior mediastinoscopy. Either a 
full mediastinal lymph node dissection or mediastinal lymph node sampling is 
performed at all other lymph node stations at the discretion of the surgeon. For right-
sided lesions, this will include lymph node station 2, 4, 7, 8, 9, 10, and 11. Station 12 
and 13 will be submitted along with the lung specimen. For left sided lesions, this 
will include lymph node station 5, 6, 7, 8, 9, 10, and 11. Station 12 and 13 will be 
submitted along with the lung specimen. On the left side, dissection or sampling of 
station 2 and 4 are at the discretion of the surgeon. 
 
Proper documentation of mediastinal lymph node sampling in operative report is 
mandatory for the study. If the specific stations are not sampled, the reason should be 
documented in operative report. Failure to document mediastinal node sampling will 
be considered major protocol violation.  
 
5.2.4 
Operative complications 
 
 
In hospital and 30 day morbidity and mortality will be prospectively monitored. 
 
 
5.3 
Supportive Care Guidelines 
 
5.3.1 All supportive measures consistent with optimal patient care will be given throughout the 
study. 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
19 
 
5.3.2 The clinical tolerance of the patients, the overall clinical tumor response, and the medical 
judgment of the investigator will determine if it is in the patient’s best interest to continue 
or discontinue treatment. If treatment is discontinued due to any toxicity, the patient must 
be followed to monitor duration of toxicity, response and time to progression, until the 
initiation of any new systemic therapy. 
 
5.3.3 Suggested supportive care medications may be substituted at the discretion of the 
investigator based on drug availability. 
 
5.3.4 Concomitant aminoglycoside antibiotic use should be avoided during cisplatin therapy 
until patient has fully recovered (i.e., at least 4 weeks from last dose of cisplatin). 
 
5.3.5 Pegylated G-CSF or G-CSF may be used at the discretion of the investigator after 
neutropenia is documented, or prophylactically to reduce the chance of febrile 
neutropenia. Growth factor use or dose reduction is only mandated, however, in the 
setting of prior febrile neutropenia. If used, it would be given on day 9, 24 hours 
following the last administration of necitumumab and gemcitabine. 
 
5.3.6 Diarrhea may occur. Appropriate supportive measures including Imodium and/or Lomotil 
should be implemented immediately to prevent dehydration. 
 
Hydration guidelines may be modified at the discretion of the treating physician provided 
adequate pre- and post- cisplatin hydration is achieved and renal function remains 
adequate. One suggested regimen consists of administering cisplatin in 500 cc to 1000 cc 
of IV fluids following adequate hydration and the establishment of adequate urinary 
output. It is suggested the pre-cisplatin hydration consistent of NS at 500cc/hr x 1 liter 
and post-cisplatin hydration consist of ½ NS + 10 meq KCl/liter + 1 gram magnesium 
sulfate/liter + 25 grams mannitol/liter at 500cc/hr for at least one hour, followed by 
additional hydration at the discretion of the investigator. 
 
5.3.7 Antiemetic therapy is critical for proper administration of cisplatin. The specific anti-
emetic regimen is at the discretion of the treating physician, provided adequate control is 
achieved. However, on the day of cisplatin therapy, the investigator should consider use 
of a steroid medication and a 5HT3 antagonist. One such regimen consists of 20mg of 
dexamethasone and a high dose of a 5HT3 antagonist (such as 2 mg oral or 10 mcg/kg IV 
granisetron or 32 mg ondansetron or equivalent) and continuing with 4 days of 
dexamethasone or equivalent steroid and 4 days of scheduled anti-emetic such as 
metoclopramide or a 5HT3 antagonist. If this regimen is ineffective, consideration of the 
long-acting 5HT3 antagonist palonosetron and the agent aprepitant should be considered 
at the discretion of the investigator. 
 
NOTE: Aprepitant should be used with caution in patients receiving concomitant 
medicinal products, including chemotherapy agents that are primarily metabolized 
through CYP3A4. Inhibition of CYP3A4 by aprepitant could result in elevated plasma 
concentrations of these concomitant medicinal products. The effect of aprepitant on the 
pharmacokinetics of orally administered CYP3A4 substrates is expected to be greater 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
20 
 
than the effect of aprepitant on the pharmacokinetics of intravenously administered 
CYP3A4 substrates.  
 
NOTE: Dexamethasone dose should be reduced by 50% when administered with 
aprepitant.  
 
5.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 3 
cycles, given 3 weeks apart, or until one of the following criteria applies: 
 
 
Disease progression 
 
Intercurrent illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) including but not limited to: 
 
Immediately and permanently discontinue necitumumab for severe (grade 3 or 4) 
IRRs 
 
Patient decides to withdraw from the study 
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
Clinical progression 
 
Patient non-compliance 
 
Pregnancy 
o All women of child bearing potential 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. Cases of 
pregnancy that occur during maternal or paternal exposures to study treatment 
should be reported.  Data on fetal outcome and breast-feeding are collected for 
regulatory reporting and drug safety evaluation. 
 
Termination of the study by sponsor 
 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and 
the corresponding dates must be documented in the Case Report Form (CRF). 
 
5.5 
Duration of Follow Up 
 
Patients will be followed for at least 2 years after the last patient has been enrolled after 
removal from study or until death, whichever occurs first. Patients removed from study 
for unacceptable adverse event(s) will be followed until resolution or stabilization of the 
adverse event. Monitoring of magnesium level for at least 8 weeks post-necitumumab 
completion will be performed. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Gemcitabine/Cisplatin 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
21 
 
6.1.1 Hematologic Toxicity (Gemcitabine) 
 
6.1.1.1 
Intra-cycle adjustments (e.g. day 8) 
 
Day 8 dose adjustment for neutropenia and/or platelets is not a permanent dose 
reduction. 
 
Absolute Neutrophil 
Count (x 106/L) 
 
Platelets (x 106/L) 
% full dose 
Gemcitabine 
≥ 1000 
AND 
≥ 75,000 
100 
500-999 
OR 
50,000-74,999 
75 
<500 
OR 
<50,000 
0 
Omitted day 8 doses of gemcitabine will not be made up. 
 
6.1.1.2 
Day 1 cycle dose adjustments (hematologic toxicity): 
 
Dose reductions are not required for neutropenia, unless febrile neutropenia occurs. If 
a platelet nadir of <25,000 is reached, future cycles require dose reduction. Day 1 
dosing may only resume for platelet count ≥100,000 and ANC ≥1500. Please see 
table below: 
 
Dose Reductions for Hematologic Toxicity 
 
Cisplatin 
Gemcitabine 
1st episode* 
No adjustment 
Dose reduce by 1 level** 
2nd episode* 
No adjustment 
Dose reduce by 1 level** 
3rd episode 
Discontinue protocol 
chemotherapy – may 
continue necitumumab 
alone 
Discontinue protocol 
therapy – may continue 
necitumumab alone 
Anemia 
No adjustment 
No adjustment 
* Episodes = Febrile Neutropenia or Platelet Nadir <25,000 
** Alternatively, if current episode is febrile neutropenia, growth factor support (G-
CSF or pegylated G-CSF) may be used with all subsequent cycles instead of dose 
reduction. If growth factor support has already been instituted, than dose reduction is 
required for the next episode of febrile neutropenia. ANC must be at least 
1,5000/mm2 and platelet count must be at least 100,000/μl on day 1 of each cycle. 
 
Dose Reduction Levels 
 
Original Dose 
Reduced Dose 
Gemcitabine 
1250 mg/m2 
950 mg/m2 
950 mg/m2 
625 mg/m2 
 
Treatment should be delayed for up to 3 weeks until the day 1 ANC is at least 
1500/mm3 and the platelet count is at least 100,000/mm3. However, if the counts have 
not recovered in 3 weeks, the patient’s protocol chemotherapy treatment will be 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
22 
 
discontinued. The patient will still be followed for toxicity and response. Patient and 
investigators need to be attentive to the possibility of fever and infection so that these 
complications can be promptly and appropriately managed.  
 
If chemotherapy must be delayed due to hematologic toxicity, CBC and platelet 
counts should be obtained weekly until the counts reach the lower limits for 
treatment. The treatment schedule will then proceed in the usual schedule.  
 
No dose reductions will be made for anemia. Patients should be supported per the 
treating physician’s discretion. The use of blood transfusions for anemia will be 
allowed as indicated. 
 
Dose reductions, once initiated, are permanent for all future cycles. If both febrile 
neutropenia and thrombocytopenia of <25,000 occur, the dose reduction will be to the 
lower dose specified.  
 
6.1.2 Gastrointestinal Toxicities (Cisplatin) 
 
Nausea and/or vomiting should be controlled with antiemetics. If grade 3 
nausea/vomiting occurs in spite of maximum antiemetics (steroid pre-medication for 4 
days after administration, 5HT3 antagonist, and aprepitant or similar agent if available), 
the dose of cisplatin should be reduced by 25% for the next course. If tolerated, increase 
back to 100% as soon as possible.  
 
NOTE: Aprepitant should be used with caution in patients receiving concomitant 
medicinal products, including chemotherapy agents that are primarily metabolized 
through CYP3A4. Inhibition of CYP3A4 by aprepitant could result in elevated plasma 
concentrations of these concomitant medicinal products. The effect of aprepitant on the 
pharmacokinetics of orally administered CYP3A4 substrates is expected to be greater 
than the effect of aprepitant on the pharmacokinetics of intravenously administered 
CYP3A4 substrates.  
 
Oral Mucositis  
If, on day 1 of any treatment cycle, the patient has >grade 1 oral mucositis, the treatment 
should be delayed until the oral mucositis has resolved to grade 1 or less. If the oral 
mucositis has not cleared in 3 weeks, the patient’s protocol chemotherapy treatment will 
be discontinued. (For grade 1 oral mucositis not related to treatment, treatment may be 
given on schedule.) If acute grade 3 oral mucositis occurs at any time, the dose of 
cisplatin should be given at 75% dose when the oral mucositis is completely cleared. This 
is a permanent dose reduction.  
 
