Clinical trial NCT02581943
Conditions: Recurrent Non-Small Cell Lung Carcinoma Stage IIIB Non-Small Cell Lung Cancer Stage IV Non-Small Cell Lung Cancer
Sponsor: Wake Forest University Health Sciences
Start date: 2016-06-17; Completion date: 2022-12-28
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized pilot phase II trial studies the effect of pembrolizumab with or without carboplatin and paclitaxel on immune response in patients with non-small cell lung cancer that has come back or stage IIIB-IV. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pembrolizumab together with carboplatin and paclitaxel may improve immune responses in patients with non-small cell lung cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine the immune effects of single agent pembrolizumab and pembrolizumab combined with low-dose carboplatin and paclitaxel.

II. Estimate the treatment response to single agent pembrolizumab and pembrolizumab combined with low-dose carboplatin and paclitaxel.

SECONDARY OBJECTIVES:

I. Determine the toxicity and tolerability of pembrolizumab and pembrolizumab combined with low-dose carboplatin and paclitaxel.

II. Assess quality of life (QOL) in patients receiving single agent pembrolizumab and pembrolizumab combined with carboplatin and paclitaxel.

III. Assess the association between immune response and clinical response.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1.

ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1, paclitaxel IV over 1 hour and carboplatin IV over 1 hour on days 1, 7 and 14.

In both arms, courses repeat every 3 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 30 days and then every 8 weeks thereafter.

Arms: arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1. Courses repeat every 3 weeks for 2 years in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive pembrolizumab IV over 30 minutes on day 1, paclitaxel IV over 1 hour and carboplatin IV over 1 hour on days 1, 7 and 14. Courses repeat every 3 weeks for 2 years in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Carboplatin intervention 2: Laboratory Biomarker Analysis intervention 3: Paclitaxel intervention 4: Pembrolizumab intervention 5: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies intervention 3: Given IV intervention 4: Given IV intervention 5: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 1 of 83  
 
Principal Investigator: 
W. Jeff Petty, MD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
 
 
 
Co-Investigators: 
Pierre L. Triozzi, MD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
 
 
Jimmy Ruiz, M.D. 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
 
 
Thomas W. Lycan, Jr., D.O. 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
 
 
Travis L. Dotson, M.D. 
Pulmonary and Critical Care 
Wake Forest School of Medicine 
 
 
 
Christina Bellinger, M.D. 
Pulmonary and Critical Care 
Wake Forest School of Medicine 
 
 
 
Stefan Grant, MD, JD 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
 
 
Tamjeed Ahmed, M.D. 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
 
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 2 of 83  
 
 
Biostatistician: 
Ralph B. D’Agostino Jr., PhD 
Wake Forest School of Medicine 
Biostatistical Sciences - Biostatistics 
 
 
 
Study Coordinator: 
Sharon Averill, RN 
Comprehensive Cancer Center of Wake Forest University 
 
 
 
Data Manager Contact: 
Amy Hughes 
Comprehensive Cancer Center of Wake Forest University 
 
 
 
Regulatory Contact: 
Emmanuel Vazquez 
Comprehensive Cancer Center of Wake Forest University 
 
 
 
Protocol Editor (original): 
Mac Robinson, PhD 
Comprehensive Cancer Center of Wake Forest University 
 
 
 
Participating Institution: 
CCCWFU 
 
Version Date: 
03/11/2020 
07/17/19 
01/28/19 
07/20/18 
06/20/18 
09/15/17 
06/01/17 
04/10/17 
03/22/17 
01/24/17 
11/30/16 
10/18/16 
08/24/16 
06/13/16 
04/28/16 
Amended: 3/12/2021 
Confidential 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 3 of 83  
 
