Conditions: EGFR Activating Mutation Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 19
Healthy volunteers: no

Brief summary:
This phase II trial studies how well targeted therapy works in treating patients with incurable non-small cell lung cancer with a genetic mutation. Giving drugs that target other genetic mutations or other specific proteins may work better when a patient has cancer caused by a driver mutation and the treatment that targets that mutation stops working.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the objective response rate among patients with high PD-L1 expressing cancers after failure of targeted therapy.

SECONDARY OBJECTIVES:

I. To compare the overall survival for patients receiving treatment targeting primary mutations, secondary mutations, or immunotherapy at the time of progression on tyrosine kinase inhibitor therapy.

II. To assess the incidence of secondary mutations in this population according to smoking status.

III. To evaluate the response rates of patients treated using these different approaches.

IV. To correlate outcomes with specific secondary genetic changes.

OUTLINE: Patients are assigned to 1 of 3 treatment arms.

ARM I (PD-L1 \>= 50%): Patients receive nivolumab intravenously (IV) over 60 minutes every 2 weeks or pembrolizumab IV every 3 weeks in the absence of disease progression or unacceptable toxicity.

ARM II (PD-L1 \< 50% without secondary oncogenic driver): Patients receive tyrosine kinase inhibitor therapy orally (PO) targeting the initial oncogenic driver or other treatment for about 3 weeks.

ARM III (PD-L1 \< 50% with secondary oncogenic driver): Patients receive tyrosine kinase inhibitor therapy PO targeting initial oncogenic driver, a drug targeting the secondary mutation, or other treatment for about 3 weeks.

After completion of study treatment, patients are followed up for a minimum of 30 days.

Arms:
arm 1: Patients receive nivolumab IV over 60 minutes every 2 weeks or pembrolizumab IV every 3 weeks in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive tyrosine kinase inhibitor therapy PO targeting the initial oncogenic driver or other treatment for about 3 weeks. arm 3: Patients receive tyrosine kinase inhibitor therapy PO targeting initial oncogenic driver, a drug targeting the secondary mutation, or other treatment for about 3 weeks.

Interventions: intervention 1: Chemotherapy intervention 2: Immunotherapy intervention 3: Laboratory Biomarker Analysis intervention 4: Nivolumab intervention 5: Pembrolizumab intervention 6: Targeted Molecular Therapy intervention 7: Tyrosine Kinase Inhibitor
Intervention descriptions: intervention 1: Receive other treatment intervention 2: Receive other treatment intervention 3: Correlative studies intervention 4: Given IV intervention 5: Given IV intervention 6: Receive drug targeting secondary mutation intervention 7: Given PO

Protocol document:
Prot_SAP_001.pdf: 
Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
 
 
Principal Investigator: 
 
W. Jeffrey Petty, MD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
wpetty@wakehealth.edu 
P 336-716-3313 
 
Co-Investigator(s):  
 
Stefan C. Grant, MBBCh, MD, JD, MBA, FACP, FACLM 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
scgrant@wakehealth.edu 
P 336-713-5172 
 
Jimmy Ruiz, MD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
jruiz@wakehealth.edu  
P 336-716-0490 
 
Kathryn Weaver, PhD 
Department of Social Sciences and Health Policy 
Wake Forest School of Medicine 
Medical Center Blvd. 
Winston-Salem, NC 27157 
keweaver@wakehealth.edu 
P 336-713-5062 
 
Kristie Foley, PhD 
Department of Social Sciences and Health Policy 
Wake Forest School of Medicine 
Medical Center Blvd. 
Winston-Salem, NC 27157 
kfoley@wakehealth.edu 
P 336-713-5084 
 
 
Payal Gandhi, PA-C 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
pgandhi@wakehealth.edu 
P 336-716-0230 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
 
 
 
Jennifer Z. Miller, PharmD, BCOP 
Cancer Center Pharmacy 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
jaziegle@wakehealth.edu 
P 336-713-3427 
 
Biostatistician: 
 
 
Ralph B. D’Agostino Jr, PhD 
Comprehensive Cancer Center of Wake Forest University 
Wake Forest School of Medicine 
Medical Center Blvd 
Winston-Salem, NC 27157 
rdagosti@wakehealth.edu 
P 336-716-9410 
 
 
Research Nurse: 
 
 
Sharon Averill 
Comprehensive Cancer Center of Wake Forest University 
Wake Forest University School of Medicine 
Medical Center Blvd 
Winston-Salem, NC 27157 
saverill@wakehealth.edu 
P 336-716-0230 
 
Study Coordinator:  
 
Meg Green 
Comprehensive Cancer Center of Wake Forest University 
Wake Forest University School of Medicine 
Medical Center Blvd 
Winston-Salem, NC 27157 
megreen@wakehealth.edu 
P 336-713-3531 
 
Regulatory Contact:  
 
Cindy Miller 
Comprehensive Cancer Center of Wake Forest University 
Wake Forest University School of Medicine 
Medical Center Blvd 
Winston-Salem, NC 27157 
cytmill@wakehealth.edu 
P 336-713-6770 
 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
 
 
Protocol Editor: 
 
 
Mac Robinson, PhD 
Comprehensive Cancer Center of Wake Forest University 
Wake Forest University School of Medicine 
Medical Center Blvd 
Winston-Salem, NC 27157 
macrobin@wakehealth.edu 
P 336-716-5096 
 
 
 
Participating Institution(s):  
WFBCCC 
 
 
Version Date: 
 
 
11-09-16 
 
Amended: 
  
 
 
10-02-17 
 
 
Confidential


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 4 of 42 
Table of Contents 
Schema ......................................................................................................................................... 6 
1.0 
Introduction and Background ............................................................................................ 7 
2.0 
Objectives ......................................................................................................................... 7 
2.1 
Primary Objective(s) ...................................................................................................... 7 
2.2 
Secondary Objective(s) ................................................................................................. 7 
3.0 
Patient Selection ............................................................................................................... 8 
3.1 
Inclusion Criteria............................................................................................................ 8 
3.2 
Exclusion Criteria .......................................................................................................... 8 
3.3 
Inclusion of Women and Minorities ............................................................................... 9 
4.0 
Registration Procedures .................................................................................................... 9 
5.0 
Study Outcomes and Study Measures ............................................................................ 10 
5.1 
Primary Outcome ........................................................................................................ 10 
5.2 
Secondary Outcomes .................................................................................................. 10 
6.0 
Treatment Plan ................................................................................................................ 11 
6.1 
Study-Related Interventions ........................................................................................ 11 
6.2 
Treatment Administration ............................................................................................ 11 
6.2.1 
Other Studies/Procedures ..................................................................................... 12 
6.2.2 
Premedication regimen and concurrent medications ............................................ 12 
6.3 
General Concomitant Medication and Supportive Care Guidelines ............................ 13 
6.4 
Duration of Therapy..................................................................................................... 13 
6.5 
Duration of Follow Up .................................................................................................. 13 
Dose Delays/Modifications .......................................................................................................... 14 
6.7 
Recommended Dose Modifications for Nivolumab (OPDIVO™) ................................ 14 
6.8 
Recommended Dose Modification for Pembrolizumab (Keytruda) ............................. 15 
7.0 
Measurement of Effect .................................................................................................... 16 
7.1 
Assessment for efficacy ............................................................................................ 16 
7.2 
Survival Outcomes .................................................................................................... 16 
8.0 
Adverse Events List and Reporting Requirements ......................................................... 16 
8.1 
Adverse Event list for Pembrolizumab ........................................................................ 16 
8.2 
Adverse Event List for Nivolumab ............................................................................... 17 
Adverse Effects ....................................................................................................................... 17 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 5 of 42 
>10% (All grades) ................................................................................................................ 17 
1-10% (all grades) ............................................................................................................... 18 
1-10% (grades 3-4) .............................................................................................................. 18 
1-10% (other clinically important adverse effects) ............................................................... 18 
8.3 
Adverse Event Characteristics .................................................................................... 18 
8.4 
STRC SAE Reporting Requirements .......................................................................... 19 
8.5 
WFUHS IRB AE Reporting Requirements .................................................................. 19 
9.0 
Pharmaceutical Information ............................................................................................ 20 
9.1 
Pharmaceutical Accountability .................................................................................... 20 
9.2 
Pembrolizumab(Keytruda) ........................................................................................... 20 
9.3 
Nivoloumab (OPDIVO) ................................................................................................ 21 
10.0 
Correlative Studies .......................................................................................................... 23 
11.0 
Data Management ........................................................................................................... 23 
12.0 
Statistical Considerations ................................................................................................ 23 
12.1 
Introduction.................................................................................................................. 23 
12.2 
Analysis of Primary Objective ...................................................................................... 24 
12.3 
Analysis of Secondary Objectives ............................................................................... 24 
12.4 
Power and Sample Size .............................................................................................. 24 
12.5 
Estimated Accrual Rate ............................................................................................... 24 
12.6 
Estimated Study Length .............................................................................................. 25 
References .................................................................................................................................. 26 
Appendix A: Subject Eligibility Checklist ..................................................................................... 27 
Appendix B: Protocol Registration Form ..................................................................................... 29 
Appendix C: Mandatory STRC SAE Reporting Guidelines ......................................................... 30 
Appendix D: Tobacco Use Case Report Form (Baseline) .......................................................... 34 
Appendix E: Tobacco Use Case Report Form (Progression) ..................................................... 35 
Appendix F: Adverse Event Log ................................................................................................. 36 
Appendix G: RECIST Measurement Form .................................................................................. 37 
Appendix H: RECIST Data Collection Form ............................................................................... 38 
Appendix I: Enrollment Mutation Case Report ............................................................................ 39 
Appendix J: Progression Mutation Case Report ......................................................................... 40 
Appendix K: Plasma/Tissue Collection ....................................................................................... 41 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 6 of 42 
Appendix L: Data Collection Form: Performance Status ............................................................ 42 
Schema 
 
Secondary oncogenic driver identified 
Continued treatment until progression 
as determined by the investigator 
No secondary oncogenic driver 
identified 
Next line of kinase 
inhibitor therapy 
targeting oncogenic 
driver or other treatment 
at the investigator’s 
discretion 
Tobacco use assessment 
PD-L1 testing 
Large scale genetic testing (Foundation preferred) 
Plan of care determined by 
Investigator classified 
Drug 
targeting 
secondary 
mutation 
Next line of kinase 
inhibitor therapy 
targeting initial 
oncogenic driver  
Other treatment at 
the investigator’s 
discretion 
PD-L1 < 50% 
PD-L1 ≥ 50% 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 7 of 42 
1.0 
Introduction and Background 
 
Lung cancer (LC) is the third most common cancer in both men and women and the 
leading cause of cancer death.1 Non-small cell (NSC) lung cancer includes three main 
subtypes, squamous cell carcinoma (25%), adenocarcinoma (40%), and large cell 
carcinoma (10%).2 Only approximately 15% of lung cancer cases are diagnosed at the 
local stage.1  
 
Major oncogenic drivers in non-small cell lung cancer include mutations in EGFR, 
translocations in Alk, and translocations in ROS-1.  National Comprehensive Cancer 
Network (NCCN) guidelines also have supported the use of medications targeting BRAF, 
Met, HER-2, and RET. Investigators have reported emergence of mutations in a 
secondary oncogenic drivers at the time of progression on tyrosine kinase inhibitor 
therapy for patients whose tumors harbor primary activating mutations in one of the 
major three (EGFR, Alk, or ROS-1) drivers. 
 