6.1.3 Renal (Cisplatin) 
 
Creatinine 
Cisplatin 
Gemcitabine 
≤ 1.5 x ULN 
100% 
100% 
> 1.5 but ≤2.0 x ULN 
50% 
100% 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
23 
 
Creatinine 
Cisplatin 
Gemcitabine 
>2.0 x ULN 
0% 
0% 
 
If serum creatinine is elevated such that treatment is not administered as scheduled (i.e. > 
2.0 X ULN), repeat the abnormal tests at weekly intervals. If the serum creatinine returns 
to ≤ 2.0 x ULN within 3 weeks, cisplatin may be reinstituted at 75% of the full dose 
during the next cycle (permanent dose reduction). A more aggressive hydration regimen 
must be instituted as well with all subsequent doses of cisplatin. If the cisplatin is held, 
the gemcitabine will be held as well so that both drugs are kept on the same schedule. If 
creatinine is still ≥ 2.0 x ULN after 3 weeks, either discuss with study chair, substitute 
with carboplatin AUC 5 as per standard protocol in the setting of cisplatin-induced 
nephrotoxicity, or discontinue protocol chemotherapy. 
 
6.1.4 Sensory or Motor Neuropathy (Cisplatin) 
 
Cisplatin doses should be modified as follows for sensory or motor neuropathy. Day 1 
value should be used in determining dose.  
 
Grade of Toxicity 
Dose 
0 
100% 
1 
100% 
2 
Delay treatment until patient recovers to grade 1 toxicity, 
then resume cisplatin treatment at 75% dose 
≥3 
Delay treatment until patient recovers to grade 1; then 
resume cisplatin treatment at 50% dose 
 
Delay cisplatin and gemcitabine until patient recovers to grade 1 toxicity. Reduce 
cisplatin dose once therapy is re-initiated. If within 3 weeks the sensory or motor 
neuropathy has not recovered to grade 1, discontinue protocol treatment. Dose reductions 
for sensory or motor neuropathy are permanent. 
 
6.1.5 Ear and Labyrinth Disorders: Hearing Impairment (Cisplatin) 
 
Cisplatin is well known to cause high-frequency hearing loss. Continued use of the drug 
does not always result in hearing loss, although it may do so. If grade 2 or worse hearing 
loss is noted, the patient should be presented with a discussion of the relative risks of 
hearing loss versus the potential benefit of continuing cisplatin therapy, and a decision 
made on the continuation of cisplatin. Severe hearing loss (grades 3 and 4) is an 
indication to discontinue the drug. 
 
6.1.6 Other Toxicities 
 
For any clinically significant grade 3 or 4 toxicity felt to be related to chemotherapy 
treatment, not mentioned above, the treatment should be delayed until the patient 
recovers completely or to grade 1 or better. The treatment should then be resumed with at 
least a 25% dose reduction in the agent felt most likely to have caused the toxicity 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
24 
 
(permanent dose reduction). At the discretion of the investigator, both drugs may be 
reduced and the reduction may be more significant if warranted. If, within 3 weeks, the 
toxicity has not resolved to grade 1 or completely recovered, discontinue protocol 
chemotherapy treatment. For grade 1 and 2 toxicities, no dose reductions are necessary 
per protocol.  
 
6.2 
Necitumumab 
 
In the case of necitumumab-related toxicity, such as grade 3 or 4 electrolyte 
abnormalities, administration of necitumumab will be interrupted, but chemotherapy will 
continue according to the planned schedule. Subsequent cycles of necitumumab may be 
administered in these patients once hypomagnesemia and related electrolyte 
abnormalities have improved to grade ≤2. 
 
In the case of chemotherapy-related toxicity, the start of the next cycle of chemotherapy 
will be delayed until recovery but necitumumab will be administered as planned. 
However, in the case of grade 3 or 4 electrolyte abnormalities, necitumumab therapy will 
also be delayed. When chemotherapy-related toxicity has resolved, chemotherapy and 
necitumumab will resume on the regular schedule. 
 
Dose modifications are permitted for necitumumab following non-life threatening 
reversible CTCAE Grade ≥3 AEs that require delay of necitumumab treatment for up to 6 
weeks following Day 1 of the most recent treatment cycle. In this setting, necitumumab 
may be re-administered at a reduced dose (600mg) if necessary only if AE is resolved to 
grade ≤2. A second dose reduction (to 400mg) is permitted for this level of event (Grade 
≥3.) 
 
If a patient experiences CTCAE Grade ≥3 hematologic toxicity possibly related to 
necitumumab, then dosing must be suspended (until the toxicity resolves to either 
baseline or at least Grade 2) and the dose of necitumumab must be reduced by 1 dose 
level (see above). 
 
If a patient experiences CTCAE Grade ≥3 non-hematologic toxicity possibly related to 
necitumumab, then dosing must be suspended (until the toxicity resolves to either 
baseline or at least Grade 1) and the dose of necitumumab must be reduced by 1 dose 
level (see above). 
 
Events that necessitate more than 2 dose reductions warrant discontinuation from 
necitumumab treatment. 
 
6.2.1 Infusion-Related Reactions (IRR) 
 
Hypersensitivity/infusion-related reactions were reported with necitumumab. The onset 
of events usually occurred after the first or second administration of necitumumab. 
Monitor patients during and following the infusion for signs of hypersensitivity and 
infusion-related reactions with resuscitation equipment readily available. For mild or 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
25 
 
moderate (grade 1 or 2) IRRs, adjust dose per table below:   
 
Toxicity 
Gradea 
 
Management Recommendations 
(Any Occurrence) 
Grade 1 
 Decrease infusion rate by 50% for the 
duration of infusion.b 
 Monitor patient for worsening of 
condition. 
Grade 2 
 Stop the infusion; when the reaction has 
resolved to ≤ Grade 1, resume infusion at 
a 50% decreased infusion rate.b 
 Monitor patient for worsening of 
condition. 
Grade 3-4 
 Stop the infusion. 
 Permanently discontinue treatment with 
necitumumab. 
a – Grade per NCI-CTCAE, Version 3.0 
b – Once the infusion rate has been reduced for a Grade 1 or 2 hypersensitivity/infusion 
related reaction, it is recommended that the lower infusion rate  be utilized for all 
subsequent infusions. The infusion duration should not exceed 2 hours. 
 
6.2.2 Dermatologic Toxicity 
 
Dose delays and or modifications for necitumumab are to be considered in case of skin 
reactions of Grade 3 or that are considered intolerable.  If a patient experiences Grade 4 
skin reactions, treatment with necitumumab should be permanently discontinued. 
 
Management Recommendations for Skin Reactions 
Toxicity 
Gradea 
 
Management Recommendations 
(Any Occurrence) 
Grade 3 
 Temporarily withhold, for a maximum of 6 weeks 
following Day 1 of the most recent treatment cycle, 
until symptoms resolve to Grade ≤ 2. 
 Following improvement to Grade ≤ 2, re-administer 
with a dose reduction of 50% (400 mg). This dose may 
be increased to 75% of the original dose (600 mg) after 
a minimum of one treatment cycle (3 weeks), if 
symptoms do not recur. 
 If symptoms do not recur for another treatment cycle, 
the dose may be re-escalated to the full recommended 
dose (800 mg). 
 Permanently discontinue if reactions do not resolve to 
Grade ≤ 2 after 6 weeks (i.e., after withholding two 
consecutive doses), or if reactions recur or become 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
26 
 
intolerable at 50% of the original dose. 
 Immediately and permanently discontinue for patients 
who experience Grade 3 skin induration / fibrosis. 
 
Grade 4 
 Immediately and permanently discontinue treatment 
with necitumumab. 
a – Grade per NCI-CTCAE, Version 3.0 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting in addition to routine reporting. 
 
7.1 
Adverse Events 
 
7.1.1 Adverse Event List for Necitumumab 
 
For a comprehensive list, please see the package insert. 
 
7.1.1.1 
Cardiopulmonary Arrest 
 
 Cardiopulmonary arrest and/or sudden death occurred in 3.0% of patients treated with 
necitumumab in combination with gemcitabine and cisplatin. Closely monitor serum 
electrolytes, including serum magnesium, potassium, and calcium, with aggressive 
replacement when warranted during and after necitumumab administration. 
 
 In cases of sudden death, investigators are requested to record on the SAE report 
form as much information as possible regarding the symptoms and signs immediately 
preceding death and any postmortem results so that an accurate cause of death may be 
established (specifically so that thromboembolism may be confirmed or denied). 
 
7.1.1.2 
Hypomagnesemia 
 
Hypomagnesemia occurred very commonly (83%) in patients receiving necitumumab 
in combination with gemcitabine and cisplatin, and was severe in 20% of patients. 
Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia prior to each 
dose of necitumumab during treatment and for at least 8 weeks following completion 
of necitumumab. Withhold necitumumab for Grade 3 or 4 electrolyte abnormalities. 
Replete electrolytes as medically appropriate. 
 
7.1.1.3 
Venous and Arterial Thromboembolic Events 
 
Venous and arterial thromboembolic events (VTE and ATE), some fatal, were 
observed with necitumumab in combination with gemcitabine and cisplatin. The 
incidence of VTE was 9% in patients receiving necitumumab plus gemcitabine and 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
27 
 
cisplatin versus 5% in patients receiving gemcitabine and cisplatin alone and the 
incidence of Grade 3 or higher VTE was 5% versus 3%, respectively. The incidence 
of fatal VTEs was similar between arms (0.2% versus 0.2%). The most common 
VTEs were pulmonary embolism (5%) and deep-vein thrombosis (2%). 
 
The incidence of ATEs of any grade was 5% versus 4% and the incidence of Grade 3 
or higher ATE was 4% versus 2% in the necitumumab plus gemcitabine and cisplatin 
versus gemcitabine and cisplatin alone, respectively. The most common ATEs were 
cerebral stroke and ischemia (2%) and myocardial infarction (1%). 
 
Treatment of any thromboembolic events occurring under necitumumab treatment 
should be as clinically indicated according to local standards, and the continuation of 
necitumumab therapy in these cases should be decided by the investigator after 
thorough risk-benefit assessment for the individual patient. 
 
 
 
Discontinue necitumumab for patients with serious or life threatening VTE or ATE. 
 
7.1.1.4 
Dermatologic Toxicities 
 
Dermatologic toxicities, including rash, dermatitis acneiform, acne, dry skin, pruritus, 
generalized rash, skin fissures, maculo-papular rash and erythema, occurred in 79% 
of patients receiving necitumumab. Skin toxicity was severe in 8% of patients. Skin 
toxicity usually developed within the first 2 weeks of therapy and resolved within 17 
weeks after onset. For Grade 3 skin reactions, modify the dose of necitumumab. 
Limit sun exposure. Discontinue necitumumab for severe (Grade 4) skin reactions, or 
for Grade 3 skin induration/fibrosis. 
 