Contents 
SCHEMA............................................................................................................................................ 5 
1.1 
Introduction and Background .................................................................................................. 6 
1.2 
Recurrent or metastatic non-small cell lung cancer and performance status of 2 ................ 6 
1.3 
Immunotherapies.................................................................................................................. 6 
1.3.1 
Immunotherapies alone .................................................................................................... 8 
1.3.2 
Immunotherapies in combination ..................................................................................... 8 
1.4 
Study Rationale .................................................................................................................... 9 
2.1 
Objectives .............................................................................................................................. 10 
2.2 
Primary Objectives ............................................................................................................. 10 
2.3 
Secondary Objectives ......................................................................................................... 10 
3.1 
Patient Selection .................................................................................................................... 10 
3.2 
Inclusion Criteria ............................................................................................................... 10 
3.3 
Exclusion Criteria .............................................................................................................. 12 
3.4 
Inclusion of Women and Minorities .................................................................................. 13 
4.1 
Registration Procedures ......................................................................................................... 13 
5.1 
Study Outcomes and Study Measures.................................................................................... 14 
5.2 
Primary Outcomes ............................................................................................................. 14 
5.3 
Secondary Outcomes.......................................................................................................... 14 
6.1 
Treatment Plan ....................................................................................................................... 15 
6.2 
Study-Related Activities .................................................................................................... 15 
6.3 
Treatment Administration .................................................................................................. 17 
6.3.2 
Paclitaxel treatment ........................................................................................................ 18 
6.3.3 
Carboplatin treatment ..................................................................................................... 18 
6.4 
General Concomitant Medication and Supportive Care Guidelines .................................. 18 
6.5 
Duration of Therapy ........................................................................................................... 18 
6.6 
Duration of Follow Up ....................................................................................................... 19 
7.1 
Dosing Delays/Dose Modifications ....................................................................................... 19 
7.2 
Pembrolizumab dose modifications for immune-related adverse events ........................... 20 
7.3 
Pembrolizumab dose modifications for non-immune-related adverse events ................... 27 
7.5 
Paclitaxel and carboplatin dose modifications ................................................................... 29 
8.1 
Measurement of Effect .......................................................................................................... 29 
8.2 
Antitumor Effect ................................................................................................................ 29 
8.2.1 
Definitions ...................................................................................................................... 30 
8.2.2 
Methods for Evaluation of Measurable Disease............................................................. 30 
8.2.3 
Response Criteria - irRECIST ........................................................................................ 30 
8.2.4 
Assessment for efficacy ................................................................................................. 32 
8.2.5 
Survival Outcomes ......................................................................................................... 32 
9.1 
Adverse Events List and Reporting Requirements ................................................................ 32 
9.2 
Adverse Event Lists ........................................................................................................... 32 
9.3 
Adverse Event Characteristics ........................................................................................... 33 
9.4 
DSMC SAE Reporting Requirements ............................................................................... 33 
9.5 
WFUHS IRB AE Reporting Requirements ....................................................................... 33 
9.6 
Sponsor Reporting Requirements ...................................................................................... 34 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 4 of 83  
9.5.2 
Events of Clinical Interest .............................................................................................. 35 
9.5.3 
Sponsor Responsibility for Reporting Adverse Events .................................................. 36 
10.1 
Pharmaceutical Information................................................................................................... 36 
10.2 Pharmaceutical Accountability .......................................................................................... 36 
10.3 KEYTRUDA (pembrolizumab) ......................................................................................... 36 
10.4 Taxol (paclitaxel) ............................................................................................................... 38 
10.5 Carboplatin ......................................................................................................................... 39 
11.1 
Correlative Studies ................................................................................................................ 39 
11.2 Tumor Correlative Studies ................................................................................................. 39 
11.3 Blood Correlative Studies .................................................................................................. 41 
11.4 Quality of Life Correlative Studies .................................................................................... 43 
12.0  Data Management.................................................................................................................... 44 
13.2 Power, sample size, and accrual rate ................................................................................. 44 
13.3 Analysis of Primary Objective ........................................................................................... 44 
13.4 Analysis of Secondary Objectives ..................................................................................... 45 
13.5 Interim Analysis Plan ......................................................................................................... 46 
References ........................................................................................................................................ 47 
Appendix A – Protocol Registration Form ....................................................................................... 49 
Appendix C – Race & Ethnicity Verification Form ......................................................................... 55 
Appendix D – Mandatory DSMC SAE Reporting Guidelines ......................................................... 56 
Screen Shots: ............................................................................................................................ 61 
Appendix E - Tumor Response Worksheet ...................................................................................... 63 
Appendix G - Study Data Collection Form ...................................................................................... 68 
Appendix H - Follow-up Form ......................................................................................................... 69 
Appendix I - EORTC QLQ-C30 English ......................................................................................... 70 
Appendix J - EORTC QLQ-LC13 English ....................................................................................... 72 
Appendix K - EORTC QLQ-C30 Spanish ....................................................................................... 73 
Appendix M – Tumor Correlative Studies Form (Pre-Study) .......................................................... 77 
Appendix N – Blood Correlative Studies Form ................................................................................ 78 
Cellular regulators ........................................................................................................................ 78 
Soluble regulators ......................................................................................................................... 78 
Appendix O – Adverse Event Log .................................................................................................... 79 
Appendix P – Pembrolizumab Guidance Document ........................................................................ 80 
Appendix Q – ECOG Performance Status ........................................................................................ 81 
Appendix R: Response Criteria ........................................................................................................ 82 
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 5 of 83  
Study follow-up 
SCHEMA 
 
 
 
 
 
 
 
•
Pembrolizumab 200 mg q3 weeks 
•
Paclitaxel 25 mg/m   weekly 
•
Carboplatin AUC = 1 mg/mL/min weekly 
End of Treatment 
study visit 
Consent and pre-study data collection 
Randomization 
Cohort 1: Pembrolizumab alone 
Cohort 2: Pembrolizumab in combination 
•
Pembrolizumab 200 mg q3 weeks 
•
Tumor reassessment at week 8 then q12 weeks 
•
QOL survey q12 weeks 
•
Correlative blood immune studies q3 weeks prior 
to pembro admin (first 3 cycles only), and at End 
of Treatment visit 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 6 of 83  
 
1.1 
Introduction and Background 
 
1.2 
Recurrent or metastatic non-small cell lung cancer and 
performance status of 2 
 
Lung cancer is the leading cause of cancer-related death worldwide. Most 
patients with advanced non-small cell lung cancer (NSCLC) are candidates for 
chemotherapy, and first-line platinum-based combination chemotherapy is 
associated with an overall response rate of 30%, median progression-free 
survival of 4 months, and median overall survival of 8–11 months for patients 
with good performance status (PS).1 The strongest predictor of survival in 
patients with advanced NSCLC is PS (Appendix Q).2 It measures the impact of 
tumor symptoms, together with other preexisting medical problems and 
comorbidities, on a patient’s ability to function daily and for self-care. Although 
combination chemotherapy has been shown to be beneficial for patients with 
good PS, PS 0 or 1, there is still debate about its efficacy for patients with a PS 
of 2, patients who are ambulatory, capable of all self-care, up and about more 
than 50% of waking hours, but unable to carry out any work.1,3 PS 2 patients 
account for up to 30% of patients with advanced NSCLC, and no treatment is 
widely accepted as standard.4 Toxicity is the major concern when prescribing 
chemotherapy in PS 2 patients, but data are conflicting.5 It was recently shown 
that in patients with stage IV NSCLC receiving palliative chemotherapy, the 
median progression free survival was 1.5 to 2.5 months with a median overall 
survival between 2 to 4 months.6 These results were not affected by patient age. 
Interestingly, patients with PS 2 that need to discontinue chemotherapy after first 
dose due to severe toxicity have a median survival of 2.5 months and a one year 
survival of only 5%.7 The overall response rate (RR) on this specific patient 
population seems to be within the single digits (0 to 10%).8 In addition to poor 
response and survival outcomes, many palliative treatments may cause 
substantial toxicity. In summary, metastatic NSCLC with PS 2 represents a 
population with a large unmet need for new treatment options in the palliative 
setting.9 
 
1.3 
Immunotherapies 
 
The importance of intact immune surveillance in controlling outgrowth of 
neoplastic transformation has been known for decades. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer 
tissue and favorable prognosis in various malignancies. In particular, the 
presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ 
regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to 
suppress immune control. The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate 
unwanted or excessive immune responses, including autoimmune reactions. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 7 of 83  
 
PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 
and CTLA-4 which has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD L2). The structure of 
murine PD-1 has been resolved. PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine- 
based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) 
and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell 
stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the 
ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade. The mechanism by which PD-1 down modulates T-cell 
responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins. PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T- 
cells, B-cells, T regs and Natural Killer cells. Expression has also been shown 
during thymic development on CD4-CD8- (double negative) T-cells as well as 
subsets of macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and 
PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors.  Both ligands 
are type I transmembrane receptors containing both IgV- and IgC-like domains in 
the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation 
triggered through the T-cell receptor.  PD-L1 is expressed at low levels on 
various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments. 
 