The plan of care for patients whose cancer progresses on treatment with one of the 
major 3 driver mutations may include sequencing of the primary driver gene for 
emergence of an additional mutation in that gene.  Immunotherapy may also benefit 
some patients with acquired resistance, but the role of these medications is not well 
defined.  High PD-L1 expression and response to immunotherapy has been reported in 
patients with oncogenic drivers who smoke cigarettes. 
 
The use of expanded genetic testing in this situation to identify mutations in genes other 
than the primary driver gene (secondary mutations) is attractive for exploring all 
available treatment options.  The outcomes of patients who undergo testing and have 
mutations in a secondary gene have not been prospectively studied.  Available options 
include alternative agent targeting the original driver mutation, changing treatment to 
target the mutation in the secondary gene, combination therapy targeting both, or other 
treatments such as chemotherapy, immunotherapy, or clinical trials.  
 
The goal of this protocol is to evaluate the efficacy of treatment tailored to the 
immunogenic and mutation profiles of patients on EGFR, MET, BRAF, V600E, RET, 
HER2, Alk, or ROS-1inhibitors at the time of progression.  This pilot study will compare 
the clinical outcomes for treatment of resistance targeting the primary mutations, 
secondary mutations, or immunotherapy. 
2.0 
Objectives 
2.1 
Primary Objective(s) 
 
 
2.1.1 To estimate the objective response rate among patients with high PD-L1 
expressing cancers after failure of targeted therapy. 
2.2 
Secondary Objective(s) 
 
2.2.1 To compare the overall survival for patients receiving treatment targeting 
primary mutations, secondary mutations, or immunotherapy at the time of 
progression on tyrosine kinase inhibitor therapy  


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 8 of 42 
 
2.2.2 To assess the incidence of secondary mutations in this population 
according to smoking status. 
 
2.2.3 To evaluate the response rates of patients treated using these different 
approaches. 
 
2.2.4 To correlate outcomes with specific secondary genetic changes. 
 
 
3.0 
Patient Selection 
3.1 
Inclusion Criteria  
 
3.1.1 
Patients must have histologically or cytologically confirmed incurable non-
small cell lung cancer that harbors an activating mutation in EGFR, MET, 
BRAF, V600E, RET, HER2, translocation in Alk, or translocation in ROS-1. 
 
 
 
 
 
 
 
3.1.2 
Patients must be receiving treatment or planning to start treatment with a 
tyrosine kinase inhibitor targeting the activated gene.   
 
 
 
 
3.1.3 
Patients may not be receiving the treatment targeting the activated gene as 
part of a clinical treatment trial other than the Precision Oncology Trial.  
 
3.1.4 
ECOG performance status of 0-3. 
 
3.1.5 
Patients must have normal organ function as defined below: 
 
- AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
 
3.1.6 
These agents may be teratogenic; therefore, women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or 
barrier method of birth control) prior to study entry and for the duration of 
study participation. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating 
physician immediately. 
 
3.1.7 
Ability to understand and the willingness to sign an IRB-approved informed 
consent document 
3.2 
Exclusion Criteria  
 
3.2.1 
Emergent need for palliative radiation. 
 
3.2.2 
Patients may not be receiving any other investigational agents for the 
treatment of non-small cell lung cancer. 
 
3.2.3 
Uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 9 of 42 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
3.2.4 
Pregnant women are excluded from this study because of the potential for 
teratogenic or abortifacient effects with chemotherapy. Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with chemotherapy, breastfeeding should be 
discontinued. 
3.3 
Inclusion of Women and Minorities 
 
Men and women of all races and ethnicities who meet the above-described 
eligibility criteria are eligible to participate in this study.  
 
The study consent form will also be provided in Spanish for Spanish-speaking 
participants. Based on WFBCCC population estimates, we expect approximately 
44% of participants to be women. Translating this to our sample size estimate of 
up to 75, we plan to enroll at least 33 women. We plan to enroll at least 11% 
Black or African Americans (N=8). Because of the low incidence of lung cancer in 
our catchment area in the Hispanic/Latino (.8% or possibly an N=1), Asian, and 
American Indian/Alaska native populations we would not expect to obtain 
individuals from these populations in this particular study. Should we not meet or 
exceed these estimates, the PI will engage the Cancer Center Health Equity 
Advisory Group to discuss strategies to enhance recruitment in these target 
populations. 
4.0 
Registration Procedures 
 
All patients entered on any WFBCCC trial, whether treatment, companion, or cancer control 
trial, must be registered with the WFBCCC Protocol Registrar or entered into ORIS Screening 
Log within 24 hours of Informed Consent. Patients must be registered prior to the initiation of 
treatment.   
 
You must perform the following steps in order to ensure prompt registration of your patient: 
 
1. Complete the Eligibility Checklist (Appendix A) 
2. Complete the Protocol Registration Form (Appendix B) 
3. Alert the Cancer Center registrar by phone, and then send the signed Informed 
Consent Form, Eligibility Checklist and Protocol Registration Form to the registrar, 
either by fax or e-mail. 
Contact Information: 
Protocol Registrar PHONE (336) 713-6767 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu) 
            
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday. 
 
4. Fax/e-mail ALL eligibility source documents with registration. Patients will not be 
registered without all required supporting documents. 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 10 of 42 
Note: If labs were performed at an outside institution, provide a printout of the results. 
Ensure that the most recent lab values are sent. 
 
To complete the registration process, the Registrar will:   
 
• 
assign a patient study number 
• 
register the patient on the study 
5.0 
Study Outcomes and Study Measures 
5.1 
Primary Outcome 
 
5.1.1 The primary outcome measure is the objective response rate among 
patients with high PD-L1 expressing cancers after failure of targeted 
therapy  
5.2 
Secondary Outcomes 
 
5.2.1 Overall survival (OS) of three patient cohorts (immunotherapy sensitive, 
primary targetable mutation, and secondary targetable mutation is the first 
secondary outcome.  
 
5.2.2 Objective response rates for the other patient cohorts (patients without 
high PD-L1 expressing cancers) and the combined population to historical 
controls receiving second or third line targeted agents. 
 
5.2.2 Toxicities which will be measured using CTCAE version 4.0  
 
5.2.3  Incidence of mutations in secondary genes 
 
5.2.4 Rate of tobacco use and mutation burden by patient group based on PD-
L1 expression (yes/no) at the time of progression. 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 11 of 42 
6.0 
Treatment Plan 
6.1 
Study-Related Interventions  
 
 
 
 
 
Pre-Studya 
 
At Each Treatment 
 
After First-Progression  
 
Follow-up 
 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Concurrent meds 
X 
 
 
 
Physical exam 
X 
 
X 
X 
Vital signs 
X 
 
X 
X 
Height, Weight, M2 
X 
 
 
 
Performance Status 
X 
 
X 
X 
Tumor measurements 
 
 
X 
Xd 
CBC w/diff, platelets 
X 
X 
X 
X 
Serum chemistryb 
X 
X 
X 
X 
B-HCGc 
X 
 
 
 
Adverse event evaluation 
 
X 
X 
X 
Tobacco Use Assessment 
X 
 
X 
 
Research blood (plasma) 
X 
 
X 
 
  Tumor Biopsy 
 
 
X 
 
a:    Pre-study requirements listed in table must be completed within 14 days prior to registration. 
b: 
Alkaline phosphatase, total bilirubin, BUN, calcium, creatinine, SGOT[AST], SGPT[ALT] 
c:    Serum pregnancy test (women of childbearing potential). 
d:    After the patient receives first dose of study drug they should be followed for progression on the following time line: for 
patients receiving nivolumab, imaging should be performed every 8 weeks +/- 3 days for the first two imaging 
studies.  For patients receiving pembrolizumab, imaging should be performed every 9 weeks +/- 3 days for the first two 
imaging studies.  After the first two imaging studies, additional follow-up imaging interval will be at the investigator’s 
discretion.  For patients receiving other treatments, all follow-up imaging intervals will be at the investigator’s discretion. 
6.2 
Treatment Administration 
 
Patients currently receiving or about to start treatment with an oral tyrosine kinase 
inhibitor for one of the major oncogenic drivers (EGFR, MET, BRAF, V600E, RET, 
HER2, Alk, or ROS-1) will be eligible.  At the time of registration, blood samples will be 
obtained for plasma and other biomarker analyses (Appendix J), tobacco use (Appendix 
D) and performance status (Appendix K) will be determined.  Treatment with an agent 
targeting the primary oncogenic driver will be continued until progression.  If a new agent 
is approved for treatment of the primary driver, patients may be changed prior to 
progression at the investigator’s discretion.   
 
At the time of progression, patients will undergo repeat biopsy to determine PD-L1 
staining and large scale genetic testing.  Foundation Medicine testing is preferred but 
patients may have testing performed by other platforms including Guardant 360.  Other 
platforms may be used after discussion with the principal investigator.  Research plasma 
and tissue will be collected (Appendix J). Patients will also complete a detailed tobacco 
use questionnaire at the time of progression (Appendix E). Further, Performance Status 
will be determined (Appendix K). While awaiting results of testing, patients may continue 
the current treatment targeting the primary oncogenic driver. 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 12 of 42 
If the PD-L1 testing result is ≥ 50%, patients will receive immunotherapy with either 
nivolumab or pembrolizumab as subsequent treatment.  If patients have PD-L1 testing 
result that is < 50%, the large scale testing will be used to determine the presence of 
absence of a secondary driver.  For the purposes of the study, a secondary oncogenic 
driver will be considered an activating genetic change in a gene other than the primary 
oncogenic driver gene that has an effective treatment.  These would include EGFR, Alk, 
ROS-1, MET, BRAF V600E, RET, and HER2.  Classification of a genetic alteration as a 
secondary driver will be determined by the investigator. 
 
For patients without secondary oncogenic drivers, treatment will be categorized as 
subsequent line of treatment, targeting the primary oncogenic driver, or other treatment.  
For patients with secondary oncogenic drivers, treatment will be categorized as 
treatment targeting secondary oncogenic driver, subsequent line of treatment targeting 
the primary oncogenic driver or other treatment.  Targeted treatments may include those 
treatments listed on NCCN Guidelines.  Initial medication dose and dose modifications 
should be implemented according to standard of care guidelines. 
 