7.1.1.5 
Infusion-Related Reactions 
 
In a study of necitumumab plus gemcitabine and cisplatin, 1.5% of necitumumab 
treated patients experienced IRRs of any severity with 0.4% Grade 3 IRR. No 
patients received premedication for IRR for the first dose of necitumumab in that 
study. Most IRRs occurred after the first or second administration of necitumumab. 
Monitor patients during and following necitumumab infusion for signs and symptoms 
of IRR. Discontinue necitumumab for serious or life-threatening IRR. 
 
7.1.2 Adverse Event List for Gemcitabine 
 
The most common adverse reactions for the single agent (≥20%) are nausea/vomiting, 
anemia, hepatic transaminitis, neutropenia, increased alkaline phosphatase, proteinuria, 
fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema. For a 
comprehensive list, please see the package insert. 
 
7.1.3 Adverse Event List for Cisplatin 
 
The most common adverse reactions for cisplatin are nausea/vomiting, peripheral 
neuropathy, nephrotoxicity, ototoxicity, anemia, neutropenia, thrombocytopenia, and 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
28 
 
hepatic transaminitis and thromboembolic events. For a comprehensive list, please see 
the package insert. 
 
7.2 
Adverse Event Characteristics  

 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov).  
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for 
expedited reporting purposes only.  
 
Attribution of the AE:  
- Definite – The AE is clearly related to the study treatment.  
- Probable – The AE is likely related to the study treatment.  
- Possible – The AE may be related to the study treatment.  
- Unlikely – The AE is doubtfully related to the study treatment.  
- Unrelated – The AE is clearly NOT related to the study treatment.  
 
An adverse event can occur on any clinical trial; it is the responsibility of the Principal 
Investigator and his/her research team to identify, review and report all necessary adverse 
events to the institutional IRB, the sponsor and governmental agencies (i.e., NCI and/or 
FDA) as appropriate. Adverse events should be identified through standard, routine 
protocol review and clinical assessment of each subject participating in the clinical trial. 
This review should be timely in order to meet the requirements for adverse event 
reporting defined below.  
 
Definitions: 
 
1. Adverse Event (AE): 
Any untoward or unfavorable medical occurrence in a human subject, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the subject’s participation in the research, whether or 
not considered related to the subject’s participation in the research. Adverse Events 
encompass both physical and/or psychological harms.  
 
In the context of multicenter clinical trials, Adverse Events can be characterized as either 
internal adverse events or external adverse events. From the perspective of one particular 
institution engaged in a multicenter clinical trial, internal adverse events are those 
adverse events experienced by subjects enrolled by the investigator(s) at that institution, 
whereas external adverse events are those adverse events experienced by subjects 
enrolled by investigators at other institutions engaged in the clinical trial. In the context 
of a single-center clinical trial, all Adverse Events would be considered internal adverse 
events.  
 
2. Unanticipated Problem: 
Any event, deviation, or problem, that meets ALL of the following criteria:  


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
29 
 
• 
unexpected; AND    
• 
possibly, probably or definitely related to study participation; AND   
• 
serious. 
 
a. Unexpected: An event can be categorized as unexpected if it occurs in one or more 
subjects participating in a research protocol; and the nature, severity, or frequency of 
which is not consistent with either: 
i. The known or foreseeable risk of adverse events associated with the procedures 
involved in the research that are described in protocol-related documents such as: the 
IRB-approved research protocol; any applicable investigator brochure: the current 
IRB-approved informed consent document; or other relevant sources of information, 
such as product labeling and package inserts; or    
ii. The expected natural progression of any underlying disease, disorder, or condition of 
the subject(s) experiencing the adverse event and the subject’s predisposing risk 
factor profile for the adverse event.  
 
b. Serious: An adverse event or suspected adverse reaction is considered "serious" if, in 
the view of either the investigator or sponsor, it results in any of the following outcomes:  
i. death, 
ii. a life-threatening adverse reaction, 
iii. inpatient hospitalization or prolongation of existing hospitalization, 
iv. persistent or significant disability/incapacity, 
v. a congenital anomaly/birth defect, 
vi. or based upon appropriate medical judgment, may jeopardize the subject’s health and 
may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition (examples of such events include allergic bronchospasm 
requiring intensive treatment in the emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse). 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  
 
 
7.3 
Reporting requirements 
 
In addition to the IRB reporting guidelines described below, all serious adverse events 
(SAE) will be reported to Lilly Global Patient Safety via fax within 24 hours with a 
causality assessment.  The Lilly Global Patient Safety Fax Number for all SAEs is 866-
644-1697 or 317-453-3402. 
 
 
7.3.1 Determination of reporting requirements 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
30 
 
Unanticipated Problems must be reported to the IRB using the Reportable Events Form 
within 5 business days of the identification of the event by the research staff. Only the 
Principal Investigator may sign off on reportable event submissions, although any 
member of the research team may initiate the report. Exceptions (e.g. when the PI is 
unavailable for an extended period of time) will be considered by the IRB on a case-by-
case basis.  
 
[N.B. Internal Adverse Events that have been anticipated in the risks outlined in the 
protocol and informed consent document, or that are clearly unrelated to the research 
protocol, or that are not serious, do not have to be reported individually to the IRB. 
However they must be recorded in the adverse events log. Anticipated non-serious 
adverse events need not be reported to the IRB or logged.] 
 
External Adverse Events that are serious, unexpected, and related or possibly related to 
the research must be reviewed by the PI. They should be submitted to the IRB only if 
they result in an amendment to the protocol or informed consent document. These AEs 
are then reported to the IRB as the basis for the proposed amendment (using the 
Amendment Form, not the Reportable Event Form).  
 
Other events that must be reported to the IRB include:  
• 
The death of a participant in a “greater-than-minimal-risk” protocol being conducted 
at a site   under the jurisdiction of the Einstein IRB, even if “anticipated”, if it occurs 
within 30 days of a   study-related procedure or the administration of a study drug.    
• 
A Protocol Deviation that may place the participant or others at greater medical, 
physiological,   social risk or economic risk than was previously known or 
recognized. 
• 
Deviation from the IRB Informed Consent Policy.    
• 
Any deviation from IRB or Institutional Policy or Procedure which has the potential 
to adversely   impact one or more subjects or the overall integrity of data collected. 
   
• 
Systematic data collection error that has the potential to adversely impact the overall 
integrity of   the data collected.    
• 
Breach of confidentiality.    
• 
Any incident, experience, or outcome that indicates that the participant or others were 
placed at   greater medical, physiological, social risk or economic risk than was 
previously known or   recognized.    
• 
Any action taken to eliminate an apparent immediate hazard to a research subject.    
• 
Incarceration of a research subject.    
• 
Sponsor or regulatory audit that requires corrective action.    
• 
Any reporting the PI is required to report directly to the FDA (e.g. the PI is the 
sponsor-Investigator, a protocol involving the use of an HUD).    
• 
Complaint from a participant or other individual when the complaint indicates 
unexpected risks   or the complaint cannot be resolved by the research team.    
• 
Disqualification or suspension of the Investigator by the FDA, NIH or other agency. 
   
• 
Suspension or restriction of an Investigator’s clinical professional license.    


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
31 
 
• 
Any reporting that the IRB cites as a condition of approval of the protocol.    
 
Reporting requirements may include the following considerations: 1) whether the patient 
has received necitumumab, gemcitabine or cisplatin; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), 
and the prior experience (expectedness) of the adverse event; and 3) whether or not 
hospitalization or prolongation of hospitalization was associated with the event. 
 
7.3.2 Expedited Reporting Guidelines 
 
Steps to determine if an adverse event is to be reported in an expedited manner: 
 
Step 1: Identify the type of event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0. The CTCAE provides descriptive terminology and 
a grading scale for each adverse event listed. A copy of the CTCAE can be downloaded 
from the CTEP home page (http://ctep.cancer.gov). Additionally, if assistance is needed, 
the NCl has an Index to the CTCAE that provides help for classifying and locating terms. 
All appropriate treatment locations should have access to a copy of the CTCAE. 
 
Step 2: Grade the event using the NCI CTCAE. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy 
(investigational or commercial). Attribution categories are as follows: Unrelated, 
Unlikely, Possible, Probable, and Definite. 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is NOT listed in section 7.1.1, 7.1.2, 
and 7.1.3. 
 
Step 5: Review the ”Additional instructions, requirements, and exceptions for this 
protocol specific requirements” for expedited reporting of specific adverse events that 
require special monitoring. 
 
Step 6: Determine if the protocol treatment given prior to the adverse event included 
investigational agent(s), a commercial agent(s), or a combination of investigational and 
commercial agents.  
 
7.3.3 Reporting methods 
 
Any event that meets the definition of an Unanticipated Problem must be reported to the 
Montefiore-Einstein IRB within 5 business days. The Unanticipated Problem Report 
Form can be found on the Einstein IRB website: 
http://einstein.yu.edu/administration/institutional-review-board/forms.aspx. All 
Reportable Events must be submitted to the IRB within 5 business days of the 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
32 
 
identification of the event by the research staff. Only the Principal Investigator may sign 
off on reportable event submissions, although any member of the research team may 
initiate the report. A record of non-reportable events and deviations must be maintained 
by the PI in a log and for greater than minimal risk studies must be submitted to the IRB 
as part of the annual review of the protocol. 
 
For events that are deemed reportable at participating sites, a copy of the reportable event 
must be submitted to Montefiore Medical Center within 2 business days. You may send 
to the Principal Investigator and the Study Coordinator. All contact information is located 
at the cover page of this document. If not reportable, Adverse Events should be logged in 
the CRF page, and any non-reportable serious and/or unanticipated adverse events should 
be logged on the Adverse Event Log provided by Montefiore for review at the 
Montefiore Data Safety Monitoring Committee meetings and during IRB annual review. 
 
An internal log(s) of all* AE, UP and PD events that come to the attention of the staff 
responsible for the research must be maintained. The log(s) will be examined by the IRB 
during the course of a routine or for-cause audit of the protocol. For studies that are 
greater than minimal risk, this log must be submitted to the IRB as part of the continuing 
review of the protocol.   *NOTE: Anticipated non-serious AEs need not be logged. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1 
Necitumumab 
 
8.1.1 Other Names 
 
Portrazza 
 
8.1.2 Classification 
 
Epidermal Growth Factor Receptor (EGFR) Antagonist 
 
8.1.3 Mode of Action 
 
Necitumumab is a recombinant human lgG1 monoclonal antibody that binds to the 
human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its 
ligands. Expression and activation of EGFR has been correlated with malignant 
progression, induction of angiogenesis, and inhibition of apoptosis. Binding of 
necitumumab induces EGFR internalization and degradation in vitro. In vitro, binding of 
necitumumab also led to antibody-dependent cellular cytotoxicity (ADCC) in EGFR-
expressing cells. 
 