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas 
PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues. 
Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in subjects with melanoma. 
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic 
intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) 
has recently been approved in the United Stated for the treatment of patients with 
unresectable or metastatic melanoma and disease progression following 
ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor.  As of 
August, 2016, Keytruda TM has been approved for the treatment of Head and 
Neck Cancer, and most recently, as of October 2016, for the treatment of Non- 
Small Cell Lung Cancer. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 8 of 83  
 
 
 
1.3.1 Immunotherapies alone 
Programmed cell death protein 1, also known as PD-1, is a 288 amino 
acid cell surface protein molecule. PD-1 has two ligands, PD-L1 and PD- 
L2, which are members of the B7 family. Several lines of evidence 
suggest that PD-1 and its ligands negatively regulate immune responses. 
Different studies have shown that the cancer microenvironment 
manipulates the PD-L1/PD-1 pathway and that the induction of PD-L1 
expression on tumor cells leads to the inhibition of immune responses 
against cancer, permitting cancer progression and metastasis.10 In a 
murine mechanistic experiment, it was shown that the induction of PD-L1 
in melanoma microenvironment is mediated by IFN-y produced by the T 
cells that are antigen experienced and therefore express PD-1.11 
 
In tumor cells, PD-L1 expression may range from 45 to 50% in NSCLC 
biopsies, irrespective of histology.12  The evidence that PD-L1 is 
commonly up-regulated in NSCLC and that PD-1 is expressed on the 
majority of tumor infiltrating lymphocytes, represented the rationale for the 
development of monoclonal antibodies against PD-L1 or PD-1, and 
several agents are currently under investigation.12,13 It has been shown 
recently, that the anti PD-1 monoclonal antibody nivolumab improves 
overall survival compared to single agent docetaxel in patients with 
metastatic NSCLC progressed to platinum-based chemotherapy and 
squamous histology. It is important to note that only patients with good 
performance status were allowed to participate in this trial; thus there is 
no data on the toxicity/efficacy profile of PD-1 check point inhibitors in 
patients with metastatic lung cancer and poor PS. The overall response 
rate to the PD-1 inhibitors nivolumab and pembrolizumab in patients with 
metastatic NSCLC (all comers) is 15 to 20%.14 The KEYNOTE-001 study 
that assessed the efficacy and safety of pembrolizumab in patients with 
advanced NSCLC showed that among all the patients, the objective 
response rate was 19.4%, and the median duration of response was 12.5 
months.23 The ORR in patients with PS 2 is not known but expected to be 
lower. Clearly new strategies are needed to improve the RR of patients 
with metastatic NSCLC and poor PS to the immune checkpoints 
inhibitors. 
 
 
1.3.2 Immunotherapies in combination 
Immune suppression mediated by myeloid derived suppressor cells 
(MDSC) and regulatory T (Treg) cells characterizes patients with 
advanced NSCLC and poor PS. Increases in these immune suppressor 
cells are also correlated with poor response to chemotherapy. Inhibiting 
PD-1 receptor/ligand interactions can abrogate the suppressive effects of 
MDSC and Treg cells but only partially.15 Several studies have shown that 
low-dose chemotherapy with taxanes and platinum compounds, alone 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 9 of 83  
 
and in combination, can reduce MDSC and Treg cells and modify the 
tumor microenvironment to promote immunogenic tumor death.16-18 Low- 
dose carboplatin and paclitaxel have been shown to enhance the 
antitumor activity of anti-PD-1 antibody in mouse models of ovarian and 
lung cancer.19 There is evidence that reductions in MDSC and Treg cells 
are involved.20 That antitumor immune responses can be promoted 
clinically with this approach was suggested by the observation that 
disease control was associated with increases in interferon-γ and 
interleukin-2 in patients with refractory ovarian cancer treated with low- 
dose carboplatin and paclitaxel.17 
 
We have examined the combination of weekly low-dose carboplatin and 
paclitaxel in combination with the anti-EGFR antibody, cetuximab, and 
have observed remarkable tumor responses and excellent tolerability in 
patient with advanced head and neck cancer and a PS of 2 (data not 
published). The ability of taxanes and platinum compounds in non- 
cytotoxic doses to block the immune-suppressive potential of MDSC and 
Treg cells represents a new therapeutic strategy for enhancing the 
efficacy of concomitant anti-PD-1 immunotherapy with pembrolizumab in 
lung cancer patients.19 The effects of pembrolizumab, alone or in 
combination with chemotherapy, on immune regulatory mechanisms in 
cancer patients with a poor PS, in general, and in patients with the highly 
immune-suppressive NSCLC, in specific, are not known. A clinical trial 
will be performed to examine these mechanisms. This trial may lead to 
improved therapy for patients with NSCLC as well as other advanced 
cancers with a poor PS. It may also lead to biomarkers of response as 
well as suggest specific interventions that can be applied to improve 
antitumor immunologic activity. 
 
1.4 
Study Rationale 
 
There remains a significant unmet medical need for additional treatment options 
for patients with recurrent or metastatic NSCLC and PS of 2. Chang et al., 
demonstrated on a mice model of ovarian cancer that with the use of dose-dense 
cisplatin+paclitaxel there is an increase immune response based on an increase 
number of IFN-γ-secreting CD14+F4/80+ macrophage and subsequent D8+IFN- 
γ+tumor-infiltrating lymphocytes.(17) We have examined a similar dose dense 
regimen based on the combination of low dose weekly carboplatin and paclitaxel 
in combination with the anti-EGFR antibody, cetuximab, and have observed 
remarkable tumor responses and excellent tolerability in patient with advanced 
head and neck small cell carcinoma (HNSCC) and poor PS.  At our institution, 
we treated 20 patients with this regimen of weekly cetuximab and carboplatin 
AUC of 1 and paclitaxel 25 mg m2. Twelve patients experienced partial response 
(60%). The median survival was 8 months for the entire cohort and 12 months for 
the responders (data not published). This preliminary data with a different 
monoclonal antibody combined with low-dose chemotherapy on a similar tumor 
model, encouraged us to move forward with the study of the same chemotherapy 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 10 of 83  
 
combination and the monoclonal antibody pembrolizumab on patient with 
NSCLC. 
 