Treatment will be administered on an inpatient or outpatient basis. Reported adverse 
events and potential risks are described in Section 9.0. No investigational or commercial 
agents or therapies other than those described below may be administered with the 
intent to treat the patient's malignancy. 
6.2.1 Other Studies/Procedures 
In relation to additional or optional tissue contribution for study subjects, all subjects will 
have blood taken at study entry and tumor biopsies and/or blood draws for plasma 
isolation at the time of first progression after initial driver mutation targeted therapy. If 
they choose to allow a portion of that tissue to be used for future research it will be 
stored in the below location:  
 
All samples and specimens should be shipped to: 
Wake Forest Cancer Center 
Tumor Tissue Core Facility 
Care of Dr. Greg Kucera 
Hanes Building Rm 4049 
Medical Center Blvd 
Winston-Salem NC 27157 
6.2.2 Premedication regimen and concurrent medications  
 
 
 
 
 
 
 
Anti-emetics: 
Anti-emetics should consist of standard 5HT3 antagonist 
medications at the investigators discretion.  Use of corticosteroids 
as prophylactic anti-emetics should generally be avoided and 
reasons for the use of these drugs as pre-medications should be 
documented. 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 13 of 42 
6.3 
General Concomitant Medication and Supportive Care 
Guidelines 
 
Patients should receive full supportive care, including transfusions of blood and blood 
products, erythropoietin, antibiotics, antiemetics, etc., as clinically indicated. Anti-
inflammatory or narcotic analgesics may be offered as needed. Medications considered 
necessary for the patient's well-being may be given at the discretion of the investigator, 
i.e., chronic treatments for concomitant medical conditions, as well as agents required 
for life-threatening medical problems, etc. The reason(s) for treatment, dosage, and 
dates of treatment should be recorded on the flow sheets. 
6.4 
Duration of Therapy 
 
The duration of the research treatment is through the first follow-up CT scan after the 
addition of second-line treatment with nivolumab or pembrolizumab.  Treatment may 
continue beyond this point at the investigator’s discretion.  In the absence of treatment 
delays due to adverse events, treatment may continue until one of the following criteria 
applies: 
 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), specifically if Grade 3 or 4 neurotoxicity is 
observed 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
6.5 
Duration of Follow Up 
 
Patients will be followed for a minimum of 30 days after the last study drug is 
administered for adverse events monitoring. Patients will be followed for a 
minimum of 30 days after removal from study or until death, whichever occurs 
first. Patients removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. Patients will be 
followed until death for monitoring survival study endpoints. 
 
6.6 
Criterial for Removal from Study 
 
Patients will be removed from the study when any of the criteria listed in section 
6.4 are met. 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 14 of 42 
Dose Delays/Modifications 
6.7 
Recommended Dose Modifications for Nivolumab (OPDIVO™) 
Table 1: 
Adverse 
Reaction  
Severity  
Dose Modification  
Colitis  
Grade 2 diarrhea or colitis  
Withhold dosea  
Grade 3 diarrhea or colitis  
Single-agent OPDIVO  
Withhold dosea  
OPDIVO, in combination with ipilimumab  
Permanently discontinue  
Grade 4 diarrhea or colitis  
Permanently discontinue  
Pneumonitis  
Grade 2 pneumonitis  
Withhold dosea  
Grade 3 or 4 pneumonitis  
Permanently discontinue  
Hepatitis  
Aspartate aminotransferase (AST)/or 
alanine aminotransferase (ALT) more than 
3 and up to 5 times the upper limit of 
normal or total bilirubin more than 1.5 and 
up to 3 times the upper limit of normal  
Withhold dosea  
AST or ALT more than 5 times the upper 
limit of normal or total bilirubin more than 3 
times the upper limit of normal  
Permanently discontinue  
Hypophysitis  
Grade 2 or 3 hypophysitis  
Withhold dosea  
Grade 4 hypophysitis  
Permanently discontinue  
Adrenal 
Insufficiency  
Grade 2 adrenal insufficiency  
Withhold dosea  
Grade 3 or 4 adrenal insufficiency  
Permanently discontinue  
Nephritis and 
Renal 
Dysfunction  
Serum creatinine more than 1.5 and up to 6 
times the upper limit of normal  
Withhold dosea  
Serum creatinine more than 6 times the 
upper limit of normal  
Permanently discontinue  
Rash  
Grade 3 rash  
Withhold dosea  
Grade 4 rash  
Permanently discontinue  
Encephalitis  
New onset moderate or severe neurologic 
signs or symptoms  
Withhold dosea  
Immune-mediated encephalitis  
Permanently discontinue  
Other  
Other Grade 3 adverse reaction  
First occurrence  
Withhold dosea  
Recurrence of same Grade 3 adverse 
reactions  
Permanently discontinue  
Life-threatening or Grade 4 adverse 
reaction  
Permanently discontinue  
Requirement for 10 mg per day or greater 
prednisone or equivalent for more than 12 
weeks  
Permanently discontinue  
Persistent Grade 2 or 3 adverse reactions 
lasting 12 weeks or longer  
Permanently discontinue  
a Resume Treatment when adverse reaction returns to Grade 0 or 1 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 15 of 42 
6.8 
Recommended Dose Modification for Pembrolizumab 
(Keytruda) 
Withhold KEYTRUDA for any of the following:  
Grade 2 pneumonitis [see Warnings and Precautions (5.1) of FDA insert]  
 
Grade 2 or 3 colitis [see Warnings and Precautions (5.2) of FDA insert]  
 
Grade 3 or 4 endocrinopathies [see Warnings and Precautions (5.4) of FDA insert]  
 
Grade 2 nephritis [see Warnings and Precautions (5.5) of FDA insert]  
 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and up to 5 
times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 3 times ULN  
 
Any other severe or Grade 3 treatment-related adverse reaction [see Warnings and Precautions  
(5.6) of FDA insert]  
Resume KEYTRUDA in patients whose adverse reactions recover to Grade 0-1.  
Permanently discontinue KEYTRUDA for any of the following:  
Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone 
replacement therapy) 
Grade 3 or 4 pneumonitis or recurrent pneumonitis of Grade 2 severity [see Warnings and 
Precautions (5.1) of FDA insert]   
Grade 3 or 4 nephritis [see Warnings and Precautions (5.5) of FDA insert]  
AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN  
 
For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT  
increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week   
 
Grade 3 or 4 infusion-related reactions [see Warnings and Precautions (5.7) of FDA insert]  
 
Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day 
within  
12 weeks  
 
Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy) that do not recover to Grade 0-1 within 12 weeks after last 
dose of KEYTRUDA 
  
Any severe or Grade 3 treatment-related adverse reaction that recurs [see Warnings and 
Precautions (5.6) of FDA insert] 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 16 of 42 
7.0 
Measurement of Effect 
7.1 
Assessment for efficacy 
The following efficacy parameters will be assessed by the investigator 
and are defined as follows: 
 
Objective response rate: the proportion of subjects who achieve complete 
or partial response according to the investigator’s assessment.  RECIST 
measurements should be performed by the investigator as the gold-
standard for classifying response. 
 
Duration of best response: the duration of time from the date of response 
until the first date of progression as determined by the investigator or 
death, whichever comes first 
 
Disease control rate: the percentage of subjects who achieved CR, PR, or 
SD which is sustained for at least 3 months. 
 
Duration of disease control: the duration of time from the date of first 
response until the first date or progression or death, whichever comes 
first 
7.2 
Survival Outcomes 
Progression-Free Survival is defined as the duration of time from the start of 
treatment to the time of investigator assessed progression, death, or date of last 
contact. 
 
Overall Survival is defined as the duration of time from the date of progression on 
current treatment targeting the primary oncogenic driver to date of death or date 
of last contact.  
8.0 
Adverse Events List and Reporting Requirements 
8.1 
Adverse Event list for Pembrolizumab 
 
Most common adverse reactions (reported in ≥20% of patients) with:  
• 
NSCLC included fatigue, decreased appetite, dyspnea and cough.  
 
Adverse Reactions in ≥10% of Patients with NSCLC Pembrolizumab 2 mg/kg every 3 
weeks or 10 mg/kg every 2 or 3 weeks N=550  
Adverse Reaction  
All Grades 
(%)  
Grade 3* (%)  
General Disorders and Administration Site Conditions  
Fatigue†  
44  
4  
Pyrexia  
12  
1  
Peripheral Edema  
10  
0  
Metabolism and Nutrition Disorders  


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 17 of 42 
Decreased appetite  
25  
1  
Respiratory, Thoracic and Mediastinal Disorders  
Dyspnea  
23  
4  
Cough‡  
29  
<1  
Gastrointestinal Disorders  
Nausea  
18  
1  
Diarrhea  
15  
1  
Constipation  
15  
<1  
Vomiting  
12  
1  
Musculoskeletal and Connective Tissue Disorders  
Arthralgia  
15  
1  
Back pain  
10  
2  
Blood and Lymphatic System Disorders  
Anemia  
12  
2  
Skin and Subcutaneous Tissue Disorders  
Pruritus  
12  
0  
Rash§  
18  
<1  
 
* Of the ≥10% adverse reactions, none was reported as Grade 4 or 5.  
† Includes the terms fatigue and asthenia  
‡ Includes the terms cough, productive cough and hemoptysis  
§ Includes the terms dermatitis, dermatitis acneiform, erythema multiforme, drug eruption, rash, 
rash generalized, rash pruritic, rash macular/maculopapular, papular 
 
8.2 
Adverse Event List for Nivolumab 
 
Most common adverse reactions have included fatigue, cough, nausea, pruritus, 
rash, decreased appetite, constipation, arthralgia, thyroid function abnormalities, 
and diarrhea. The most frequent serious adverse drug reactions were renal 
failure, dyspnea, and pneumonitis. Additional AEs are listed below: 
 
Adverse Effects 
>10% (All grades) 
NSCLC 
• 
Fatigue (50%) 
• 
Lymphopenia (47%) 
• 
Dyspnea, hyponatremia (38%) 
• 
Musculoskeletal pain (36%) 
• 
Cough (32%) 
• 
Nausea (29%), anemia (28%), constipation (24%) 
• 
Increases creatinine (22%) 
• 
Hypercalcemia, hypokalemia, hypomagnesemia (20%) 
• 
Vomiting, asthenia (19%) 
• 
Hypocalcemia, hyperkalemia, diarrhea (18%) 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 18 of 42 
• 
Edema, pyrexia (17%) 
• 
Abdominal pain, rash, increased AST (16%) 
• 
Increased alkaline phosphatase, thrombocytopenia (14%) 
• 
Chest pain, arthralgia, decreased appetite and weight (13%) 
• 
Increased ALT (12%), pruritus (11%) 
1-10% (all grades) 
NSCLC 
• 
Pneumonia (10%) 
• 
Pain (10%) 
1-10% (grades 3-4) 
NSCLC 
• 
Dyspnea (9%) 
• 
Fatigue (7%) 
• 
Musculoskeletal pain (6%) 
• 
Pneumonia (5%) 
• 
Decreased appetite (2.6%) 
• 
Pain (2.6%) 
• 
Nausea (1.7%) 
• 
Abdominal pain (1.7%) 
• 
Asthenia (1.7%) 
• 
Edema (1.7%) 
• 
Cough (1.7%) 
1-10% (other clinically important adverse effects) 
NSCLC 
• 
General disorders and administration site conditions: Stomatitis 
• 
Nervous system disorders: Peripheral neuropathy 
• 
Infections and infestations: Bronchitis, upper respiratory tract infection 
8.3 
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.   
 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 19 of 42 
• 
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. 
8.4 
STRC SAE Reporting Requirements 
 
The Safety and Toxicity Reporting Committee (STRC) is responsible for reviewing SAEs 
for WFBCCC Institutional studies as outlined in Appendix B. STRC currently requires 
that all unexpected 4 and all grade 5 SAEs on these trials be reported to them for 
review. All WFBCCC Clinical Research Management (CRM) staff members assisting a 
Principal Investigator in investigating, documenting and reporting an SAE qualifying for 
STRC reporting are responsible for informing a clinical member of the STRC as well as 
the entire committee via the email notification procedure of the occurrence of an SAE.  
8.5 
WFUHS IRB AE Reporting Requirements 
 
Any unanticipated problems involving risks to subjects or others and adverse events 
shall be promptly reported to the IRB, according to institutional policy. Reporting to the 
IRB is required regardless of the funding source, study sponsor, or whether the event 
involves an investigational or marketed drug, biologic or device. Reportable events are 
not limited to physical injury, but include psychological, economic and social harm. 
Reportable events may arise as a result of drugs, biological agents, devices, procedures 
or other interventions, or as a result of questionnaires, surveys, observations or other 
interactions with research subjects. 
 