8.1.4 Storage and Stability 
 
Store vials in a refrigerator at 2° to 8°C (36° to 46°F) until time of use. Keep the vial in 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
33 
 
the outer carton in order to protect from light. DO NOT FREEZE OR SHAKE the vial. 
 
8.1.5 Dose Specifics 
 
Necitumumab will be given at a dose of 800 mg administered as an intravenous infusion 
over 60 minutes on Days 1 and 8 of each 3-week cycle prior to gemcitabine and cisplatin 
infusion. Each cycle is to be repeated every 3 weeks for 3 cycles. 
 
8.1.6 Preparation 
 
Inspect vial contents for particulate matter and discoloration prior to dilution. Discard the 
vial if particulate matter or discoloration is identified. Store vials in a refrigerator at 2° to 
8°C (36˚ to 46˚F) until time of use. Keep the vial in the outer carton in order to protect 
from light. 
 Dilute the required volume of necitumumab with 0.9% Sodium Chloride Injection, 
USP in an intravenous infusion container to a final volume of 250 mL. Do not use 
solutions containing dextrose. 
 Gently invert the container to ensure adequate mixing. 
 DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other 
solutions or co-infuse with other electrolytes or medication. 
 Store diluted infusion solution for no more than 24 hours at 2° to 8°C (36° to 46°F), 
or no more than 4 hours at room temperature (up to 25°C [77°F]). 
 Discard vial with any unused portion of necitumumab. 
 
8.1.7 Administration 
 
Visually inspect the diluted solution for particulate matter and discoloration prior to 
administration. If particulate matter or discoloration is identified, discard the solution. 
 
Administer diluted necitumumab infusion via infusion pump over 60 minutes through a 
separate infusion line. Flush the line with 0.9% Sodium Chloride Injection, USP at the 
end of the infusion. 
 
8.1.8 Incompatibilities 
 
No information available. 
 
8.1.9 Availability 
 
Necitumumab is supplied in single-dose vials as a sterile, preservative-free solution: 
800 mg/50 mL (16 mg/mL). 
 
8.2 
Gemcitabine 
 
8.2.1 Other Names 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
34 
 
2'-Deoxy-2',2'-difluorocytidine monohydrochloride, Gemzar  
 
8.2.2 Classification 
 
Antimetabolite (nucleoside pyrimidine analogue) 
 
8.2.3 Mode of Action 
 
Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA 
synthesis (S phase) and also blocking the progression of cells through the G1/S phase 
boundary. Gemcitabine is metabolized intracellularly initially by deoxycitidine kinase to 
monophosphate nucleoside and subsequently to the active diphosphate (dFdCDP) and 
triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is attributed to a 
combination of two actions of the diphosphate and the triphosphate nucleosides, which 
leads to inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits 
ribonucleotide reductase, which is responsible for catalyzing the reactions that generate 
the deoxynucleoside triphosphates for   DNA synthesis. Inhibition of this enzyme by the 
diphosphate nucleoside causes a reduction in the concentrations of deoxynucleotides, 
including dCTP. Second, gemcitabine triphosphate competes with dCTP for 
incorporation into DNA. The reduction in the intracellular concentration of dCTP (by the 
action of the diphosphate) enhances the incorporation of gemcitabine triphosphate into 
DNA (self-potentiation). After the gemcitabine nucleotide is incorporated into DNA, only 
one additional nucleotide is added to the growing DNA strands. After this addition, there 
is inhibition of further DNA synthesis. DNA polymerase epsilon is unable to remove the 
gemcitabine nucleotide and repair the growing DNA strands (masked chain termination). 
In CEM T lymphoblastoid cells, gemcitabine induces internucleosomal DNA 
fragmentation, one of the characteristics of programmed cell death. 
 
8.2.4 Storage and Stability 
 
Unreconstituted drug vials are stored at controlled room temperature. Reconstituted 
solution should be stored at controlled room temperature and used within 24 hours. 
Solutions of gemcitabine should not be refrigerated; crystallization may occur. The 
unused portion should be discarded. 
 
8.2.5 Dose Specifics 
 
Gemcitabine will be given by IV at a dose of 1250 mg/m2 over 30 minutes on days 1 and 
8 of each cycle (immediately prior to cisplatin administration on Day 1). Each cycle is to 
be repeated every 3 weeks for 3 cycles. 
 
8.2.6 Preparation 
 
Reconstitute the 200 mg vial with 5 mL and the 1 g vial with 25 mL preservative free 
normal saline to make a solution containing 38 mg/mL. Shake to dissolve.  
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
35 
 
8.2.7 Administration 
 
The drug may be administered as prepared above or further diluted with normal saline to 
a minimum concentration of 0.1 mg/mL. Gemcitabine is commonly diluted in 100 mL or 
250 mL of saline. Reconstitution at greater than 40 mg/mL may result in incomplete 
dissolution of drug. The drug is typically administered over 30 minutes.  
 
8.2.8 Incompatibilities 
 
No information available. 
 
8.2.9 Availability 
 
Gemcitabine is commercially available in 200 mg and 1 g vials. 
 
8.3 
Cisplatin 
 
8.3.1 Other Names 
 
Cis-diaminedichloroplatinum, Cis-diaminedichloroplatinum (II), 
diaminedichloroplatinum, cis-platinum, platinum, Platinol, Platinol-AQ, DDP, CDDP, 
DACP, NSC 119875. 
 
8.3.2 Classification 
 
Alkylating agent. 
 
8.3.3 Mode of Action 
 
Inhibits DNA synthesis by forming inter- and intra-strand crosslinks. Other possible 
mechanisms include chelation of DNA and binding to cell membranes thereby 
stimulating immune mechanisms. 
 
8.3.4 Storage and Stability 
 
Intact vials of cisplatin are stored at room temperature. Solutions diluted with sodium 
chloride or dextrose are stable for up to 72 hours at room temperature. Due to the risk of 
precipitation, cisplatin solutions should not be refrigerated.  
 
8.3.5 Dose Specifics 
 
Cisplatin will be given by IV at a dose of 75 mg/m2 over 60 minutes on day 1 of each 
cycle (each cycle to be repeated every 3 weeks for 3 cycles), immediately following 
gemcitabine.  
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
36 
 
8.3.6 Preparation 
 
The desired dose of cisplatin is diluted with 250-1000 mL of saline and/or dextrose 
solution. Varying concentrations of 0.225-5% sodium chloride and 5% dextrose may be 
used. To maintain stability of cisplatin, a final sodium chloride concentration of at least 
0.2% is recommended.  
 
8.3.7 Route of Administration 
 
Cisplatin is usually administered as an intravenous infusion over 30 minutes to 24 hours; 
multiday continuous infusions are occasionally used. The drug may also be administered 
intra-arterially, intraperitoneally and intravesicularly.  
 
8.3.8 Incompatibilities 
 
Amsacrine, cefepime, gallium nitrate, mesna, piperacillin, sodium bicarbonate, thiotepa. 
Cisplatin may react with aluminum which is found in some syringe needles or IV sets, 
forming a black precipitate.  
 
8.3.9 Compatibilities 
 
Admixture: Amphotericin-B, aztreonam, carmustine, cefazolin, cephalothin, droperidol, 
etoposide, floxuridine, hydroxyzine, ifosphamide, leucovorin, magnesium sulfate, 
mannitol, potassium chloride. 
 
Y-site: Allopurinol, bleomycin chlorpromazine, cimetidine, cyclophosphamide, 
dexamethasone, diphenhydramine, doxapram, doxorubicin, famotidine, filgrastim, 
fludarabine, fluorouracil, furosemide, ganciclovir, heparin, hydromorphone, lorazepam, 
melphalan, methotrexate, methylprednisolone, metoclopramide, mitomycin, morphine, 
ondansetron, paclitaxel, prochlorperazine, ranitidine, sargramostim, vinblastine, 
vincristine, vinorelbine.  
 
Consult your pharmacist regarding specific concentrations.  
 
8.3.10 Availability 
 
Commercially available as a mg/mL solution in 50 and 100 mg vials.  
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Exploratory Correlative Studies 
 
9.1.1 EGFR Expression by Immunohistochemistry on Paraffin-Embedded Tissue 
 
To evaluate whether EGFR expression by immunohistochemistry (IHC) is correlated 
with response rate to necitumumab. Pre-chemotherapy diagnostic tissue biopsy (if 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
37 
 
adequate tissue available) and tissue specimens obtained from post-chemotherapy 
surgical resection will be evaluated for EGFR expression by IHC. EGFR expression by 
immunohistochemistry will be scored based on the H-score. Based on the H-score, 
samples from pre- and post-surgery will be classified as either “EGFR expressors” or 
“EGFR non-expressors.” 
 
9.1.1.1 
Collection of Specimen(s) 
 
We will put all effort to obtain the diagnostic tissue blocks from the diagnostic biopsy 
for the pre-chemotherapy EGFR expression analysis. Post-treatment EGFR 
expression analysis will be obtained from the surgical resection. Pre- and post-
treatment tumor specimens will be obtained in available patients. 
 
9.1.1.2 
Handling of Specimens(s) 
 
Baseline levels of EGFR expression (if pre-treatment tissue available) and post-
treatment EGFR expression will be evaluated in paraffin embedded tissue and fresh 
frozen tissue (if available) by immunochemistry. 
 
9.1.1.3 
Site(s) Performing Correlative Study 
 
Immunohistochemistry for EGFR expression will be performed at Montefiore 
Medical Center. 
 
9.1.2 EGFR Gene Copy Number by FISH 
 
To determine if EGFR positivity by EGFR copy number on pre-chemotherapy diagnostic 
tissue biopsy (if adequate tissue available) and tissue specimens obtained from post-
chemotherapy surgical resection is correlated with response rate to necitumumab. EGFR 
positive by FISH is defined by the Colorado Scoring Criteria by >40% of cells displaying 
>4 copies of the EGFR signal, or EGFR to CEP7 ratio >2 over all scored nuclear, or gene 
clusters (>4 spots) or >15 copies of the EGFR signals in >10% of tumor cells. 
 
9.1.2.1 
Collection of Specimen(s) 
 
We will put all effort to obtain the diagnostic tissue blocks from the diagnostic biopsy 
for the pre-chemotherapy EGFR gene copy number by FISH analysis. Post-treatment 
EGFR gene copy number analysis will be obtained from the surgical resection. Pre- 
and post-treatment tumor specimens will be obtained in available patients. 
 