Based upon the available non-clinical and clinical safety data, the limited survival 
benefit provided by the currently available treatment options to patients, the 
limited life expectancy due to malignant disease, and the strength of the scientific 
hypotheses under evaluation, the treatment proposed for evaluation in this study 
may have the potential to provide meaningful clinical benefit with a manageable 
safety and tolerability profile by generating higher rate and durable clinical 
responses, thereby improving quality of life (QOL) and potentially extending 
survival. Therefore, the investigation of the immune-modulatory effects of the 
combination of pembrolizumab with low dose carboplatin and paclitaxel in this 
patient population is acceptable and the benefit/risk assessment for this study is 
favorable per the proposed study design. 
 
 
2.1 
Objectives 
 
2.2 
Primary Objectives 
 
2.2.1 Determine the immune effects of single agent pembrolizumab and 
pembrolizumab combined with low-dose carboplatin and paclitaxel 
 
2.2.2 Estimate the treatment response to single agent pembrolizumab and 
pembrolizumab combined with low-dose carboplatin and paclitaxel 
 
2.3 
Secondary Objectives 
 
2.3.1 Determine the toxicity and tolerability of pembrolizumab and 
pembrolizumab combined with low-dose carboplatin and paclitaxel 
 
2.3.2 Assess QOL in patients receiving single agent pembrolizumab and 
pembrolizumab combined with carboplatin and paclitaxel 
 
2.3.3 Assess the association between immune response and clinical response 
 
 
3.1 
Patient Selection 
 
3.2 
Inclusion Criteria 
 
3.2.1 
Patients must have histologically or cytologically confirmed NSCLC that is 
advanced/metastatic (stage IIIb/IV) or recurrent (progression after surgery or 
radiation or chemo-radiation treatment for loco-regional disease). Patients 
with epidermal growth factor (EGFR) mutation, anaplastic lymphoma kinase 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 11 of 83  
 
(ALK) gene rearrangement or ROS1 translocation must have received an 
approved EGFR, ALK, or ROS1-directed therapy and have signs of disease 
progression prior to receiving pembrolizumab. 
 
3.2.2 
Patients must be willing to provide tissue from a newly obtained core or 
excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen 
obtained up to 12 weeks (84 days) prior to date of signing consent. 
 
Subjects for whom newly-obtained samples cannot be provided (e.g. 
inaccessible or subject safety concern) may submit an archived specimen 
(up to 3 years) only upon agreement from the Sponsor. At least 4 mm of 
tumor tissue will be needed for PD-L1 staining. 
 
3.2.3 
Patients who have received zero (0) to two (2) previous lines of systemic 
chemotherapy and are not currently receiving chemotherapy treatment 
(within 2 weeks of randomization). 
 
3.2.4 
At least one measurable lesion as defined by RECIST v1.1 on screening 
computed tomography (CT) or magnetic resonance imaging (MRI) 
 
3.2.5 
Age >18 years. 
 
3.2.6 
ECOG performance status of 2. 
 
3.2.7 
Patients must have normal organ and marrow function as defined below: 
 
- white blood cell count 
> 2,500 cells/mcL 
- absolute neutrophil count 
>1,500/mcL 
- platelets 
>100,000/mcL 
- hemoglobin 
≥ 9 g/dL 
- total bilirubin 
≤ 2.0 x upper limit of normal (ULN) 
- AST(SGOT)/ALT(SGPT) 
< 2.5 x ULN 
Or ≤ 5 x ULN in presence of liver 
metastases 
- creatinine 
 
within normal institutional limits 
OR 
- creatinine clearance 
> 50 mL/min for patients with creatinine 
levels above institutional normal 
- potassium 
≥ lower limit of normal 
 
3.2.8 
Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) for the 
duration of study participation and for 4 weeks after the final administration of 
study drugs. Should a woman become pregnant or suspect she is pregnant 
while participating in this study, she should inform her treating physician 
immediately. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
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3.2.9 
Ability to understand and the willingness to sign an IRB-approved informed 
consent document. 
 
3.3 
Exclusion Criteria 
 
3.3.1 
Known active (untreated) central nervous system (CNS) metastases that 
require steroids. Subjects with CNS metastases who have completed a 
course of therapy would be eligible for the study provided they are clinically 
stable for at least 2 weeks before study entry, defined as: 
• No evidence of new or enlarging CNS metastasis or new neurological 
symptoms attributable to CNS metastases. 
• Asymptomatic and receiving either no or stable doses of 
anticonvulsants and total doses of corticosteroids equivalent to 10 mg 
of prednisone or less. 
 
3.3.2 
Current or previous other malignancy within 2 years of study entry, except 
cured basal or squamous cell skin cancer, superficial bladder cancer, 
prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other 
noninvasive or indolent malignancy without sponsor approval. 
 
3.3.3 
History of previous exposure to an anti PD1/PD-L1 agent 
 
3.3.4 
Patients receiving any other investigational agents and or more than two 
different chemotherapy regimens for treatment of metastatic disease. 
 
3.3.5 
Has had prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 
Grade 1 or at baseline) from adverse events due to a previously administered 
agent. 
- 
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this 
criterion and may qualify for the study. 
 
- 
Note: If subject received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention 
prior to starting therapy. 
 
3.3.6 
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to pembrolizumab, paclitaxel or carboplatin. 
 
3.3.7 Current uncontrolled cardiac disease such as angina or myocardial infarction, 
congestive heart failure including New York Heart Association functional 
classification of 3, or arrhythmia requiring treatment. 
 
3.3.8 History of pneumonitis or active lung infection. 
 
3.3.9 
Chronic or current active infectious disease requiring systemic antibiotics, 
antifungals, or antivirals. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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3.3.10 Patients receiving chronic steroids and or immunosuppression. 
 
3.3.11 Known HIV infection, Hepatitis B virus (HBV) or hepatitis C virus (HCV) 
viremia or at risk for HBV reactivation. HBV DNA and testing for HCV RNA 
must be undetectable. At risk for HBV reactivation is defined as hepatitis B 
surface antigen positive or anti-hepatitis B core antibody positive. 
 
3.3.12 History of autoimmune disease(s). 
 
3.3.13 Psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.3.14 Any other condition or circumstance that could interfere with adherence to 
the study’s procedures or requirements, or otherwise compromise the study’s 
objectives such as history of, or any evidence of active, non-infectious 
pneumonitis. 
 