All members of the research team are responsible for the appropriate reporting to the 
IRB and other applicable parties of unanticipated problems involving risk to subjects or 
others. The Principal Investigator, however, is ultimately responsible for ensuring the 
prompt reporting of unanticipated problems involving risk to subjects or others to the 
IRB. The Principal Investigator is also responsible for ensuring that all reported 
unanticipated risks to subjects and others which they receive are reviewed to determine 
whether the report represents a change in the risks and/or benefits to study participants, 
and whether any changes in the informed consent, protocol or other study-related 
documents are required. 
 
Any unanticipated problems involving risks to subjects or others occurring at a site 
where the study has been approved by the WFUHS IRB (internal events) must be 
reported to the WFUHS IRB within 7 calendar days of the investigator or other members 
of the study team becoming aware of the event. 
 
Any unanticipated problems involving risks to subjects or others occurring at another site 
conducting the same study that has been approved by the WFUHS IRB (external 
events) must be reported to the WFUHS IRB within 7 calendar days of the investigator 
or other members of the study team becoming aware of the event. 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 20 of 42 
Any event, incident, experience, or outcome that alters the risk versus potential benefit 
of the research and as a result warrants a substantive change in the research protocol or 
informed consent process/document in order to insure the safety, rights or welfare of 
research subjects. 
9.0 
Pharmaceutical Information 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 9.2 for the drugs 
listed here.  
 
For experimental or targeted drugs directed at secondary mutations, please refer to the 
FDA or Company package insert for Pharmaceutical information related to adverse 
events, preparation, administration, storage, stability and disposal. 
9.1 
Pharmaceutical Accountability 
 
Drug accountability logs will be maintained for agents used under this protocol. 
These logs shall record quantities of study drug received and quantities 
dispensed to patients, including lot number, date dispensed, patient identifier 
number, patient initials, protocol number, dose, quantity returned, balance 
remaining, and the initials of the person dispensing the medication.  
9.2 
Pembrolizumab(Keytruda) 
 
 
Product description:   
Pembrolizumab for injection: 50 mg lyophilized powder in single-use vial for 
reconstitution (3). Pembrolizumab for injection: 100 mg/4 mL (25 mg/mL) solution 
in a single-use vial. The solution should be clear to slightly opalescent, colorless 
to slightly yellow. Discard the vial if visible particles are observed 
 
Solution preparation:  
 
Reconstitution of KEYTRUDA for Injection (Lyophilized 
Powder)   
 
Add 2.3 mL of Sterile Water for Injection, USP by 
injecting the water along the walls of the vial and not 
directly on the lyophilized powder (resulting 
concentration 25 mg/mL).  
  
 
Slowly swirl the vial. Allow up to 5 minutes for the 
bubbles to clear. Do not shake the vial.  
 
Preparation for Intravenous Infusion   
 
Visually inspect the solution for particulate matter and discoloration prior 
to administration. The solution is clear to slightly opalescent, colorless to 
slightly yellow. Discard the vial if visible particles are observed.   
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
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 
Dilute KEYTRUDA injection (solution) or reconstituted lyophilized powder 
prior to intravenous administration.   
 
 
Withdraw the required volume from the vial(s) of KEYTRUDA and transfer 
into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, 
USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle 
inversion. The final concentration of the diluted solution should be 
between 1 mg/mL to 10 mg/mL.   
 
 
Discard any unused portion left in the vial 
 
Storage requirements: The product does not contain a preservative.  
Store the reconstituted and diluted solution from the KEYTRUDA 50 mg 
vial either:   
 
At room temperature for no more than 6 hours from the time 
of reconstitution. This includes room temperature storage of 
reconstituted vials, storage of the infusion solution in the IV 
bag, and the duration of infusion.  
 
 
 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 
hours from the time of reconstitution. If refrigerated, allow the diluted 
solution to come to room temperature prior to administration.  
 
 
Do not freeze 
Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial 
either:   
 
At room temperature for no more than 6 hours from the time 
of dilution. This includes room temperature storage of the 
infusion solution in the IV bag, and the duration of infusion.  
 
 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more 
than 24 hours from the time of dilution. If refrigerated, allow 
the diluted solution to come to room temperature prior to 
administration.  
 
 
Do not freeze. 
 
Stability: Keytruda is stable for no longer that 6 hours at room temperature from 
the time of reconstitution and no longer than 24 hours under refrigeration at 2°C 
to 8°C (36°F to 46°F) 
9.3 
Nivoloumab (OPDIVO) 
 
 
Product description:   
OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard 
the vial if the solution is cloudy, discolored, or contains extraneous particulate 
matter other than a few translucent-to-white, proteinaceous particles. 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 22 of 42 
OPDIVO for injection is supplied at 40 mg/4 mL and 100 mg/10 mL in a single 
use vial. 
 
Solution preparation:  
 
Withdraw the required volume of OPDIVO and transfer into an intravenous 
container.   
 
Dilute OPDIVO with either 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP to prepare 
an infusion with a final concentration ranging from 1 
mg/mL to 10 mg/mL.   
 
Mix diluted solution by gentle inversion.  
 
Do not shake.   
 
Discard partially used vials or empty vials of OPDIVO 
 
Storage requirements:  
The product does not contain a preservative. 
  
After preparation, store the OPDIVO infusion either:   
 at room temperature for no more than 4 hours from the time of 
preparation. This includes room temperature storage of the infusion in 
the IV container and time for administration of the infusion or  
  
 under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 
hours from the time of infusion preparation.  
 
 Do not freeze. 
 
Stability:   
OPDIVO is stable for no more than 4 hours at room temperature from the time of 
preparation and for no more than 24 hours under refrigeration 2°C-8°C (36°F to 
46°F) 
 
Route of administration:   
Intravenous 
 
Administration   
 
Administer the infusion over 60 minutes through an intravenous line 
containing a sterile, non-pyrogenic, low protein binding in-line filter (pore 
size of 0.2 micrometer to 1.2 micrometer). 
 
Do not coadminister other drugs through the same intravenous line.  
 
Flush the intravenous line at end of infusion. When administered in 
combination with ipilimumab, infuse OPDIVO first followed by 
ipilimumab on the same day.  
 
 
Use separate infusion bags and filters for each infusion. 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 23 of 42 
Disposal: Caution should be exercised in handling and preparing OPDIVO for 
Injection, USP. Several guidelines on this subject have been published. To 
minimize the risk of dermal exposure, always wear impervious gloves when 
handling vials containing OPDIVO for Injection, USP. Dispose through the 
Institutional waste stream and guidelines. 
10.0 Correlative Studies 
NA 
11.0 Data Management 
 
Informed consent document 
ORIS 
Patient eligibility form (Appendix A) 
ORIS 
Protocol registration form (Appendix B) 
ORIS 
Tobacco Use Case Report form: Baseline (Appendix D) 
REDCap 
Tobacco Use Case Report form: Progression (Appendix E) 
REDCap 
Adverse Event Log (Appendix F) 
ORIS 
RECIST Data collection form (Appendix H) 
REDCap 
Enrollment Mutation Case Report form (Appendix I) 
REDCap 
Progression Mutation Case Report form (Appendix J) 
REDCap 
Data Collection Form: Performance Status (Appendix L) 
REDCap 
12.0 Statistical Considerations 
12.1 Introduction 
 
By design patients will be enrolled in this study prior to the determination of their 
PD-L1 status.  In addition, among patients with low PD-L1 expression (<50%) it 
cannot be determined prospectively how many patients after disease progression 
will have a secondary oncogenic driver identified.  Thus, patients upon 
enrollment may enter one of three arms to be determined at a later time – 1) PD-
L1 expression ≥ 50%, 2) PD-L1 expression <50% with secondary oncogenic 
driver identified and 3) PD-L1 expression <50% without secondary oncogenic 
driver identified.  It is anticipated that less than 50% of patients will have PD-L1 
expression ≥ 50%, thus this arm – which is the focus of the primary objective – 
will take longer to fill.  In order to manage the overall sample size expectations of 
this study, the design will allow enrollment to continue until 15 patients are 
enrolled in the PD-L1 expression ≥ 50% arm (sample size needed based on 
Simon’s two stage design described below).  Each of the other two arms will 
allow enrollment until a minimum of 15 and maximum of 30 patients are enrolled 
into each arm.  If the maximum (n=30) is reached in either of the PD-L1 
expression < 50% arms, then new patients eligible for those arms will not be 
included in the follow-up assessments. 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 24 of 42 
12.2 Analysis of Primary Objective 
 
Objective response rate in the patients with high PD-L1 expressing cancers after 
failure of targeted therapy is the primary outcome of interest.  To examine this, a 
Simon's two-stage design (Simon, 1989) will be used. The null hypothesis that 
the true objective response rate is 10% will be tested against a one-sided 
alternative. In the first stage, 8 patients will be accrued. If there are zero 
responses in these eight patients, the study will be stopped. Otherwise, seven 
additional patients will be accrued for a total of 15. The null hypothesis will be 
rejected if 4 or more responses are observed in 15 patients. This design yields a 
type I error rate of 0.054 and power of 90.5% when the true objective response 
rate is 40%. 
12.3 Analysis of Secondary Objectives 
 
Overall survival (OS) will be determined from the date of progression on primary 
targeted treatment to death.  The three cohorts of interest, described above, will 
have OS estimated using Kaplan-Meier methods and survival rates will be 
compared using log-rank tests.   Next, objective response rates will be estimates 
in the two PD-L1 expression < 50% arms.  Confidence intervals for each of these 
rates will be estimated.  An exploratory comparison will be made among the 
three groups comparing CR/PR vs SD/PD among the groups using a Fisher’s 
exact test (for the 2x3 table).  
 
Toxicities for each group will be estimated and described using counts and 
frequencies by grade, location and relatedness.  
 