9.1.2.2 
Handling of Specimens(s) 
 
Baseline levels of EGFR gene copy number (if pre-treatment tissue available) and 
post-treatment EGFR gene copy number will be evaluated in paraffin embedded 
tissue and fresh frozen tissue (if available) by FISH. 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
38 
 
9.1.2.3 
Site(s) Performing Correlative Study  
 
Fluorescence in-situ hybridization will be performed by Montefiore Medical Center. 
 
9.1.3 Antibody-Dependent Cellular-Mediated Cytotoxicity (ADCC) Testing on Peripheral 
Blood Mononuclear Cells (PBMCs) and on Paraffin Embedded Tissue by 
Immunohistochemistry  
 
To compare markers of antibody-dependent cellular-mediated cytotoxicity (ADCC) pre-
necitumumab and post-completion of necitumumab administration by peripheral blood 
collection and conducting flow cytometry of effector cells (T-cell subsets, NK-cells), 
measuring IL-2 and IL-12 cytokine levels and evaluation of regulatory T-cells (anti-CD4, 
anti-CD8, anti-CD20 and anti-FoxP3+) from tumor tissue by immunohistochemistry. 
 
9.1.3.1 
Collection of Specimen(s) 
 
We will collect 5 ml of peripheral blood prior to initiation of neoadjuvant therapy, 
prior to cycle 2 and cycle 3 of neoadjuvant therapy and following completion of 
neoadjuvant therapy. 
 
We will put all effort to obtain the diagnostic tissue blocks from the diagnostic biopsy 
for the pre-chemotherapy presence of regulatory T-cells (Treg). Post-treatment Treg 
presence or absence will be obtained from the surgical resection. Pre- and post-
treatment tumor specimens will be obtained in available patients. 
 
9.1.3.2 
Handling of Specimen(s) 
 
Flow cytometry of peripheral blood mononuclear cells will be analyzed for CD3-
CD56+ NK cells and T-cell subsets. Measurement of IL-2 and IL-12 will also be 
conducted. 
 
Baseline levels of regulatory T-cells (Treg CD4+CD25high+FoxP3+) (if pre-treatment 
tissue available) and post-treatment Tregs will be evaluated in paraffin embedded 
tissue and fresh frozen tissue (if available) by immunochemistry. 
 
9.1.3.3 
Site(s) Performing Correlative Study 
 
Flow cytometry, cytokine level measurement and immunochemistry will be 
performed by Montefiore Medical Center. 
 
9.2 
Priority of Exploratory Correlative Studies 
 
 
In the event that inadequate amount of tissue is available for all 3 correlative studies 
(EGFR expression testing by IHC, EGFR gene copy number by FISH and ADCC testing on 
paraffin embedded tissue by IHC), the studies should be conducted in this order of priority: 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
39 
 
 
1. EGFR expression testing by IHC 
 
2. ADCC testing on paraffin embedded tissue by IHC 
 
3. EGFR gene copy number by FISH


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
40 
 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy. Scans 
and x-rays must be done <4 weeks prior to the start of therapy. In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.  Day 1 of Cycles 2 and 3 (during Weeks 4 and 7) may be 
started ±3 days of scheduled date.  
 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10-12 
Wk 
13-15 
Wk 
 16-20 
Off Studye 
Necitumumab 
 
A 
A 
 
A 
A 
 
A 
A 
 
 
 
 
 
Gemcitabine 
 
B 
B 
 
B 
B 
 
B 
B 
 
 
 
 
 
Cisplatin 
 
C 
 
 
C 
 
 
C 
 
 
 
 
 
 
Surgical Resection 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X--------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Vital signs 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Performance status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
CBC w/diff, plts 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
Serum chemistrya, b 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
 
Radiologic evaluationd 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
B-HCG 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
EGFR Expression by IHC 
Xe 
 
 
 
 
 
 
 
 
 
 
 
X 
 
EGFR Copy Number by FISH 
Xe 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PBMC for ADCC activity 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
FoxP3+ by IHC 
Xd 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
A: 
Necitumumab: Dose as assigned; administration schedule 
B: 
Gemcitabine: Dose as assigned; administration schedule 
C:  Cisplatin: Dose as assigned; administration schedule 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, phosphorus, 
potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
b:  
Serum magnesium should be followed for at least 8 weeks following the completion of necitumumab. 
c: 
Serum pregnancy test (women of childbearing potential). 
d:  
PET/CT at diagnosis; follow-up imaging at week 10-12 may be CT Chest/Abdomen/Pelvis or PET/CT if able to obtain 
e: 
If adequate tissue sample is available.  
f:  
Off-study evaluation. 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
41 
 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 3 
weeks. In addition to a baseline scan, confirmatory scans should also be obtained 2-4 
weeks prior to surgical resection. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with necitumumab. 
 
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. (Note: Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
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. 
 
11.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in 
follow-up, only the short axis will be measured and followed. 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
42 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] 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.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
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. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
43 
 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  
 
FDG-PET . While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a 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. 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
44 
 
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. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
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 (<1 cm). 
 
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 (0.5 cm). 
(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. 
 
11.1.4.2 
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 
[<1 cm] 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). 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
45 
 
11.1.4.3 
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. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**   Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note: 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. 
 
11.1.5 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 is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
46 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
11.2 
Other Response Parameters 
 
Pathologic complete response (pCR) will be evaluated separately at the lung primary 
tumor and nodal sites. It will be defined as the absence of residual invasive disease 
following neoadjuvant treatment. 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described elsewhere in this section. The 
Protocol Principal Investigator is responsible for monitoring the conduct and progress of 
the clinical trial, including the ongoing review of accrual, patient-specific clinical and 
laboratory data, and routine and serious adverse events; reporting of expedited adverse 
events; and accumulation of reported adverse events from other trials testing the same 
drug(s). The Protocol Principal Investigator and statistician have access to the data at all 
times. 
 
All Study Investigators at participating sites who register/enroll patients on a given 
protocol are responsible for timely submission of data via the mechanism described 
elsewhere in this section. All studies are also reviewed in accordance with the enrolling 
institution’s data safety monitoring plan. 
 
This trial will be monitored by the Albert Einstein Cancer Center Data Safety Monitoring 
Committee (AECC DSMC). A copy of the monitoring plan is maintained at the CPDMU. 
The DSMC as part of its function performs quarterly reviews of Clinical Trials 
Compliance Audits, monthly reviews Adverse Events Reports, and monthly reviews of 
internally monitored Phase I/Phase II trials for accrual and response. Other monitoring 
activities are established as necessary in a protocol specific manner.  
 
This trial will be part of the monthly Quality Assurance Audits. Each patient will be 
evaluated within 8 weeks of registration. This permits evaluation of consent, eligibility, 
and treatment/dose modification/Adverse Event (AE) reporting, and data quality for the 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
47 
 
first cycle (or month) of treatment.  
 
This trial may also be eligible for quarterly Quality Enhancement Audit. Each audit 
consists of a review of regulatory documents, pharmacy drug accountability (if 
applicable) and patient case review, confirming eligibility, protocol compliance and 
source documentation  
 
The results of the audit will be presented at the following month’s DSMC meeting. The 
DSMC has the authority to close trial to patient accrual should the risk to patients be 
excessive or results require a corrective plan from the Principal Investigator. All study 
suspensions and closures will be forwarded to the IRB and study sponsor. All audit 
reports are forwarded to the DSMC and presented to the DSMC by the Audit Committee 
Coordinator.  
 
12.2 
Data Management 
 
This trial will be monitored by the Albert Einstein Cancer Center Data Safety Monitoring 
Committee (AECC DSMC). A copy of the monitoring plan is maintained at the CPDMU. 
The DSMC as part of its function performs quarterly reviews of Clinical Trials 
Compliance Audits, monthly reviews Adverse Events Reports, and monthly reviews of 
internally monitored Phase I/Phase II trials for accrual and response. Other monitoring 
activities are established as necessary in a protocol specific manner.  
 
12.3 
Collaborative Agreements Language 
 
N/A 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design 
 
This will be a single-arm study to primarily evaluate the feasibility of administering 
necitumumab added to gemcitabine and cisplatin as neoadjuvant treatment in treatment-
naïve patients with stage IB (tumor size >4cm), II or IIIA squamous NSCLC. Feasibility 
will be assessed by the proportion of patients able to proceed to surgery after 
administering necitumumab in the neoadjuvant setting. These patients would otherwise 
be offered standard adjuvant chemotherapy (without necitumumab) for squamous cell 
lung cancer. Determination of surgical resectability will be reviewed at a 
multidisciplinary thoracic tumor board, attended by surgical oncology, medical oncology, 
radiation oncology, radiology, and pathology. 
 
13.2 
Primary Endpoint 
 
The primary endpoint is a binary outcome: whether the patient is eligible to proceed to 
surgery following neoadjuvant chemotherapy with at least 1 cycle of necitumumab, 
gemcitabine and cisplatin. If the proportion of patients proceeding to surgery is greater 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
48 
 
than 90%, the regimen is considered to be acceptable; if less than 70% of patients eligible 
to proceed to surgery, the regimen is deemed unacceptable and not feasible. A Simon’s 
optimal two-stage design will be used with 80% power and a two-sided type I error rate 
less than 10%. Specifically, after testing necitumumab on 6 patients in the first stage, the 
trial will be terminated if 4 or fewer are eligible for surgery. If the trial goes on to the 
second stage, a total of 20 patients will be studied. If the total number of patients eligible 
for surgery is less than or equal to 16, the drug is rejected and the regimen is deemed not 
feasible. The proportion of eligibility for surgery will be reported as well as its 95% CI.  
 
13.3 
Secondary Endpoints 
 
 
 
Secondary endpoints include: 
 Response (CR or PR) by RECISTv1.1 
 Pathologic complete response rate (pCR) 
 Disease-free survival/Progression-free survival defined as the duration from date 
of study enrollment to date of first documentation of progression assessed by 
central review or symptomatic deterioration (as defined above), or death due to 
any cause. Patients last known to be alive without report of progression are 
censored at date of last disease assessment. For patients with a missing scan (or 
consecutive missing scans) whose subsequent scan determines progression, the 
expected date of the first missing scan (as defined by the disease assessment 
schedule) will be used as the date of progression. 
 Overall survival 
 Safety assessment and toxicity evaluation as defined by Common Terminology 
Criteria for Adverse Events (CTCAE) v4.0 with neoadjuvant chemotherapy and 
necitumumab. 
 