3.3.15 Has an active infection requiring systemic therapy. 
 
3.3.16 Pregnant women are excluded from this study because of the potential for 
teratogenic or abortifacient effects. Because there is an unknown but 
potential risk for adverse events in nursing infants, breastfeeding should be 
discontinued prior to study entry. 
 
3.4 
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 CCCWFU population estimates, we expect approximately 
40% of participants to be women. Translating this to our sample size estimate of 
40, we plan to enroll at least 16 women. We do not expect the percentage of 
Hispanic/Latino or racial minority lung cancer patients to be higher than the 
percentage of Hispanic or racial minority new cancer patients seen at CCCWFU 
(1.7% and 14.4%, respectively); similar to the percentage of newly diagnosed 
cancer patients, we plan to enroll at least 14% (5) racial minority patients. While 
we do not expect higher percentages than that of Hispanic/Latino newly 
diagnosed cancer patients (1.7%), we plan to enroll at least one Hispanic/Latino 
patient. 
 
 
4.1 
Registration Procedures 
 
All patients entered on any CCCWFU trial, whether treatment, companion, or cancer control 
trial, must be registered with the CCCWFU Protocol Registrar or entered into ORIS Screening 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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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 B) 
2. Complete the Protocol Registration Form (Appendix A) 
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. 
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 
• 
randomize the patient 
• 
register the patient on the study 
 
 
5.1 
Study Outcomes and Study Measures 
 
5.2 
Primary Outcomes 
 
5.2.1 Immune effects of single agent pembrolizumab and pembrolizumab 
combined with carboplatin and paclitaxel. 
 
5.2.2 Objective response rate, duration of best response, disease control rate, 
and duration of disease control, as defined by section 8.1. 
 
5.3 
Secondary Outcomes 
 
5.3.1 Toxicity and tolerability, as assessed by CTCAE version 4.0. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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5.3.2 QOL, as assessed by EORTC QLQ-30 and EORTC QLQ-LC13 
questionnaires. 
 
5.3.3 Associations between change in immune markers and treatment 
response (irCR, irPR, irSD, irPD) 
 
 
6.1 
Treatment Plan 
 
The proposed study is a randomized, two arm parallel assignment, open label, phase II, 
basic science study. The study consists of screening (≤ 14 days), subsequent treatment 
(until disease progression or treatment intolerance), and long-term follow-up. The 
enrollment period of the study is expected to be approximately 18 months. Enrollment in 
the study will end when 40 subjects have been randomized and have received at least 
one dose of therapy. The duration of participation will vary among individual subjects 
due to factors such as disease progression and time of enrollment. However, patients 
will receive active therapy up to two years if clinically indicated. Whenever possible, 
enrolled subjects should complete the study per protocol. However, individual subjects 
may withdraw from the study prematurely at any time, (e.g., subject decides to 
discontinue participation due to an adverse event). Subjects who are noncompliant with 
the study’s requirements may also be removed from the study at any time by the 
investigator. 
 
6.2 
Study-Related Activities 
 
After providing written informed consent, subjects will be screened for eligibility 
within 14 days of randomization (28 days for CT or PET/CT and 42 days for MRI) 
(Appendices A, B, and F). Qualified subjects will be staged by a CT 
chest/abdomen or CT portion of a PET/CT, and a brain MRI at baseline 
(Appendix E). 
 
Qualified subjects will be randomized 1:1 ratio to receive single agent 
pembrolizumab every three weeks or the combination of pembrolizumab every 
three weeks and low dose carboplatin and paclitaxel given on a weekly schedule. 
Randomization of all subjects will be stratified by receipt of prior systemic 
chemotherapy for recurrent metastatic disease (yes or no) and histology 
(squamous vs. non squamous). 
 
Target and non-target lesions will be followed by CT or MRI for PFS according to 
immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) at 
Week 8 (± 3 days), and every 12 weeks (± 7 days) thereafter (Appendix E). If 
there is suspicion of tumor progression at eight weeks, a second CT/MRI study 
four weeks after will need to be done as a confirmatory test (Appendix E). 
Treatment will be discontinued for subjects with confirmed radiographic disease 
progression. Upon discontinuation of treatment, subjects will complete the End of 
Treatment visit (Appendix G) and will be followed for survival (Appendix H). 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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Pre- 
Study
a 
Prior to Each 
Pembrolizumab 
Treatmentb 
Week 8(± 3 
days), then 
every 12 weeks 
(± 7 days) 
Every 12 
weeks 
Week 20 (± 3 
days), then 
every 8 weeks 
(± 7 days) 
End of 
Treatment 
visitc 
Follow- 
up 
Informed consent 
X 
Demographics 
X 
Medical historyd 
X 
Concurrent meds 
X 
X 
X 
Physical exam 
X 
X 
X 
Vital signse 
X 
X 
X 
Height (Pre-Study and EOT 
only), Weight, M2 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
Tumor measurementsf 
X 
X 
Xg 
CBC w/diff, platelets 
X 
X 
X 
Serum chemistryh 
X 
X 
X 
B-HCGi 
X 
TSH, T3, T4 
X 
Xj 
Urinalysis 
X 
X 
X 
Tumor biopsyk 
X 
Tumor correlative studiesl 
X 
Blood correlative studiesm 
Xn 
X 
Quality of Life 
questionnaireso 
X 
X 
Adverse event evaluation 
X 
X 
X 
X 
X 
X 
X 
a Pre-study requirements listed in table must be completed within 14 days prior to randomization (28 days for CT or PET/CT and 42 
days for MRI ).  Tumor correlative studies report (Appendix M) can be obtained within 28 days of randomization. 
b Appendix G. 
c if not completed within the previous 14 days, and  prior to initiation of other anti-cancer therapy. See Appendix G. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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6.3 
Treatment Administration 
 
Treatment can be administered on an inpatient or outpatient basis. Reported adverse 
events and potential risks are described in Section 9.0. Appropriate dose modifications 
for are described in Section 7.0. No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the 
patient's malignancy. Patients will receive active therapy up to two years if clinically 
indicated. 
 