The incidence of mutations in secondary genes will be determined for patients in 
the two PD-L1 expression < 50% arms as well.  Next, we will examine whether 
smoking status (defined as Current, Former, Never) is related to the prevalence 
of any mutations identified (present/absent) using Cochran-Maentel Haenzel 
tests.  These tests will be performed overall and then separately in the three 
arms defined above 
12.4 Power and Sample Size 
 
As described above the primary power calculation for this study is based on the 
Simon two-stage design to test the null hypothesis that the objective response 
rate is 10% versus the alternative that it is 40% in the high PD-L1 expressing 
group.  With the design described above there is 90% power with a sample size 
of 15.  Furthermore, in the two other arms (with sample sizes between 15 to 30 
total patients each), we can estimate the rate of CR/PR (for objective response 
rate) with precision of ±18.7% (for n=30) or ± 26.1% (for n=15) using 2-sided 
Exact Clopper-Pearson confidence intervals.  
12.5 Estimated Accrual Rate 
 
 
It is estimated that 20 patients per year will be accrued. 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 25 of 42 
12.6 Estimated Study Length 
 
With a total sample size needed of between 45 (allowing for 15 per arm) and 75 
(allowing for up to 30 in the two PD-L1 expression < 50% arms) the study is 
expected to take at least 3 years to complete.  It is anticipated that additional 
sites may be invited to participate after the trial is open and if this occurs the total 
study length will decrease 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 26 of 42 
References 
 
1. 
SEER Cancer Statistics Review, 1975-2011. Bethesda, MD: National Cancer Institute; 
2014. 
2. 
PDQ® Non-Small Cell Lung Cancer Treatment. 08/06/14 ed. Bethesda, MD: National 
Cancer Institute. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/non-
small-cell-lung/healthprofessional. . 
3. 
Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 
1997;111:1710-7. 
4. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-
PD-1 antibody in cancer. The New England journal of medicine. Jun 28 
2012;366(26):2443-2454. 
5. 
Johnson DB, Rioth MJ, Horn L. Immune checkpoint inhibitors in NSCLC. Current 
treatment options in oncology. Dec 2014;15(4):658-669. 
 
 
 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 27 of 42 
Appendix A: Subject Eligibility Checklist 
 
 
IRB Protocol No.  00041150 
WFBCCC Protocol No. 62716 
Study Title: Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression for 
Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Principal Investigator: W. Jeff Petty, MD  
 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria is 
NOT met 
Source Used to 
Confirm * 
Patients must have histologically or 
cytologically confirmed incurable non-small 
cell lung cancer that harbors an activating 
mutation in EGFR, MET, BRAF, V600E, 
RET, HER2, translocation in Alk, or 
translocation in ROS-1 
□ 
□ 
 
Patients must be receiving treatment or 
planning to start treatment with a tyrosine 
kinase inhibitor targeting the activated gene.   
 
□ 
□ 
 
Patients may not be receiving the treatment 
targeting the activated gene as part of a 
clinical treatment trial other than the 
Precision Oncology Trial. 
□ 
□ 
 
ECOG performance status of 0-3 
□ 
□ 
 
These agents may be teratogenic; therefore, 
women of child-bearing potential and men 
must agree to use adequate contraception 
(hormonal or barrier method of birth control) 
prior to study entry and for the duration of 
study participation. Should a woman become 
pregnant or suspect she is pregnant while 
participating in this study, she should inform 
her treating physician immediately 
□ 
□ 
 
 
 
 
 
AST(SGOT)/ALT(SGPT) <2.5 X institutional 
upper limit of normal 
□ 
□ 
 
Ability to understand and the willingness to 
sign an IRB-approved informed consent 
document 
□ 
□ 
 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 28 of 42 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria is 
present 
Source Used to 
Confirm * 
Emergent need for palliative radiation 
□ 
□ 
 
Patients may not be receiving any other 
investigational agents for treatment of non-small 
cell lung cancer 
□ 
□ 
 
Uncontrolled intercurrent illness including, but not 
limited to ongoing or active infection, symptomatic 
congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study 
requirements. 
□ 
□ 
 
Pregnancy 
□ 
□ 
 
 
This subject is      
 eligible /  ineligible     for participation in this study. 
 
ORIS Assigned PID: __________________  
 
 
 
 
 
 
 
 
Signature of research professional confirming eligibility:_______________________ Date: 
_______________ 
 
Signature of Treating Physician:  _____________________________________  
Date:  _______________ 
 
Signature of Principal Investigator**:  _____________________________________  
Date:  _______________ 
 
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing 
the source, specifically state which document in the medical record was used to assess eligibility. Also 
include the date on the document. Example: “Pathology report, 01/01/14” or “Clinic note, 01/01/14” 
 
**Principal Investigator signature can be obtained following registration if needed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
ClinicalTrials.gov:  NCT02949843 
 
Protocol version date 05/17/18  
 
 
 
 
Page 29 of 42 
Appendix B: Protocol Registration Form 
 
DEMOGRAPHICS 
Patient: Last Name: _____________________ First Name: ___________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
SEX:   
  Male      Female 
Ethnicity (choose one):   Hispanic 
Non-Hispanic 
Race (choose all that 
apply): 
 WHITE           BLACK            ASIAN 
 PACIFIC ISLANDER                 NATIVE AMERICAN 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2   
 
Primary Diagnosis: ____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
 
Performance Status: ___ ___ ___    ECOG   Karnofsky 
 
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, Monday – Friday. 
 
Completed Eligibility Checklist and Protocol Registration Form must be hand delivered, faxed or e-mailed to 
the registrar at 336-7136772 or registra@wakehealth.edu. 
 
 
 
 
 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to 
registration) 
 YES   NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by ORIS): 
___ ___ ___ ___ ___ ___ ___ ___ 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers  
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
 
 
Protocol version date 04/27/17  
 
 
 
 
Page 30 of 42 
 
Appendix C: Mandatory STRC SAE Reporting Guidelines 
 
Safety and Toxicity Review Committee (STRC; 
previously known as CROC)  Serious Adverse 
Event (SAE) Notification SOP 
     Date: 6/20/2016 
 
 
Mandatory STRC SAE Reporting Requirements  
 
This document describes STRC reporting and use of the electronic submission form that is 
submitted for unexpected grade 4 and any grade 5 (death during protocol intervention) SAEs 
on CCCWFU Institutional interventional trial patients. There are multiple entities that require 
reporting of SAEs. Each entity has different rules for what is reported, and how it is reported.  
 
Rules used by other entities (Institutional Review Board (IRB), AdEERS, MedWatch, etc.) should 
NOT be used to evaluate whether an event should be reported to STRC. Only the rules for 
reporting described in this document should be considered. 
 
As defined in the NCI Data Table 4 reporting guidelines, CCCWFU Institutional Interventional 
studies covered by these reporting requirements are defined as: In-house, internally reviewed 
trials, including those collaborative studies conducted with industry sponsorship in which the 
center is a primary contributor to the design, implementation, and monitoring of the trial, or 
participation in a multi-site trial initiated by an institutional investigator at another center.  
Institutional trials are almost always authored by a researcher here at CCCWFU. Institutional 
protocols are labeled NCI Code=”I” for Institutional on the protocol screen in ORIS. Cooperative 
group protocols are not considered Institutional, but Research Base trials are classified as 
Institutional. 
 
The STRC is responsible for reviewing SAEs for CCCWFU Institutional Interventional studies, as 
defined above. STRC currently requires that unexpected grade 4 and all grade 5 SAEs on these 
trials be reported to the STRC for review. All Clinical Protocol and Data Management (CPDM) staff 
members assisting a PI in documenting and reporting an SAE that qualifies for STRC reporting are 
responsible for informing a clinical member of the STRC by phone (or in-person), followed by 
informing the entire committee via the required email notification. 
 
THESE REPORTING REQUIREMENTS APPLY TO any faculty or staff member on the study team 
for a CCCWFU Institutional Interventional trial. Once an event is observed, it is the 
responsibility of the person who observed the event to be sure that it is reported. 
 
What is considered an SAE under this mandatory procedure? 
Any unexpected grade 4 event and all grade 5 events (death during protocol intervention) 
should be reported. These events should be reported if they occur while a patient is on study 
treatment or if they occur within 30 days of last study treatment (even if patient begins a new 
treatment during the 30 days). This window of 30 days should be the standard window to be 
used in all protocols unless a specific scientific rationale is presented to suggest that a shorter 
window can be used to identify events.  In addition, if it is not clear whether the Grade 4 is 
unexpected it should be reported. 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers  
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
 
 
Protocol version date 04/27/17  
 
 
 
 
Page 31 of 42 
 
 
Table 1: Summary of STRC Reporting Requirements for Institutional Pilot, Phase 1, Phase 2  
and Phase 3 Interventional Trials  
STRC reporting may not be appropriate for specific expected adverse events for protocols. In 
those situations the adverse events that will not require STRC reporting must be specified in the 
text of the approved protocol. 
 
STRC notification responsibilities of the person handling the reporting/documenting of the 
SAE: 
1. Make a phone call (or speak in person) to the appropriate clinical member of the STRC as 
listed below (page if necessary)—see note 2 below 
2. Submit the STRC Notification Form WITHIN 24 HOURS of first knowledge of the event. This 
form is found at either the ORIS main menu page or by going to 
http://ccc.wfubmc.edu/oris/strc.aspx. 
This will ensure that all persons that need to be made aware of the event (i.e., study team 
members and STRC members) will be notified; remember to file a copy of your 
confirmation. (Form instructions will walk you through the required fields, consult the help 
page for further instructions.) 
3. Ensure that you document that the appropriate person(s) on the STRC has been contacted.  
This documentation is placed on the STRC Notification form described above. 
4. Follow up with/update the clinical member(s) of STRC regarding any new developments or 
information obtained during the course of the SAE investigation and reporting process. 
 