The pathologic complete response rate (pCR) will be evaluated using a one-stage design 
on these 20 patients. If the total number of patients with pCR is less than or equal to 2, 
the study will fail to conclude an adequate increase in pCR. This sample size has 80% 
power to detect an increase of pCR from the historical control of 4% to a target of 20%, 
with a type I error rate not more than 10%. 
 
The clinical response rate, frequency and severity of toxicities, and estimated 2-year 
disease-free survival of these patients will be estimated by proportions and presented with 
associated 95% confidence intervals. With 20 patients, proportions can be estimated with 
standard error not more than 6%. Any toxicity with at least 10% prevalence has at least 
an 88% chance of being observed. A Kaplan-Meier survival curve will also be generated 
to report the overall survival. 
 
13.4 
Sample Size/Accrual Rate 
 
In this study, we plan to accrue 22 patients in order to obtain a preliminary estimate of the 
proportion of patients able to proceed to surgery and assess the feasibility of the regimen 
and account for a 10% attrition rate. The finding of the study will be used to design future 
more definitive studies to evaluate the efficacy of this regimen defined as clinical 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
49 
 
response and/or pathological response in comparison with standard therapy. 
 
This study will be conducted within the major oncology practice sites of the Montefiore 
Health System, the largest provider of healthcare and particularly oncological care in the 
Bronx and Lower Westchester region of New York. The study will be primarily 
conducted at Montefiore Medical Center, which sees approximately 400 lung cancer 
patients each year, and its new affiliate site, White Plains Hospital, which sees 
approximately 200 lung cancer patients each year. Of the approximately 600 lung cancer 
patients, we estimate approximately 30 patients per year across the health system will 
present with resectable squamous NSCLC. In addition to these Centers, the trial will be 
performed at up to 2 additional Centers in the NY/NJ region. We estimate that the 
proposed study can be fully accrued within 18-24 months of study activation, and should 
take approximately 30 months to complete the study. We expect an accrual rate of 1-2 
patients per month for a total duration of 12-18 months of study activation. 
 
13.5 
Correlative Studies 
 
EGFR expression by immunohistochemistry will be scored based on the H-score. Based 
on the H-score, samples from pre- and post-surgery will be classified as either “EGFR 
expressors” or “EGFR non-expressors.” EGFR gene copy number by FISH will be either 
positive or negative based on Colorado Scoring Criteria and correlated with response rate 
of necitumumab. The EGFR expression will be correlated with response rate of 
necitumumab using a two-sample t-test by comparing the EGFR levels between 
responders and non-responders. 
 
In addition, presence of markers for antibody-dependent cellular-mediated cytotoxicity 
(ADCC) will be investigated on pre-necitumumab and post-completion of necitumumab 
doses by peripheral blood collection and subsequent flow cytometry of effector cells (T-
cell subsets, NK-cells) and cytokines (IL-2, IL-12) and correlated with response rate of 
necitumumab. FoxP3+ for regulatory T-cell expression by immunochemistry on pre-
necitumumab (if adequate tissue available) and post-necitumumab treatment on surgical 
resection will be conducted and correlated with response rate of necitumumab. Analysis 
of within person change from pre- to post-necitumumab will be compared using a paired 
t-test. Further, the change between pre- and post-necitumumab will be correlated with 
response rate of necitumumab. 
 
 
 
 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
50 
 
 
REFERENCES 
 
1. 
Youlden DR, Cramb SM, Baade PD. The International Epidemiology of Lung 
Cancer: geographical distribution and secular trends. J Thorac Oncol 2008;3:819-31. 
2. 
Song WA, Zhou NK, Wang W, et al. Survival benefit of neoadjuvant chemotherapy 
in non-small cell lung cancer: an updated meta-analysis of 13 randomized control trials. J Thorac 
Oncol 2010;5:510-6. 
3. 
Scagliotti GV, Pastorino U, Vansteenkiste JF, et al. Randomized phase III study of 
surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-
small-cell lung cancer. J Clin Oncol 2012;30:172-8. 
4. 
Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival 
for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: 
analysis of data from the phase 3 FLEX study. Lancet Oncol 2012;13:33-42. 
5. 
Paz-Ares L, Socinski MA, Shahidi J, et al. Correlation of EGFR-expression with 
safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open-label, phase III study 
of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone in the first-line 
treatment of patients with stage IV squamous non-small-cell lung cancer. Ann Oncol 2016. 
6. 
Bleeker WK, Lammerts van Bueren JJ, van Ojik HH, et al. Dual mode of action of a 
human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy. J 
Immunol 2004;173:4699-707. 
7. 
Dechant M, Weisner W, Berger S, et al. Complement-dependent tumor cell lysis 
triggered by combinations of epidermal growth factor receptor antibodies. Cancer Res 
2008;68:4998-5003. 
8. 
Srivastava RM, Lee SC, Andrade Filho PA, et al. Cetuximab-activated natural killer 
and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and 
neck cancer patients. Clin Cancer Res 2013;19:1858-72. 
9. 
Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with 
advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 
2009;373:1525-31. 
10. 
Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin 
versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous 
non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. 
Lancet Oncol 2015;16:763-74. 
11. 
Herbst R, Redman MW, Kim ES, et al. A randomized, phase III study comparing 
carboplatin/paclitaxel or carboplatin/paclitaxel/bevacizumab with or without concurrent 
cetuximab in patients with advanced non-small cell lung cancer (NSCLC): SWOG S0819.  
World Conference on Lung Cancer. Denver, CO.2015. 
12. 
Hirsch FR, Herbst RS, Olsen C, et al. Increased EGFR gene copy number detected by 
fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated 
with cetuximab and chemotherapy. J Clin Oncol 2008;26:3351-7. 
13. 
Kurai J, Chikumi H, Hashimoto K, et al. Antibody-dependent cellular cytotoxicity 
mediated by cetuximab against lung cancer cell lines. Clin Cancer Res 2007;13:1552-61. 
14. 
Genova C, Hirsch FR. Clinical potential of necitumumab in non-small cell lung 
carcinoma. Onco Targets Ther 2016;9:5427-37. 
15. 
Trivedi S, Concha-Benavente F, Srivastava RM, et al. Immune biomarkers of anti-


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
51 
 
EGFR monoclonal antibody therapy. Ann Oncol 2015;26:40-7. 
16. 
Pircher A, Gamerith G, Amann A, et al. Neoadjuvant chemo-immunotherapy 
modifies CD4(+)CD25(+) regulatory T cells (Treg) in non-small cell lung cancer (NSCLC) 
patients. Lung Cancer 2014;85:81-7. 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
52 
 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 
0
APPENDIX B 
INFORMED CONSENT 
 
ALBERT EINSTEIN COLLEGE OF MEDICINE 
MONTEFIORE MEDICAL CENTER 
 
 
DOCUMENTATION OF INFORMED CONSENT AND HIPAA AUTHORIZATION 
 
A Feasibility and Biomarker Study to Evaluate Necitumumab in the Neoadjuvant 
Setting with Gemcitabine and Cisplatin in Surgically Resectable Squamous Cell 
Lung Cancer 
 
OR 
 
Study Title for Participants: 
Testing the Addition of Necitumumab to Standard Chemotherapy with 
Gemcitabine and Cisplatin Before Surgery in Squamous Cell Lung Cancer 
 
Introduction 
You are being asked to participate in a research study called A Feasibility and 
Biomarker Study to Evaluate Necitumumab in the Neoadjuvant Setting with 
Gemcitabine and Cisplatin in Surgically Resectable Squamous Cell Lung Cancer. 
Your participation is voluntary -- it is up to you whether you would like to participate. It is 
fine to say “no” now or at any time after you have started the study. If you say “no,” your 
decision will not affect any of your rights or benefits or your access to care. 
 
The researchers in charge of this project are 
called the “Principal Investigators.” His name is 
Dr. Balazs Halmos. You can reach Dr. Halmos at:  
Office Address: 
1695 Eastchester Road, 2nd Floor 
Bronx, NY 10461 
Telephone #: 718-405-8404 
For questions about the research study, or if you 
believe you have an injury, contact the Principal 
Investigator or the IRB. 
The Institutional Review Board (IRB) of 
the Albert Einstein College of Medicine 
and Montefiore Medical Center has 
approved this research study. The IRB # 
is in the stamp in the upper right hand 
corner. If you have questions regarding 
your rights as a research subject you may 
contact the IRB office at 718-430-2253, by 
e-mail at irb@einstein.yu.edu, or by mail: 
 
Einstein IRB  
Albert Einstein College of Medicine 
1300 Morris Park Ave., Belfer Bldg #1002 
Bronx, New York 10461 
Support for this research study is provided by Eli 
Lilly. 
 
Why is this study being done?  
 
The goal of this study is to explore whether it is possible to add another drug called 
necitumumab to standard treatment for patients with squamous cell lung cancer that 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 
1
can be surgically removed. This study is important because we want to determine 
whether there is added benefit to giving necitumumab with chemotherapy before 
surgery. It is currently already known that chemotherapy given before or after surgery 
has better outcomes compared to only receiving surgery. Results from this study would 
help to develop more effective treatments for patients with squamous cell lung cancer 
like you. 
 
The U.S. Food and Drug Administration (FDA) has approved necitumumab in 
combination with chemotherapy drugs called gemcitabine and cisplatin to treat stage IV 
or metastatic squamous cell lung cancer, but the FDA has not approved necitumumab 
to treat squamous cell lung cancer that can be surgically removed. 
 
Analyzing the tumor cells from many cases of squamous cell lung cancer has shown 
that this cancer often expresses a special protein called EGFR on the tumor cell. 
Necitumumab is a type of treatment called a monoclonal antibody that specifically 
targets EGFR on cancer cells. 
 
Results from a published medical study showed that patients with stage IV or metastatic 
squamous cell lung cancer who received necitumumab with gemcitabine and cisplatin 
showed a small, but significant, improvement in survival. We believe trying to gather 
more information about the way necitumumab interacts with cancer cells will help us to 
learn how to use necitumumab more effectively. 
 
This study will allow us to see the effects of treating an earlier stage of squamous cell 
lung cancer using necitumumab with gemcitabine and cisplatin. It will also allow us to 
better analyze tumor cells after they have been treated with necitumumab and 
chemotherapy that are obtained after surgical resection. Although it is not guaranteed, 
some people who receive chemotherapy before surgery have tumor shrinkage. Other 
blood samples that will be drawn during the treatment will also allow us to see the effect 
of necitumumab on both the body and the tumor cells. We also want to observe any 
side effects that may result from this treatment. 
 