REGIMEN DESCRIPTION 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
Cohort 1 
Pembrolizumab 
200 mg 
30 minute intravenous 
infusion 
Day 1 
3 weeks 
Cohort 2 
Pembrolizumab 
200 mg 
30 minute intravenous 
infusion at least 1 hour prior 
to administration of paclitaxel 
and carboplatin 
Day 1 
3 weeks 
Paclitaxel 
25 mg/m2 
1 hour intravenous infusion 
beginning at least 1 hour after 
the completion of 
pembroluzumab 
Days 1, 8 and 
15 
Carboplatin 
AUC = 1 
mg/mL/min 
1 hour intravenous infusion 
following completion of 
paclitaxel 
Days 1, 8 and 
15 for 4 cycles 
(12 weeks) 
 
6.3.1 Pembrolizumab treatment 
Pembrolizumab will be given every three weeks with a dose of 200 mg on 
Cycle 1 Day 1 (C1D1) and every three weeks thereafter. Patients will 
d  Including history of prior anticancer interventions and histological or cytological confirmation of NSLC. 
e  temperature, T; blood pressure, BP; respiration rate, RR; heart rate, HR. 
f  Appendix E.  Qualified subjects will be staged by a CT chest/abdomen or CT portion of a PET/CT (within 28 days of randomization, 
and a brain MRI (within 42 days prior to randomization). 
g  for subjects who have not had an imaging study within the previous 4 weeks. 
h  total bilirubin, BUN, creatinine, creatinine clearance, potassium, SGOT[AST], SGPT[ALT]. 
i  Serum pregnancy test (women of childbearing potential). 
j Prior to each infusion of pembrolizumab only. 
k A  fresh  tumor  tissue  sample  should  be  collected  prior  to  enrollment  for  patients.  See  Inclusion  Criteria  3.1.2  for  additional 
information. 
l Appendix M. 
m Section 11.2 and Appendix N. 
n  prior to receiving the first dose of  pembrolizumab treatment (C1D1), and on C2D1 and C3D1 prior to pembrolizumab treatment
administration. Twenty (20) ml of blood is to be collected in two EDTA-containing vacutainers and sent to Dr. Triozzi’s laboratory,
Room 5029, Hanes Building. 
o  Appendices I – L. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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receive active therapy up to two years if clinically indicated. The drug will 
be administered as a 30 minutes intravenous (IV) infusion. 
 
6.3.2 Paclitaxel treatment 
Subjects assigned to the combination therapy will receive Paclitaxel 25 
mg/m2 as a 1 hour infusion on C1D1 and then weekly. Paclitaxel 
administration should begin ≥ 1 hour following completion of 
Pembrolizumab administration. Patients will receive active therapy up to 
two years if clinically indicated 
 
6.3.3 Carboplatin treatment 
Subjects assigned to the combination therapy will receive Carboplatin at 
an AUC of 1 mg/mL/min as a 1 hour infusion on C1D1 and then weekly. 
Carboplatin administration should begin following completion of Paclitaxel 
administration. The carboplatin dose will be based upon the subject’s 
screening glomerular filtration rate (GFR) in mL/min. The Calvert formula 
will be used for carboplatin dosing: 
Total Dose (mg) = (target AUC) x (GFR + 25). The carboplatin dose will 
be capped at 150 mg. 
Patients will receive active therapy up to 12 weeks if clinically indicated 
 
 
6.4 
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. 
 
6.5 
Duration of Therapy 
 
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 toxicity related to the administration of the study required 
medications, 
• 
Patient lost to follow-up after repeated attempts to contact, 
• 
Onset of an adverse event that would make ongoing treatment in the current 
clinical trial inadvisable, as deemed by the investigator, medical monitor, or 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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study sponsor ( there will be no limit in the number of treatment cycles a 
patient can receive), 
• 
Patient decides to withdraw from the study, 
• 
Patient non-compliance with the study’s requirements and/or procedures, as 
determined by the investigator, medical monitor, or study sponsor, or 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
• 
Patient completed two years of therapy. 
 
In the event a subject is withdrawn from treatment prematurely, the End of 
Treatment evaluations should be completed, and the subject should be followed 
for survival, if possible. 
 
6.6 
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 every 8 weeks until death for monitoring survival study 
endpoints, including vital status, disease state, and initiation of any new 
anticancer interventions (Appendix H). 
 
 
7.1 
Dosing Delays/Dose Modifications 
 
In order to maintain dose-intensity and cumulative dose-delivery, reasonable efforts 
should be made to minimize dose reductions and treatment delays. Any subject whose 
treatment is delayed should be evaluated on a weekly basis until adequate hematologic 
and non-hematologic parameters have been met. 
 
Toxicities may require the dose reduction of one or more of the study required 
medications. The investigator will carefully assess all treatment-associated toxicities 
and, whenever possible, determine if the toxicities can reasonably be attributed to a 
single agent or a causal relationship with one of the agents can reasonably be ruled out. 
If appropriate, dose reductions should not affect the dose of other products. 
 
• 
Toxicity grades are defined using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 
• 
Any subject who requires a dose reduction due to drug-related toxicity will 
continue to receive the reduced dose for the remainder of study treatment 
• 
Dose escalations are not allowed 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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7.2 
Pembrolizumab dose modifications for immune-related adverse 
events 
 
For the general management of immune-related adverse events due to 
pembrolizumab consider: 
1) Patient evaluation to identify any alternative etiology. 
2) In the absence of a clear alternative etiology, all events of an inflammatory 
nature should be considered to be immune-related. 
3) Symptomatic and topical therapy should be considered for low-grade events. 
4) Systemic corticosteroids should be considered for a persistent low-grade 
event or for a severe event. 
5) More potent immunosuppressives should be considered for events not 
responding to systemic steroids. 
 
See table below for organ specific dose adjustments and management of 
pembrolizumab immune-related adverse effects. 
 
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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7.3 
Pembrolizumab dose modifications for non-immune-related 
adverse events 
 
Dose modifications are not required for adverse events that are not deemed to 
be related to study treatment (ie events due to underlying disease) or for 
laboratory abnormalities not deemed to be clinically significant. 
 
Grade 1: No dose modification. 
 
Grade 2: Hold Pembrolizumab dose until resolution to Grade ≤1 or baseline. 
Grade 3: Hold Study Regimen until resolution to Grade ≤ 1 or baseline. 
For adverse events that downgrade to Grade ≤ 2 within 7 days or resolve to 
Grade ≤1 or baseline within 14 days, resume Pembrolizumab administration at 
next scheduled dose. Otherwise, discontinue Pembrolizumab. 
 