 
 
 
ADVERSE EVENT 
Grade 1, Grade 2, Grade 3 
 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Not Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Unlikely 
Not Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Possible 
Not Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Probable 
Not Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Definite 
Not Required 
Not 
Required 
REPORT TO 
STRC 
Not 
Required 
REPORT TO 
STRC 
REPORT TO 
STRC 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers  
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
 
 
Protocol version date 04/27/17  
 
 
 
 
Page 32 of 42 
 
Elements to complete the electronic STRC form: 
Please use ‘reply to All’ when responding with one of these terms:  Definite, Probable, 
Possible, Unlikely, or Unrelated 
1. Patient ID (ORIS PID) 
2. Patient Name 
3. Patient MR# 
4. CCCWFU(ORIS) Study Number 
5. Title 
6. PI Name 
7. PI Contact Number 
8. PI Comments 
9. STRC Clinician notified by Phone 
10. Notified Date 
11. Notified Time 
12. STRC Clinician Comments 
13. Category [This is the Grade – Either Unexpected Grade 4 or Grade 5 should be entered] 
14. Additional Information (IRB Reporting)(after discussion with PI or STRC Clinician 
i. Is This Event Related to Protocol Treatment? 
ii. Is Suspension of the Protocol Needed? 
iii. Any Changes to Consent or Protocol Needed? 
iv. Was Nature or Severity of Event Unexpected? 
15. Date of the event.  
16. Brief description (include brief clinical history relevant to this event, including therapies 
believed related to event).  
17. Date of Last Dose before event 
18. Relevant tests/labs.  
19. Other Relevant Treatment Information 
20. Other Comments/Notes (include regimen of chemo and dates the patient received them 
if known). 
21. Cc (email) (include treating Physician; separate email list with comma”,”) 
22. Your Name 
23. Your Email 
24. Confirm Your Email 
 
The Clinical Members of STRC to Notify by Phone or Page: 
 
Bayard Powell, MD – Director-at-Large, CCCWFU; Chair, PRC; Section Head, 
Hematology/Oncology.  6-7970 / 6-2701 / Pager 336-806-9308 
Antonius Miller, MD – Hematology Oncology 6-7970 / 6-7414 / Pager 704-637-8384 
Glenn Lesser, MD – Hematology Oncology 6-9527 / 6-7972 / Pager 336-806-8397 
Kathryn Greven, MD – Vice Chair – Radiation Oncology. 3-3600 / 3-6505 / Pager 336-806-
8314 
Marissa Howard-McNatt, MD – General Surgery 6-0545 / 336-806-6438 
Mercedes Porosnicu, MD- Hematology Oncology 6-7980 / 6-0230 / Pager 336-806-9150 
 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers  
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
 
 
Protocol version date 04/27/17  
 
 
 
 
Page 33 of 42 
 
Definition of Unavailable:  
As a general guideline if the first clinician that is contacted does not respond to the phone call or 
page within a reasonable amount of time, then initiate contact with their backup.  Give the 
back-up a reasonable amount of time to respond to a phone call or page before contacting 
another member. This is a general guideline.  You must use your best judgment as a clinical 
research professional given the time of day, severity of the SAE, and other circumstances as to 
when it is appropriate to contact backup clinicians.  If the event occurs near the end of day, then 
leave messages (voice or email) as appropriate and proceed with submitting your STRC 
notification form.  The important criteria is that you have taken reasonable steps to notify and 
document that you have initiated some type of contact to one or more of the clinical members 
of STRC. 
 
STRC CLINICAN RESPONSIBILITY: 
It is the responsibility of the STRC clinician to review all reported events, evaluate the events as 
they are reported; and communicate a response to the Investigator, event reporter and the 
members of STRC. The review will include but not be limited to the information reported; there 
may be times when additional information is needed in order for an assessment to be made and 
further communication directly with the investigator may be warranted. STRC reserves the right 
to agree with the investigator’s assessment if STRC does not agree with the investigator. STRC 
reserves the right to suspend the trial pending further investigation. 
Is there any immediate danger or harm that could be present for a future patient based on the 
information provided in the STRC report – and if so an immediate suspension of enrollment 
should take place. 
 
AMENDMENTS TO PREVIOUS REPORTS 
If you are not able to supply all pertinent information with the initial submission, once the 
additional information is available do not submit a new report. Go to the original email that was 
received by STRC and others “reply to all” and entitle your email “Amendment for (list date of 
event and patient ID) this will avoid duplications of the same event. List the additional 
information which you are reporting. 
 
Acronyms and Definitions 
STRC-Safety and Toxicity Review Committee 
SAE-Serious Adverse Event 
IRB-Institutional Review Board 
CCCWFU-Comprehensive Cancer Center Wake Forest University 
ORIS-Oncology Research Information System 
NCI-National Cancer Institute 
CPDM-Clinical Protocol and Data Management 
Interventional Trials-Therapeutic Level 1 and Level 2 trials 
Therapeutic Level 1-A cancer treatment protocol aimed at directly treating/curing the patient’s 
cancer. 
Therapeutic Level 2-A therapeutic protocol not cancer treatment involves clinical activity to 
treat symptoms, improve the patient’s quality of life, or prevent cancer. 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers  
Wake Forest Baptist Comprehensive Cancer Center (CCCWFU) 
CCCWFU 62716 
 
 
Protocol version date 04/27/17  
 
 
 
 
Page 34 of 42 
 
Appendix D: Tobacco Use Case Report Form (Baseline) 
 
 
CASE REPORT STUDY FORM FOR PATIENT TOBACCO USE 
TO BE USED AT BASELINE 
 
Study Number: _______________ PID: _______________ 
 
Investigator: William J. Petty, M.D. 
Date: ___________________ 
 
Research Personnel Filling out form________________________________________  
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for  
Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Comprehensive Cancer Center of Wake Forest University (WFBCCC) 
WFBCCC # 62716 
 
 
Protocol version date 04/27/17  
 
 
 
 
Page 35 of 42 
 
Appendix E: Tobacco Use Case Report Form (Progression) 
 
A CASE REPORT STUDY FORM FOR PATIENT TOBACCO USE 
TO BE USED AT PROGRESSION 
 
Study Number: _______________ PID: _______________ 
 
Investigator: William J. Petty, M.D. 
Date: ___________________ 
 
Research Personnel Filling out form________________________________________  
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression for  
Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Comprehensive Cancer Center of Wake Forest University (WFBCCC) 
WFBCCC # 62716 
 
 
Protocol version date 04/27/17  
 
 
 
 
Page 36 of 42 
 
Appendix F: Adverse Event Log 
 
WFBCCC Adverse Event (AE) Log 
PI: William J. Petty, MD 
 
PID: _________________ 
 
MRN: ________________ 
 
 
 
Cycle Start Date: _____________ 
Cycle End Date: 
_______________ 
 
Cycle #: __________ 
 
 
 
 
Adverse Event 
CTC Term 
Value 
(-5 if non-
numeric) 
Grade  
(0-5) 
per CTC 
Start 
Date 
Attribution 
1=Related 
2=Probably 
3=Possible 
4=Unlikely 
5=Unrelate
d 
Treating MD 
Initials/Date 
End 
Date 
Expecte
d 1=Yes    
0=No 
*Serious 
Adverse 
Event (SAE)   
1=Yes 
0=No 
Dose 
Limiting 
Toxitity 
(DLT) 
1=Yes 
0=No 
Action 
Taken 
1=None    
2=Tx 
withheld 
3=Tx 
D/C   
4=Tx 
adjusted 
5=Other 
Reportable
?   1=IRB  
2=STRC  
3=FDA  
4=Sponsor 
 
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
*Serious Adverse Event: Hospitalization; Disability; Birth Defect; Life-threatening; Death. 
CTCAE Version 4 - http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Comprehensive Cancer Center of Wake Forest University (WFBCCC) 
WFBCCC # 62716 
 
Protocol version date 04/27/17  
 
 
 
 
Page 37 of 42 
 
Appendix G: RECIST Measurement Form  
 
Instructions: Complete and submit this form as required by the protocol.  Do not leave any entries blank.  Enter -1 to indicate that 
an answer is unknown, unobtainable, not applicable or not done.  Retain a copy for your records and submit original to the 
WFBCCC Data Management Center. 
 
WFBCCC Study Number: __________________________               WFBCCC Patient ID: ________________________________ 
 
Patient Name: ____________________________________               MRN: ___________________________________ 
WFUHS/Affiliate: 
____________________________________________________________________________________________________ 
(Specify) 
 LIST ALL TARGET AND NON-TARGET SITES TO BE USED FOR RESPONSE: 
 
 
 
 
 
 
Date of Observation (mm/dd/yy) 
 
 
 
 
 
 
Cycle: 
 
 
 
 
 
 
TARGET LESIONS 
Response Status (CR, PR, SD, PD) 
 
 
 
 
 
 
List sites for response: 
Means of 
Evaluation 
Measurement 
Measurement 
Measurement 
Measurement 
Measurement 
Measurement 
1. 
 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
 
4. 
 
 
 
 
 
 
 
5. 
 
 
 
 
 
 
 
Total sum of LD for all Target Lesions: 
 
 
 
 
 
 
NON-TARGET LESIONS 
Response Status  
(CR, Incomplete Response/SD, PD): 
 
 
 
 
 
 
List sites for response 
Means of 
Evaluation 
 
Measurement 
Measurement 
Measurement 
Measurement 
Measurement 
Measurement 
1. 
 
 
 
 
 
 
 
2. 
 
 
 
 
 
 
 
3. 
 
 
 
 
 
 
 
4. 
 
 
 
 
 
 
 
5. 
 
 
 
 
 
 
 
6. 
 
 
 
 
 
 
 
7. 
 
 
 
 
 
 
 
Observer Signature: 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Comprehensive Cancer Center of Wake Forest University (WFBCCC) 
WFBCCC # 62716 
 
Protocol version date 04/27/17  
 
 
 
 
Page 38 of 42 
 
ORIS ID: __ __ __ __ __ __ __ __ 
 
 
Date___ ___ /___ ___ /___ ___ 
Appendix H:RECIST Data Collection Form  
 
 
 
Study Visit: 
 
 After First Progression 
 Follow-Up (8 Weeks Nivo or 9 Weeks Pembro depending upon treatment) 
 Other visit: (please specify) ________________ 
 
Date of Scan: ___ ___ /___ ___ /___ ___ 
 
Imaging Modality: 
 CT 
 PET/CT 
 MRI  
 Other____________  
 
Evaluation of Target Lesions 
 
   Complete Response (CR) 
 
   Partial Response (PR) 
 
   Progressive Disease (PD): Date of progression ___ ___ /___ ___ /___ ___ 
 
   Stable Disease (SD) 
 
   NE  
 
Evaluation of Non-Target Lesions 
 
   Complete Response (CR) 
 
   Non-CR/Non-PD 
 
   Progressive Disease (PD): Date of progression ___ ___ /___ ___ /___ ___ 
 
   NE  
 
Overall Response this Visit 
   Complete Response (CR) 
   Partial Response (PR) 
 
   Progressive Disease (PD):  Date of progression ___ ___ /___ ___ /___ ___ 
 
   Stable Disease 
 
   NE  
 
 
Treating Physician Signature: ______________________ 
Date: ___ ___ /___ ___ /___ ___ 
 
PI Signature: ___________________________________ 
Date: ___ ___ /___ ___ /___ ___ 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Comprehensive Cancer Center of Wake Forest University (WFBCCC) 
WFBCCC # 62716 
 
Protocol version date 04/27/17  
 
 
 
 
Page 39 of 42 
 
Appendix I: Enrollment Mutation Case Report 
 
CASE REPORT STUDY FORM FOR PRIMARY GENETIC DRIVER MUTATION 
TO BE USED AT ENROLLMENT 
Study Number: ______________________________ 
 
PID: _____________________________ 
 
Investigator: William J. Petty, M.D. 
 
Date: ___________________ 
 
PRIMARY DRIVER MUTATION 
EGFR  ☐  
Alk 
 ☐ 
ROS-1  ☐  
MET 
 ☐  
BRAF ☐  
V600E  ☐  
RET 
 ☐  
HER2  ☐
 
 
Test Method 
FoundationOne Testing 
 ☐ 
                     Other    ☐ 
 
Guardent360 Testing  
 ☐  
 
MEDICATION USE RELATED TO THE DRIVER MUTATION 
 
Gene Targeted Therapy? 
Yes☐  
No ☐ 
 
Name of Targeted Therapy_______________________________________ 
 
Current Dose________________________ 
 
 
Person Filling out form________________________________________ Date_____________ 
 
Physician Signature__________________________________________ Date______________ 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Comprehensive Cancer Center of Wake Forest University (WFBCCC) 
WFBCCC # 62716 
 
Protocol version date 04/27/17  
 
 
 
 
Page 40 of 42 
 
Appendix J: Progression Mutation Case Report 
 
CASE REPORT STUDY FORM FOR SECONDARY DRIVER MUTATION 
TO BE USED AT THE POINT OF DISEASE PROGRESSION 
 
Study Number: ______________________________ 
 
PID: _____________________________ 
 
Investigator: William J. Petty, M.D. 
 