Why am I being asked to participate?  
 
You are being asked to participate in this study because you have been diagnosed with 
a type of lung cancer called Squamous Cell Lung Cancer. Your physicians have 
determined that you have stage IB (with tumor size >4cm), stage II, or IIIA disease and 
may benefit from chemotherapy prior to surgical resection. 
 
At this point, there may be other standard treatment options for patients with your 
condition. Standard of care treatment includes the option of chemotherapy prior to 
surgical resection or receiving chemotherapy after surgical resection. You are being 
offered this study because your physician thinks that a drug called necitumumab in 
addition to the standard of care of gemcitabine and cisplatin prior to surgical resection 
might have added benefit. 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 
2
How many people will take part in the research study? 
 
You will be one of about 22 people who will be participating in this study. 
 
How long will I take part in this research? 
 
It will take you about 6 months to complete this research study.  During this time, we 
will ask you to make 7 study visits to Montefiore Medical Center. 
 
What will happen if I participate in the study?   
 
The Screening Visit will take about 30 minutes.  During this visit, we will do some tests 
and procedures to see if you are eligible to take part in this research study.  The study 
doctor will review the results of these tests and procedures.  If you aren’t eligible, the 
study doctor will tell you why.  At this visit we will: 
 Ask you about your medical history 
 Give you a physical exam, including height, weight, and “vital signs” (blood 
pressure, temperature, heart and breathing rates) 
 Draw a blood sample of about two (2) tablespoons of blood to be drawn from one 
of your veins to conduct laboratory tests of blood cell counts (number of each 
type of blood cell), chemistries (elements and minerals in your blood). 
 Ask you for a urine sample 
 Test your urine for pregnancy, if you are a female able to become pregnant.  
Pregnant women cannot take part in this research study. 
 You will have a PET/CT scan, if not already done as part of your standard work 
up, to determine the extent of your disease and stage 
 If you have stage IIIA disease, we will obtain a MRI Brain to complete staging. 
 
It is possible that after these tests and procedures are reviewed, you will not be able to 
take part in the study. There may also be other reasons why you cannot participate 
which will be discussed with you by your doctor. 
 
If you are eligible for the medical study, you will begin treatment within 2 weeks. 
 
This will be a single arm medical study and all the patients in the medical study will 
receive the same kind of treatment. 
 
Treatment will be given in cycles. 
 
 You will be asked to return to the clinic once every three weeks for a visit with 
your physician during the treatment with necitumumab, gemcitabine and 
cisplatin. You will be receiving the chemotherapy over a period of about 9 weeks 
then be evaluated for surgery. 
 One cycle is three weeks (21 days). You will need to come to the clinic to receive 
the treatment. 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 
3
 You will have two (2) tubes of blood drawn prior to each chemotherapy session, 
about 2 tablespoons, to check your blood cell counts (number of each type of 
blood cell) and chemistries (elements and minerals in the blood). This blood draw 
would have been done even if you were not in this study and receiving standard 
of care chemotherapy. 
 You will have one (1) additional tube of blood drawn on day 1 of each cycle for 
research purposes to check the possible effect of necitumumab on your blood 
cells. 
 You will receive necitumumab and gemcitabine once a week during week 1 and 
week 2, and cisplatin once a week during week 1. During week 3 you will receive 
no treatment. 
 We will continue the same treatment regimen for three cycles (9 weeks). 
 Necitumumab, gemcitabine and cisplatin will be given by intravenous infusion 
through your veins. Treatment during week 1 with necitumumab, gemcitabine 
and cisplatin will last between 4-5 hours. Treatment during week 2 with 
necitumumab and gemcitabine will last between 2-3 hours. 
 After three (3) cycles of chemotherapy treatment, you will have a CT or PET/CT 
scan to determine whether you are responding to treatment (i.e. whether or not 
the tumor became smaller in size or remains stable) or not. You will then be 
evaluated by a surgeon who will recommend if you should have surgical removal 
of the remaining tumor. 
 Your treatment after the surgery will be determined by your treating physician 
and it will be influenced by your response to the treatment with necitumumab, 
gemcitabine and cisplatin. 
 
It is important to understand that taking part in this study requires a commitment from 
you to visit the clinic for the regular appointments. You may withdraw from the study at 
any time. 
 
A description of this clinical trial will be available on 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. 
 
Laboratory Research Studies 
 
If you participate in this study, your tumor tissue collected from a previous biopsy or 
surgery will be sent to researcher to determine several molecular and cellular 
biomarkers in the tumor. Researchers hope this research will help them understand how 
your disease responds to the treatment. 
 
The results of the laboratory research studies will not be sent to you or your doctor, will 
not be placed in your medical records, and will not affect your care. These tests are for 
research purposes only. 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 
4
Genetic Testing  
 
Genes are made up of DNA, and have the information needed to build and operate the 
human body. Your tumor tissue will be tested for genetic changes that may reveal 
genetic information about your tumor. The meaning of the results of this genetic 
research is not known; therefore we will not give you the results of these studies. You 
should be aware that insurance companies sometimes use information from genetic 
testing to deny life insurance or disability coverage to applicants. If you decide to 
participate in this research study, if your insurance company asks, you should state that 
although you have had a genetic test performed as part of a research study, the test is 
investigational and has no clinical meaning, and you will not be provided with the 
results. 
 
Specimen Banking (Future Use and Storage) 
 
We will store your specimens and information about you in a “biobank,” which is a 
library of information and specimens (tissue and blood) from many studies. These 
specimens and information cannot be linked to you. In the future, researchers can apply 
for permission to use the specimens and information for new studies to prevent, 
diagnose, or treat disease, including genetic research. Your specimens and information 
may be kept for a long time, perhaps longer than 50 years. If you agree to the future 
use, some of your de-identified genetic and health information (not linked to you) may 
be placed into one or more scientific databases. These may include databases 
maintained by the federal government. 
 
You can choose not to participate in the biobank and still be part of the main study and 
this will not affect your treatment at this facility. 
 
INITIAL ONE (1) OF THE FOLLOWING OPTIONS 
_______ I consent to have my specimens and information about me used for future 
research studies. 
_______ I do NOT consent to have my specimens and information about me used for 
future research studies. Information about me will be kept as long as required by 
regulations and institutional policy, but will not be used for future studies.  
 
Will I be paid for being in this research study?  
 
You will not receive any payment or other compensation for taking part in this study. 
 
Some researchers may develop tests, treatments or products that are worth money. 
You will not receive payment of any kind for your specimens and information or for any 
tests, treatments, products or other things of value that may result from the research. 
 
Will it cost me anything to participate in this study?  
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 
5
 Taking part in this study may lead to added costs to you or your insurance 
company There may be extra costs that may or may not be covered. 
 There is no cost to you for necitumumab. However, you or your insurance 
company will be paying for the costs of other necessary medications for your 
disease, routine blood tests, scans, other laboratory tests, surgical procedures 
and your routine medical care. 
 If your insurance company does not cover the cost of routine care, then you will 
have to pay these costs. You have the right to ask what it will cost you to take 
part in this study or to have other treatments. 
 You will not be charged for any research related studies like the laboratory and 
future research done on your blood or tumor tissue, if you agree. 
 
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. 
 
What will happen if I am injured because I took part in this study? 
 
If you are injured as a result of this research, only immediate, essential, short term 
medical treatment, as determined by the participating hospital or sponsoring company 
will be available for the injury without charge to you personally.  
 
 No monetary compensation will be offered. 
 You are not waiving any of your legal rights by signing this informed consent 
document 
 
Immediately report any discomforts, problems or injuries you experience during the 
course of your participation in the study to Dr. Balazs Halmos at (718) 405-8404. 
 
What else do I have to do? 
 
 You must tell the research study doctor about any past and present diseases or 
allergies you are aware of and about all medications you are taking including 
“over-the-counter” remedies and nutritional supplements or herbs. 
 If you do not feel well at any time, call your doctor or the research study doctor 
immediately.  
 Drugs may cause a reaction that, if not treated promptly, could be life-
threatening.  It is important that you report all symptoms, reactions and 
other complaints to the research study doctor.  
 If you think you have become pregnant, contact your research study doctor 
immediately.  


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 
6
 If any other doctor recommends that you take any medicine, please inform 
him/her that you are taking part in a research study. You should give the other 
doctor the research study doctor’s name and phone number. 
 You may carry out all your normal daily activities. 
 
Confidentiality 
 
We will keep your information confidential. Your research records will be kept 
confidential and your name will not be used in any written or verbal reports. Your 
information will be given a code number and separated from your name or any other 
information that could identify you. The form that links your name to the code number 
will be kept in a secure manner and only the investigator and study staff will have 
access to the file. All information will be kept in a secure manner and computer records 
will be password protected. Your study information and specimens will be kept as long 
as they are useful for this research. 
 
Medical information collected during the research, such as test results, may be entered 
into your Montefiore electronic medical record and will be available to clinicians and 
other staff at Montefiore who provide care to you. 
 
The only people who can see your research records are: 
 the research team and staff who work with them 
 the organization that funded the research 
 organizations and institutions involved in this research: Eli Lilly 
 groups that review research (the Einstein IRB, and the Office for Human 
Research Protections, and the US Food and Drug Administration) 
 
These people who receive your health information, may not be required by privacy laws 
to protect it and may share your information with others without your permission, if 
permitted by laws governing them.  All of these groups have been asked to keep your 
information confidential. 
 
Are there any risks to me?  
 
Blood Draw 
Rarely, the vein where we inserted the needle will become sore or red. Sometimes, a 
temporary harmless “black and blue” may develop. Very rarely, fainting may occur.  
 
Risks of Taking Necitumumab 
Common side effects (in 100 patients receiving necitumumab, 20 or more patients might 
experience): 
 Skin rash 
 Vomiting 
 Diarrhea 
 Low magnesium 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 
7
Less common side effects (in 100 patients receiving necitumumab, 6 to 20 patients 
might experience): 
 Loss of weight 
 Headache 
 Inflammation of the mouth or lips 
 Coughing up of blood 
 Blood clot 
 
Uncommon side effects (in 100 patients receiving necitumumab, 5 or less patients might 
experience): 
 Reaction while the drug is being infused through your vein 
 Cardiac arrest 
 Blood clot in the lung 
 Breakdown in the skin 
 
There may be other risks of necitumumab that are currently unknown. 
 