Grade 4: Discontinue Pembrolizumab 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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7.4 
Management of infusion reactions related to Pembrolizumab 
Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion. See table 
below for infusion reaction treatment guidelines. 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr). Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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7.5 
Paclitaxel and carboplatin dose modifications 
 
 
 
7.6 
Chemotherapy-induced nausea and vomiting 
Nausea and vomiting may be acute (onset 1–4 hours after infusion) or 
delayed (begins or persists ≥ 24 hours after infusion). To combat 
chemotherapy-induced nausea and vomiting, the following algorithm 
should be used: 
 
a) Nonsteroidal anti-emetics, such as a 5-HT3 antagonist (e.g., 
ondansetron), should be utilized for first-line management of 
symptoms 
b) If dexamethasone on Day 1 followed by nonsteroidal antiemetics on 
subsequent days does not sufficiently manage symptoms, 
dexamethasone 8 mg orally may be administered on Day 2 and/or 
Day 3. 
 
 
8.1 
Measurement of Effect 
 
8.2 
Antitumor Effect 
 
Qualified subjects will be staged by a CT chest/abdomen or CT portion of a 
PET/CT, and a brain MRI at baseline (Appendix E). Target and non-target 
lesions will be followed by CT or MRI for PFS according to immune-related 
Response Evaluation Criteria In Solid Tumors (irRECIST) at Week 8 (± 3 days), 
and every 12 weeks (± 7 days) thereafter (Appendix E). If there is suspicion of 
tumor progression at eight weeks, a second CT/MRI study four weeks after will 
need to be done as a confirmatory test. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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8.2.1 Definitions 
 
• 
Evaluable for toxicity: All patients will be evaluable for toxicity from the 
time of their first treatment with pemetrexed 
• 
Inevaluable for objective response: When no imaging/measurement is 
done at all at a particular time point, the patient is not evaluable (NE) at 
that time point. 
o If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time 
point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would most likely happen 
in the case of PD. 
 
8.2.2 Methods for Evaluation of Measurable Disease 
 
Unscheduled evaluations may be done at the discretion of the 
investigator as needed to assess the subject’s clinical status. 
 
The imaging technique used for each subject (CT or MRI) is at the 
discretion of the investigator, but the same technique must be used for 
each individual subject throughout the study. Imaging should not be 
delayed in case of missed doses or dose delays. 
 
8.2.3 Response Criteria - irRECIST 
 
Total Measured Tumor Burden 
 
The total measured tumor burden (TMTB) is established at baseline as 
the sum of the longest diameters (SOD)—the shortest axes should be 
used for lymph nodes—of all target lesions (≤ 2 lesions per organ, ≤ 5 
lesions total). At each subsequent tumor assessment (TA), the SOD of 
new, measurable lesions (≥ 10 mm [lymph nodes ≥ 15 mm in shortest 
diameter]; ≤ 2 new lesions per organ, ≤ 5 new lesions total) is added to 
the SOD of the target lesions to provide the updated TMTB: 
TMTB = SOD target lesions + SOD new, measurable lesions 
Percentage changes in TMTB at each TA describe the size and growth 
kinetics of both old and new, measurable lesions as they appear. At each 
TA, the response in TMTB is defined as follows: 
o Complete Response (irCR): Complete disappearance of all target 
and new, measurable lesions, with the exceptions of lymph nodes 
which must decrease to < 10 mm in short axis 
o Partial Response (irPR): Decrease in TMTB ≥ 30% relative to 
baseline 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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o Stable Disease (irSD): Not meeting criteria for irCR or irPR, in 
absence of irPD 
o Progressive Disease (irPD): Increase in TMTB ≥ 20% relative to 
nadir 
 
Response in Non-Target Lesions 
 
The presence of non-target lesions is established at baseline; at each TA, 
the presence of any new, non-measurable lesions is assessed. The 
presence of new, non-measurable lesions will rule out an overall 
response of irCR. An increase in the size or number of new, non- 
measurable lesions does not necessarily imply an overall response of 
irPD; if these lesions become measurable (≥ 10 mm [lymph nodes ≥ 15 
mm in shortest diameter]; up to 2 new lesions per organ, total 5 new 
lesions) at a subsequent TA, their measurement will, at that point, start to 
contribute to the TMTB. 
 
The response in non-target lesions is defined as follows: 
o Complete Response (irCR): Complete disappearance of all non- 
target lesions 
o non-irCR/non-irPD: Non-target lesions do not meet the criteria for 
irCR or irPD 
o Progressive Disease (irPD): Unequivocal increase in the number 
or size of non-target lesions. To achieve unequivocal progression 
of non-target lesions, there must be a substantial worsening of 
non-target disease of a magnitude that, according to the treating 
physician, warrants a change in anticancer therapy 
NOTE: Equivocal findings of progression of non-target lesions 
(e.g., small and uncertain new lesions; cystic changes or necrosis 
in existing lesions) should be considered irSD and treatment may 
continue until the next scheduled assessment. 
 
Overall Response 
The overall response according to irRECIST is derived from the 
responses in TMTB as well as the presence of any non-target lesions as 
follows: 
o Complete Response (irCR): Complete disappearance of all 
lesions (whether measurable or not); lymph nodes must decrease 
to < 10 mm in shortest dimension 
o Partial Response (irPR): Decrease in TMTB ≥ 30% relative to 
baseline 
o Stable Disease (irSD): Not meeting criteria for irCR or irPR, in 
absence of irPD 
o Progressive Disease (irPD): Increase in TMTB ≥ 20% relative to 
nadir 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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8.2.4 Assessment for efficacy 
The following efficacy parameters will be assessed by independent 
radiology review according to irRECIST, and are defined as follows: 
 
Objective response rate: the proportion of subjects who achieve complete 
or partial response 
 
Duration of best response: the duration of time from the date 
measurement criteria are first met for irCR, or irPR (if irCR is never met), 
until the first date that irPD is confirmed by independent radiology review 
or death, whichever comes first 
 
Disease control rate: the percentage of subjects who achieved irCR, irPR, 
or irSD 
 
Duration of disease control: the duration of time from the date 
measurement criteria are first met for irCR, irPR, or irSD, until the first 
date that irPD is confirmed by independent radiology review or death, 
whichever comes first 
 
8.2.5 Survival Outcomes 
Progression-free survival: the duration of time from randomization to the 
time of irPD or death, whichever comes first. 
 
Overall survival is defined as the duration of time from randomization to 
the time of death due to any cause, or the date the subject was last 
confirmed to be alive. 
 