 
 
Prior Agent _____________ 
 
Date: ___________________ 
 
Maximum Tolerated Dose________ 
PD-L1 STATUS
PD-L1 Score*________________  
 
*If <50% Move to Secondary Driver Mutation section 
 
 SECONDARY DRIVER MUTATION 
 
Secondary Driver Mutation Identified? 
Yes☐  
No ☐ 
 
Identity of Secondary Driver Mutation________________________ 
 
Treatment Arm Assigned:   
Arm 1(>50% PD-L1)    ☐    
Arm 2(<50% PD-L1, 2o driver)   ☐    
Arm 3 (<50% PD-L1, no 2o driver) ☐  
Test Method 
FoundationOne Testing 
 ☐ 
                     Other    ☐ 
Guardent360 Testing  
 ☐  
 
Source Evidence of Secondary Driver Mutation Status 
NCCN ☐ 
 
 
Published Paper  ☐ 
Citation________________________________ 
 
Case Study 
☐ 
       Citation_________________________________ 
 
Other_________________________________________________________ 
 
Person filling out form________________________________________ Date_____________ 
 
Physician Signature__________________________________________ Date______________ 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Comprehensive Cancer Center of Wake Forest University (WFBCCC) 
WFBCCC # 62716 
 
Protocol version date 05/17/18  
 
 
 
Page 41 of 42 
 
Appendix K: Plasma/Tissue Collection 
 
CASE REPORT STUDY FORM FOR TISSUE COLLECTION 
 
 
Study Number: ______________________________ 
 
PID: _____________________________ 
 
Investigator: William J. Petty, M.D. 
 
Date: ___________________ 
 
All tissues and plasma should be sent to the Tumor Tissue Core. 
Wake Forest Cancer Center 
Tumor Tissue Core Facility 
Care of Dr. Greg Kucera 
Hanes Building Rm 4049 
Medical Center Blvd 
Winston-Salem NC 27157 
 
 
Baseline 
 
Plasma □ 
 
Person collecting: ______________________ Time:__________ Date:_____________ 
 
 
 
Disease Progression 
 
Plasma □ 
 
Person collecting: ______________________ Time:__________ Date:_____________ 
 
 
 
 
 
 
 
 
 


Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression 
for Patients with Non-Small Cell Lung Cancers Harboring Major Oncogenic Drivers 
Comprehensive Cancer Center of Wake Forest University (WFBCCC) 
WFBCCC # 62716 
 
Protocol version date 05/17/18  
 
 
 
Page 42 of 42 
 
Appendix L: Data Collection Form: Performance Status 
 
PID: _______________________ 
Date Completed: ____ / ____ / ____ 
 
Investigator: William J. Petty, M.D. 
Study Number: __________________________ 
 
 
Visit:    
 Pre-study    
 First Progression   
 Other (Specify: _________________________________) 
 
ECOG Performance Status (Date Performed: ____ / ____ / ____) 
  0:  Fully active, able to carry on all pre-disease performance without restriction. 
  1:  Restricted in physically strenuous activity but ambulatory and able to carry out work of a  
light or sedentary nature, e.g., light house work, office work.  
  2:  Ambulatory and capable of all self-care but unable to carry out any work activities. Up  
and about more than 50% of waking hours. 
  3:  Capable of only limited self-care. Confined to bed or chair more than 50% of waking    
hours. 
  4:  Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
 
 
 
Research Personnel Filling out form________________________________________ 
Date_____________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ICF_000.pdf: 
Comprehensive Cancer Center of Wake 
Forest University (CCCWFU) CCCWFU 62716
Version:10-26-17
Page 1 of 12
Department of Comprehensive Cancer Center/Section of Hematology Oncology
PHASE II PILOT STUDY EVALUATING STRATEGIES TO OVERCOME RESISTANCE AT THE 
TIME OF PROGRESSION FOR PATIENTS WITH NON-SMALL CELL LUNG CANCERS 
HARBORING MAJOR ONCOGENIC DRIVERS
Informed Consent Form to Participate in Research
William J. Petty, M.D., Principal Investigator
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you have non-small cell lung cancer that results from a genetic change called a 
“driver mutation”.  Also, you are either being treated for this type of cancer now or will be 
starting this treatment with a special targeting treatment toward this mutation. Your participation 
is voluntary. Please take your time in making your decision as to whether or not you wish to 
participate. Ask your study doctor or the study staff to explain any words or information 
contained in this informed consent document that you do not understand. You may also discuss 
the study with your friends and family.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to find out what other treatment options work when a 
patient has cancer caused by a driver mutation and the treatment that targets that mutation stops 
working. The study is being done to find out what effects (good and bad) giving drugs that target 
other genetic mutations or other specific proteins that could contribute to your cancer 
progressing has on you and your condition.
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
75 people at Wake Forest School of Medicine will take part in this study.
WHAT IS INVOLVED IN THE STUDY?
If you qualify for this study, you will be asked to sign this form. Study staff will ask you for your 
medical history, you will receive a physical exam, your vital signs will be taken, your 
performance status will be determined (this will help indicate how the cancer is effecting your 
everyday functioning), and you will have approximately 3 teaspoons of your blood drawn. You 
will have periodic blood draws throughout the study as part of your normal care and for research 
purposes. You will continue or begin targeted treatment of your cancer until or if your cancer 
progresses. If your cancer progresses, then you will give approximately 3 teaspoons of blood  to 
determine if you qualify for therapy that stimulates your immune system, or have a biopsy of 
your tumor or give blood for genetic testing to determine if there is a second genetic mutation 
that can be targeted for treatment. Then you will be treated with these therapies (second line 
therapies) for approximately 3 weeks or as long as your doctor thinks is best.
Drugs used in this study are FDA approved.
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If you take part in this study, you will or may have the following tests and procedures:
Blood drawing
You will have approximately 3 teaspoons of blood withdrawn from a vein at every blood draw. 
At the start of the study you will have a blood draw for research purposes and for your standard 
of care. Then you will have a blood draw every 3 months or more until if/when your cancer 
progresses. At this point you will have another blood draw*. After you start the second line of 
chemotherapy for your cancer relapse or progression, you will have a blood draw 4 weeks later. 
After that you will have a blood draw again every 3 months until if/when your cancer progresses. 
The total amount of blood withdrawn during the study will depend on how long you will be in 
the study. This is a part of your normal care (standard of care) and a part of the research. 
*For research, this blood draw will be performed specifically for genetic testing and for testing 
of a particular marker that is involved in preventing your immune system from fighting your 
cancer. 
CT Scans
A CT scan may be performed if your doctor suggests it. A CT scan allows your doctor to look at 
your cancer to determine the size of the cancer. This would be a part of your standard of care.
Tissue Biopsy of your Cancer
To determine if your cancer has specific genetic mutations that cause it to progress a tissue 
biopsy may be performed if requested by your doctor. This is a part of the research purpose of 
the study. 
We can send copies of your test results to your personal physician. Even if you do not wish to 
have any of your medical information sent to your physician, you can still participate in this 
research study. 
Do you request that we send important medical findings from your study tests/exams to your 
personal physician? 
[   ] Yes
[   ] No
___________ Initials
As part of this study, a blood sample and/or tumor sample will be obtained and DNA from your 
blood or tumor sample will be purified. DNA, or deoxyribonucleic acid, stores and transmits 
inherited traits, such as eye color or blood type.  As part of this research project, your DNA will 
be studied in an effort to find out if there are genes that contribute to medical conditions that are 
part of this study. We will only be looking at genes that are known to be involved in cancer. 
Once we know what genes that may be involved from your sample, we would attempt to treat 
your cancer in a way that would target those genes.  These results will be placed in your medical 
records as they would directly influence your care and cancer treatment.
Storage of Biological Tissue
If you agree to participate in this study, we would like to use a portion of your blood or a portion of the 
tissue from your tumor biopsy to use for future research. This sample will be kept and may be used in 
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future research to learn more about other diseases.  Your sample will be obtained at the Comprehensive 
Cancer Center at Wake Forest Baptist Medical Center. The sample will be stored in the Tumor Tissue 
and Pathology Shared Resource at Wake Forest Baptist Medical Center and it will be used only by 
researchers approved by the Principal Investigator of this study, William J. Petty, M.D.  An Institutional 
Review Board (IRB) must also approve any future research study using your tissue sample. You do not 
have to allow a portion of the blood or tissue for future research outside of this study in order to 
participate in this study. 
If you would like to allow a portion of the blood or tumor tissue for future research, please indicate your 
wishes below:
____Yes, you may use a portion of my blood and tumor tissue for future research
____No, you may NOT use a portion of my blood and tumor tissue for future research
Print Name_______________________________________
Sign Name_______________________________________ Date_________________
Your blood/tissue sample will be stored de-identified, which means that no identifying 
information will be stored with it. Researchers will not know the name, date of birth, medical 
record number, social security number, etc., of the person who donated the sample.
The research that may be performed with your blood/tissue sample is not designed to help you 
specifically. There is no personal benefit to you from taking part in this aspect of the research 
study. It might help people who have diseases at some point in the future, but it is not known if 
this will happen. The results of the research performed with your blood /tissue will not be given 
to you or your doctor. The results will not be put in your medical record. The research using your 
blood/tissue sample will not affect your care.
Your blood/tissue sample will be used only for research and will not be sold. The findings from 
this research may result in the future development of products that are of commercial value. 
There are no plans to share any of the profits with you which may occur as a result of the 
research.
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for up to 3 years or until if your doctor believes you should no longer be 
in the study depending on the status of your condition. 
You can stop participating at any time. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. 
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. Risks and side effects related to the procedures, nivolumab, pembrolizumab, 
and targeted treatment drugs we are studying include:
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Risks of Targeted Treatment Drugs
In this study you will be tested for genetic changes that likely contribute to your cancer. Many 
genetic changes may be involved. There may be special drugs that can be used to treat these 
genetic changes. However, it is impossible to predict exactly which mutations and drugs will be 
used at this time. Therefore, if you have a genetic change that can be treated with a drug, your 
research staff will communicate the appropriate risks about the drugs before administering the 
drugs.
 