Risks of Taking Gemcitabine and Cisplatin (These drugs are part of standard 
treatment.) 
Common side effects (in 100 patients receiving gemcitabine and cisplatin, 20 or more 
patients might experience): 
 Nausea 
 Vomiting 
 Infection, especially when white blood cell count is low 
 Anemia which may require blood transfusions 
 Bruising, bleeding 
 Kidney damage, which may cause swelling, may require dialysis 
 Hearing loss including ringing in ears 
 Flu-like symptoms of muscle pain, fever, headache, chills and fatigue 
 Rash 
 Hair loss 
 Muscle weakness 
 Blood in urine 
 Feeling of “pins and needles” in arms and legs 
 Numbness and tingling of the arms and legs 
 Tiredness 
 Difficulty sleeping 
 Swelling of arms, legs 
 
Less common side effects (in 100 patients receiving gemcitabine and cisplatin, 6 to 20 
patients might experience): 
 Allergic reaction which may cause rash, low blood pressure, wheezing, shortness 
of breath, swelling of the face or throat 
 Confusion 
 Difficulty with balance 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 
8
 Diarrhea, constipation 
 Sores in mouth which may cause difficulty swallowing 
 Fluid in the organs which may cause low blood pressure, shortness of breath, 
swelling of ankles 
 Brain damage, Reversible Posterior Leukoencephalopathy Syndrome, which may 
cause headache, seizure, blindness 
 
Uncommon side effects (in 100 patients receiving necitumumab, 5 or less patients might 
experience): 
 Cancer of bone marrow (leukemia) caused by chemotherapy later in life 
 Seizure 
 Abnormal heartbeat 
 Heart failure or heart attack which may cause shortness of breath, swelling of 
ankles, and tiredness 
 Blisters on the skin 
 Sores on the skin 
 Blood clot 
 Liver damage which may cause yellowing of eyes and skin, swelling 
 Damage to organs which may cause shortness of breath 
 Scarring of the lungs 
 Fluid around lungs 
 Blockage of the airway which may cause cough 
 
Risks to Women Who Are or May Become Pregnant 
The effect of necitumumab on an embryo or fetus (developing baby still in the womb), or 
on a breastfeeding infant, is unknown and may be harmful.  Because of these unknown 
risks, women cannot take part in this study if they are: 
 Pregnant 
 Trying to become pregnant 
 Breastfeeding or sharing breast milk 
 
If you are a menopausal woman and have not had a menstrual period for the past 12 
months or more, you will not need to have a pregnancy test.  Also, you will not need to 
have a pregnancy test if you have had a hysterectomy (surgical removal of your uterus 
and/or ovaries).  All other female subjects must have a negative pregnancy test before 
starting the study drug. 
 
If you are sexually active and able to become pregnant, you must agree to use one of 
the birth control methods listed below.  You must use birth control for 3 months after 
completing necitumumab. 
 
Acceptable birth control methods for use in this study are: 
 Hormonal methods, such as birth control pills, patches, injections, vaginal ring, or 
implants 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 
9
 Barrier methods (such as a condom or diaphragm) used with a spermicide (a 
foam, cream, or gel that kills sperm) 
 Intrauterine device (IUD) 
 Abstinence (no sex) 
 
If you miss a period, or think you might be pregnant during the study, you must tell the 
study doctor immediately.  If you become pregnant, you must stop taking the study 
drug. 
 
For your safety during this study, call your study doctor BEFORE you take any: 
 New medications prescribed by your doctor 
 Other medications sold over-the-counter without a prescription 
 Dietary or herbal supplements 
 
Allergic Reaction to Study Drug 
Any drug can cause an allergic reaction which could be mild or more serious and can 
even result in death.  Common symptoms of an allergic reaction are rash, itching, skin 
problems, swelling of the face and throat, or trouble breathing.  If you are having trouble 
breathing, call 911 immediately. 
 
New Findings 
If we learn any significant new findings during the study that might influence your 
decision to participate, we will contact you and explain them. We will discuss the new 
findings with you and whether you want to continue in the study. If you decide to 
withdraw, your study doctor will make arrangements for your care to continue. If you 
decide to continue in the study, you will be asked to sign an updated consent form. 
 
Also, on receiving new information, your study doctor might consider it to be in your best 
interests to remove you from the study. He/she will explain the reasons and arrange for 
your care to continue. 
 
Unknown Risks 
We have described all the risks we know. However, because this is research, there a 
possibility that you will have a reaction that we do not know about yet and is not 
expected. If we learn about other risks, we will let you know what they are so that you 
can decide whether or not you want to continue to be in the study. 
 
Are there possible benefits to me?  
 
You may or may not receive personal, direct benefit from taking part in this study. 
Although it is not possible to predict or guarantee whether any person benefit will result 
from your participation in this study, one possible benefit is decreasing the size of your 
tumor with necitumumab followed by complete surgical resection. Although this does 
not guarantee cure, it may increase your chances of being cured or living longer. In 
addition, the information learned from this study will benefit other patients with 
squamous cell lung cancer in the future. 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 10
 
What choices do I have other than participating in this study? 
 
You can refuse to participate in the study. If you decide not to participate, the medical 
care providers at this facility will still give you all of the standard care and treatment that 
is appropriate for you.  
 
Your other choices are: 
 You may choose not to participate in this medical study and/or take part in 
another medical study. 
 You may receive chemotherapy followed by surgery. 
 You may receive surgical resection followed by either chemotherapy alone or 
chemotherapy and radiation. 
 You may receive other investigational protocols with chemotherapy that may be 
available for your disease. 
 You may choose no treatment. 
 
Please ask any questions you may have and take as much time as you need to make 
your decision. 
 
Are there any consequences to me if I decide to stop participating in this study? 
 
No. If you decide to take part, you are free to stop participating at any time without 
giving a reason. This will not affect your care and you will continue to be treated at this 
facility. However, some of the information may have already been entered into the study 
and that will not be removed. The researchers and the sponsor may continue to use and 
share the information they have already collected. 
 
To revoke (take back) your consent and authorization, you must contact the Principal 
Investigator in writing at the address on page 1 of this form. However, you may first call 
or speak to the Principal Investigator and he will stop collecting new information about 
you.  If you take back your consent and authorization, you will not be allowed to 
continue to participate in this research study.  
 
Can the study end my participation early? 
 
We will not let you participate in the study any more if: 
 Your disease becomes worse. 
 Your medical condition changes during treatment and continuing in the study 
does not appear to be in your best interest, you will be told, the treatment will be 
stopped, and other options for your medical care will be discussed with you. 
 Any severe or life-threatening side effects develop. The drugs will be stopped if 
such side effects develop and appropriate medical care will be provided. 
 Any safety issues or regulatory requirements arise that would cause the end of 
your participation in the study or that would end the study altogether. 
 You are a woman, and you become pregnant. 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 11
 
In addition, your participation will end if the investigator or study sponsor stops the study 
earlier than expected. 
 
You may stop participating at any time. However, if you decide to stop participating in 
this medical study we encourage you to talk to the study doctor first. 
 
Who can answer my questions about the study? 
 
Researcher’s Name: Dr. Balazs Halmos 
Office Address: 1695 Eastchester Road, Bronx, NY 10461 
Office Phone: 718-405-8404 
 
 If any questions arise related to this medical study, or you believe you have any 
injury related to this study, you can call the researchers above. 
 You may also call [RESEARCH NURSE]. 
 If you have questions regarding your rights as a research participant, you may 
also call the Manager of Einstein IRB at (718) 430-2253, Monday through Friday 
between 9 AM and 5 PM. 
 
CONSENT TO PARTICIPATE 
I have read the consent form and I understand that it is up to me whether or not I participate. I 
know enough about the purpose, methods, risks and benefits of the research study to decide 
that I want to take part in it. I understand that I am not waiving any of my legal rights by signing 
this informed consent document. I will be given a signed copy of this consent form. 
 
Printed name of participant 
Signature of participant 
Date 
Time 
Printed name of the person 
conducting the consent 
process 
Signature 
Date 
Time 
 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 
0
APPENDIX C 
STUDY SCHEMA FOR PARTICIPANT 
 


IRB NUMBER: 2017-8108
IRB APPROVAL DATE: 11/28/2017
IRB EXPIRATION DATE: 10/10/2018
 
 
0
APPENDIX D 
STUDY CALENDAR FOR THE PARTICIPANT 
 
Of note, treatment can sometimes be delayed for abnormal blood tests, side effects or other 
events and this schedule may need to be changed if necessary. 
 
Time 
Schedule of Treatment/Tests/Imaging/Procedure 
Pre-Study 
 Clinic visit to obtain medical history, medication list, physical exam, 
vital signs, level of activity 
 Baseline blood tests 
 Baseline EKG 
 PET/CT scan if not already completed 
 MRI Brain for stage IIIA patients only 
Week 1 
 Clinic visit for history and physical exam 
 Pre-chemotherapy blood tests and research blood test 
 Cycle 1 Day 1 of Necitumumab, Gemcitabine and Cisplatin 
Week 2 
 Pre-chemotherapy blood tests 
 Cycle 1 Day 8 of Necitumumab and Gemcitabine 
Week 3 
Week Off of Treatment 
Week 4 
 Clinic visit for history and physical exam 
 Pre-chemotherapy blood tests and research blood test 
 Cycle 2 Day 1 of Necitumumab, Gemcitabine and Cisplatin 
Week 5 
 Pre-chemotherapy blood tests 
 Cycle 2 Day 8 of Necitumumab and Gemcitabine 
Week 6 
Week Off of Treatment 
Week 7 
 Clinic visit for history and physical exam 
 Pre-chemotherapy blood tests and research blood test 
Cycle 3 Day 1 of Necitumumab, Gemcitabine and Cisplatin 
Week 8 
 Pre-chemotherapy blood tests 
 Cycle 3 Day 8 of Necitumumab and Gemcitabine 
Week 9 
Week Off of Treatment 
Week 10-12 
 Clinic visit for history and physical exam 
 Post-chemotherapy blood tests including magnesium and research 
blood test 
 Repeat PET/CT or CT Chest/Abdomen/Pelvis to evaluate for 
response 
 Re-evaluation by surgeon 
4-6 weeks after 
completing 
chemotherapy 
If the tumor has decreased in size or remained stable and you are 
medically fit, you will undergo surgical resection.  
4 weeks after 
surgery 
 Clinic visit for history and physical exam 
 Routine blood tests including magnesium levels for at least 8 weeks 
following completion of necitumumab. 
 Continued routine followup of your disease.