Risks of Nivolumab
Most common adverse reactions have included fatigue, cough, nausea, pruritus (itching), rash, 
decreased appetite, constipation, arthralgia (joint pain), thyroid function abnormalities, and 
diarrhea. The most frequent serious adverse drug reactions were renal failure, dyspnea (difficulty 
breathing), and pneumonitis. Additional AEs are listed below:
Adverse Effects
>10% (All grades)
NSCLC (Non-Small Cell Lung Cancer)

Fatigue (50%)

Lymphopenia: low lymphocytes, a white blood cell (47%)

Dyspnea (difficulty breathing), hyponatremia (low blood sodium levels) (38%)

Musculoskeletal pain (36%)

Cough (32%)

Nausea (29%), anemia (low red blood cells) (28%), constipation (24%)

Increases creatinine (22%)

Hypercalcemia (high blood calcium), hypokalemia (low potassium in the blood), 
hypomagnesemia (low magnesium in the blood) (20%)

Vomiting, asthenia (weakness, lack of energy) (19%)

Diarrhea (18%)

Edema (swelling), fever (17%)

Abdominal pain, rash, increased AST (liver enzyme associated with damage) 
(16%)

Increased alkaline phosphatase, thrombocytopenia (low level of blood platelets) 
(14%)

Chest pain, arthralgia (joint pain), decreased appetite and weight (13%)

Increased ALT (liver enzyme associated with damage) (12%), pruritus (itchy 
skin) (11%)
1-10% (all grades)
NSCLC

Pneumonia (10%)

Pain (10%)
1-10% (grades 3-4)
NSCLC

Dyspnea (difficulty breathing) (9%)

Fatigue (7%)

Musculoskeletal pain (6%)
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
Pneumonia (5%)

Decreased appetite (2.6%)

Pain (2.6%)

Nausea (1.7%)

Abdominal pain (1.7%)

Asthenia (weakness, lack of energy) (1.7%)

Edema (1.7%)

Cough (1.7%)
1-10% (other clinically important adverse effects)
NSCLC

General disorders and administration site conditions: Stomatitis

Nervous system disorders: Peripheral neuropathy

Infections and infestations: Bronchitis, upper respiratory tract infection
Risks of Pembrolizumab
 Most common adverse reactions (reported in ≥20% of patients) with: 

NSCLC included fatigue, decreased appetite, dyspnea (difficulty breathing) and cough. 
Other risks include:
Adverse Reactions in ≥10% of Patients with NSCLC 
Pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg every 2 
or 3 weeks N=550 
Adverse Reaction 
All Grades 
(%) 
Grade 3* (%) 
General Disorders and Administration Site Conditions 
Fatigue† 
44 
4 
Pyrexia (fever)
12 
1 
Peripheral Edema (swelling from 
fluid)
10 
0 
Metabolism and Nutrition Disorders 
Decreased appetite 
25 
1 
Respiratory, Thoracic and Mediastinal Disorders 
Dyspnea (difficulty breathing)
23 
4 
Cough‡ 
29 
<1 
Gastrointestinal Disorders 
Nausea 
18 
1 
Diarrhea 
15 
1 
Constipation 
15 
<1 
Vomiting 
12 
1 
Musculoskeletal and Connective Tissue Disorders 
Arthralgia (joint pain)
15 
1 
Back pain 
10 
2 
Blood and Lymphatic System Disorders 
Anemia 
12 
2 
Skin and Subcutaneous Tissue Disorders 
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Pruritus (itchy skin)
12 
0 
Rash§ 
18 
<1 
* Of the ≥10% adverse reactions, none was reported as Grade 4 or 5. 
† Includes the terms fatigue and asthenia 
‡Includes the terms cough, productive cough and hemoptysis 
§ Includes the terms dermatitis, dermatitis acneiform, erythema multiforme, drug eruption, rash, rash generalized, 
rash pruritic, rash macular/maculopapular, papular
Risks of Biopsy
An open or thoracoscopic lung biopsy is a surgical procedure that is performed under general 
anesthesia. As with any surgical procedure, complications may occur. Some possible 
complications may include, but are not limited to, the following:

Blood loss or clots

Pain or discomfort

Infection

Pneumonia
A needle or transbronchial lung biopsy is performed under light sedation and/or local anesthesia. 
Some possible complications of these procedures may include, but are not limited to, the 
following:

Pneumothorax is when air becomes trapped in the pleural space causing the lung to collapse

Bleeding in the lung

Infection
Risks of  Local Anesthesia
There may be some tingling and pain when the drug is administered, and when it is wearing off, 
and there may be some bruising, but these are usually minor.
Temporary adverse effects that affect some people include:

blurred vision, dizziness, and vomiting

headache

muscle twitching

continuing numbness, weakness, or tingling
An allergic reaction could develop hives, itching, and breathing difficulties.
If you are pregnant, or suspect that you may be pregnant, you should notify your doctor.
If the biopsy is performed using an X-ray (CT or fluoroscopy), the amount of radiation used 
during the procedure is considered minimal; therefore, the risk for radiation exposure is very 
low.
There may be other risks depending on your specific medical condition. Be sure to discuss any 
concerns with your doctor prior to the procedure.
Risks of Blood Draws
You may experience discomfort, bruising and/or bleeding where the needle is inserted. 
Occasionally some people become dizzy lightheaded or feel faint. Infection may occur on rare 
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occasions.  Frequent donation of blood can result in low iron in your blood (iron deficient 
anemia).  
Other Risks
In addition, there is a slight risk of a breach of confidentiality.  We will do our best to protect 
your confidential information.  There also may be other side effects that we cannot predict. You 
should tell the research staff about all the medications, vitamins and supplements you take and 
any medical conditions you have. This may help avoid side effects, interactions and other risks.
Taking part in this research study may involve providing information that you consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
your information safe.
Reproductive Risks and other Issues to Participating in Research
Due to known risks and potential harm to the unborn fetus, sexually active women of 
childbearing potential must use a reliable method of birth control while participating in this 
study. Reliable methods of birth control are: abstinence (not having sex), oral contraceptives, 
intrauterine device (IUD), DepoProvera, tubal ligation, or vasectomy of the partner (with 
confirmed negative sperm counts) in a monogamous relationship (same partner). An acceptable, 
although less reliable, method involves the careful use of condoms and spermicidal foam or gel 
and/or a cervical cap or sponge. We encourage you to discuss this issue further with your 
physicians if you have any questions.
Pregnant women are excluded from participation in this study. Because some methods of birth 
control are not 100% reliable, a pregnancy test is required at least 10 days from your last normal 
menstrual period, if you are a sexually active woman of childbearing potential.
Contraceptive Measures for Males
Your participation in this research study may damage your sperm, which could cause harm to a 
child that you may father while on this study. Such harm may be currently unforeseeable. If you 
are sexually active, you must agree to use a medically acceptable form of birth control in order to 
be in this study and for 2 years months afterwards. Medically acceptable contraceptives include: 
(1) surgical sterilization (such as a vasectomy), or (2) a condom used with a spermicide. 
Contraceptive measures such as Plan B (TM), sold for emergency use after unprotected sex, are 
not acceptable methods for routine use. You should inform your partner of the potential for harm 
to an unborn child. She should know that if pregnancy occurs, you will need to report it to the 
study doctor, and she should also promptly notify her doctor.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct benefit to you. We hope the 
information learned from this study will benefit other people in the future. The benefits of 
participating in this study may be: decreased or stabilized tumor size.
Based on experience with nivolumab, pembrolizumab and other targeted therapies in patients 
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with similar cancers, researchers believe it may be of benefit to subjects with your condition. 
However, because individuals respond differently to therapy, no one can know in advance if it 
will be helpful in your particular case.
WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment. You should talk to your doctor about all 
the choices you have. Instead of being in this study, you have these options:

Other chemotherapies 

Comfort care, which is an option if you decide that you do not want any more active 
treatment for your cancer. Comfort care includes pain medication and other types of 
support. It aims to maintain your comfort and dignity rather than cure disease. Usually 
this care can be provided at home. If you think you might prefer comfort care, please 
discuss this with your family, friends, and your doctor.
 
You could be treated with nivolumab or pembrolizumab even if you do not take part in the study.
WHAT ARE THE COSTS?
Taking part in this study may lead to added costs to you or your insurance company. We will 
give you an estimate of what the added cost may be based on your particular situation and 
insurance coverage.
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals.  Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others.  There is always some risk that even de-identified information might be re-identified. 
Participant information may be provided to Federal and other regulatory agencies as required.  
The Food and Drug Administration (FDA), for example, may inspect research records and learn 
your identity if this study falls within its jurisdiction.
The purpose of this research study is to obtain data or information on the safety and/or 
effectiveness of nivolumab, pembrolizumab and other targeted chemotherapy drugs; the results 
will be provided to the sponsor, the Food and Drug Administration and other federal and 
regulatory agencies as required.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a research study.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
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WILL YOU BE PAID FOR PARTICIPATING?
You will receive no payment or other compensation for taking part in this study. Parking will be 
validated for study-related visits.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by Wake Forest Baptist Medical Center Comprehensive Cancer 
Center. The sponsor is providing money or other support to Wake Forest Health Sciences to help 
conduct this study. 
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at 
.
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the insurer is required by 
law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call William J. Petty, M.D. at 
What About My Health Information?
In this research study, any new information we collect from you and information we get from 
your medical records or other facilities about your health or behaviors is considered Protected 
Health Information. The information we will collect for this research study includes:  your health 
history, how you respond to study procedures, laboratory and other test results, and physical 
examinations.
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study will be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations. 
We will make every effort to keep your Protected Health Information private. We will store 
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records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
provide required reports and to get approval for new products.  
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; the Institutional Review Board; representatives 
of Wake Forest University Health Sciences and North Carolina Baptist Hospital; representatives 
from government agencies such as the Food and Drug Administration (FDA), and the 
Department of Health and Human Services (DHHS) and similar agencies in other countries.
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
1) Monitors, auditors, IRB or other regulatory agencies will be granted direct access to the 
participant’s original medical record for verification of clinical trial procedures or data, 
without violating confidentiality of the participant and to the extent permitted by other 
applicable laws.
2) Representatives from government agencies such as the US Food and Drug 
Administration (FDA).
3) The study Principal Investigator, his staff and approved members of the laboratory and 
study team at Wake Forest Baptist Health and Wake Forest Health Sciences or 
individuals of other laboratories performing work on the project on behalf of Wake 
Forest Health Sciences and Wake Forest Baptist Medical Center.
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups it may no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for at least six years after the study is finished. At that time any 
research information not already in your medical record will either be destroyed or it will be de-
identified and any research information entered into your medical record will be kept for as long 
as your medical record is kept by the Medical Center. You will not be able to obtain a copy of 
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your Protected Health Information in the research records until all activities in the study are 
completely finished. 
You can tell William J. Petty, M.D.  that you want to take away your permission to use and share 
your Protected Health Information at any time by sending a letter to this address:
William J. Petty, M.D.
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time. 
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital.  These will be kept secure, with access to this 
information limited to individuals with proper authority, but who may not be directly involved 
with this research study.
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study 
participants. Information about your participation in the study will be placed in the NCBH 
medical record, along with any routine medical test results that were obtained at NCBH as part 
of this study. 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
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at any time. This could be for any reason (scientific or clinical) that the Investigator feels 
necessary in relation to your condition and the study.
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, William J. Petty, M.D. at 
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
.
You will be given a copy of this signed consent form. 
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent (Printed):_____________________________
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
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