 
9.1 
Adverse Events List and Reporting Requirements 
 
9.2 
Adverse Event Lists 
Pembrolizumab: Most common adverse reactions (reported in ≥20% of patients) 
included fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, 
arthralgia, and diarrhea. The most frequent serious adverse drug reactions 
reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and 
cellulitis. 
 
Paclitaxel: The most common adverse reactions (incidence ≥25%) include 
neutropenia, leukopenia, anemia, infections, hypersensitivity reactions, abnormal 
ECG, peripheral neuropathy, myalgia/arthralgia, nausea/vomiting, diarrhea, 
mucositis, and alopecia. 
 
Carboplatin: Bone marrow suppression is the dose-limiting toxicity of Carboplatin. 
The most common adverse reactions (incidence ≥20%) during therapy with 
carboplatin as a single agent were thrombocytopenia, neutropenia, leukopenia, 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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anemia, nausea/vomiting, blood urea elevation, alkaline phosphatase elevation, 
electrolyte depletion, and pain. 
 
 
9.3 
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 4.03 will be utilized for AE reporting. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.03. A 
copy of the CTCAE version 4.03 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 
above) for expedited reporting purposes only. 
 
• 
Attribution of the AE: 
 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
9.4 
DSMC SAE Reporting Requirements 
 
The Date and Safety Monitoring Committee is responsible for reviewing SAEs for 
WFBCCC Institutional studies are outlined in Appendix D. All Adverse Events that occur 
during protocol intervention and are coded as either 1) unexpected grade 4, 2) 
unplanned inpatient hospitalization  ≥ 24 hours (regardless of grade), or grade 5 (death) 
must be reported to the DSMC using the SAE console in WISER. 
 
All WFBCCC Clinical Protocol and Data Management (CPDM) staff members assisting 
a Principal Investigator in investigating, documenting and reporting an SAE qualifying for 
DSMC reporting are responsible for informing a clinical member of the DSMC as well as 
the entire committee via the email notification procedure of the occurrence of an SAE.  
 
9.5 
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. 
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
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CCCWFU # 62415 
 
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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. 
 
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. 
 
9.6 
Sponsor Reporting Requirements 
 
9.5.1 Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during 
any use of Merck’s product that: 
• 
Results in death; 
• 
Is life threatening; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalization; 
• 
Is a congenital anomaly/birth defect; 
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose; 
• 
Is another important medical event 
 
Any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause other than progression of the cancer under study that 
occurs to any subject from the time the consent is signed through 90 days 
following cessation of treatment, or the initiation of new anti-cancer therapy, 
whichever is earlier, whether or not related to Merck product, must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety 
and will be handled in the same manner as SAEs. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention 
of the investigator at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety facsimile number: +1-215-993-1220 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as 
required by FDA. Investigators will cross reference this submission according to 
local regulations to the Merck Investigational Compound Number (IND, CSA, 
etc.) at the time of submission. Additionally investigators will submit a copy of 
these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 
993-1220) at the time of submission to FDA. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
9.5.2 Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of 
Clinical Interest (ECI) and must be recorded as such on the Adverse Event 
case report forms/worksheets and reported within 24 hours to the Sponsor and 
within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220) Events of clinical interest for this trial include: 
 
1. an overdose of Merck product that is not associated with clinical symptoms or 
abnormal laboratory results. 
 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the 
upper limit of normal and an elevated total bilirubin lab value that is greater 
than or equal to 2X the upper limit of normal and, at the same time, an 
alkaline phosphatase lab value that is less than 2X the upper limit of normal, 
as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing. 
 
1.   Additional adverse events: 
 
A separate guidance document has been provided entitled “Event of Clinical 
Interest Guidance Document” (previously entitled, “Event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document”). This document can be 
found in Appendix O and provides guidance regarding identification, evaluation 
and management of ECIs and irAEs. 
 
ECIs (both non-serious and serious adverse events) identified in this guidance 
document from the date of first dose through 90 days following cessation of 
treatment, or 30 days after the initiation of a new anticancer therapy, whichever is 
earlier, need to be reported within 24 hours to the Sponsor and within 2 working 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993- 
1220), regardless of attribution to study treatment, consistent with standard SAE 
reporting guidelines. 
 
Subjects should be assessed for possible ECIs prior to each dose. Lab results 
should be evaluated and subjects should be asked for signs and symptoms 
suggestive of an immune-related event. Subjects who develop an ECI thought to 
be immune-related should have additional testing to rule out other etiologic 
causes. If lab results or symptoms indicate a possible immune-related ECI, then 
additional testing should be performed to rule out other etiologic causes. If no 
other cause is found, then it is assumed to be immune-related. 
 
 
9.5.3 Sponsor Responsibility for Reporting Adverse Events 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations. 
 
 
10.1 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 9.0. 
 
 
10.2 Pharmaceutical Accountability 
 
Pembrolizumab, paclitaxel and carboplatin are commercially available. 
 
10.3 KEYTRUDA (pembrolizumab) 
 
Product description: Include the available dosage forms, ingredients, and 
packaging, as appropriate. Also state the agent's supplier. 
 
Marketed Packs: When Study Drug is provided in the marketed package, Merck 
will not supply any Chemistry, Manufacturing, Control (CMC) information. 
Institution’s regulatory submission should reference the Merck Marketing 
Authorization. If any additional labelling of containers is required, e.g. to add 
Study Protocol number, and it has not been agreed for Merck to perform the 
additional labelling, it is Institution’s responsibility to arrange for this action to be 
done in accordance with U.S. regulations. 
 
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). 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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• 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. 
• 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: 
Do not freeze. 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. 
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. 
 
Stability: Include the stability of the original dosage form, reconstituted solution, 
and final diluted product, as applicable. 
 
Route of administration: Administer infusion solution intravenously over 30 
minutes through an intravenous line containing a sterile, non-pyrogenic, low- 
protein binding 0.2 micron to 5 micron in-line or add-on filter. Do not co- 
administer other drugs through the same infusion line. 
 
Disposal: To minimize the risk of dermal exposure, always wear impervious 
gloves when handling vials containing paclitaxel. If paclitaxel contacts the skin, 
immediately wash the skin thoroughly with soap and water. If paclitaxel contacts 
mucous membranes, the membranes should be flushed immediately and 
thoroughly with water. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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10.4 Taxol (paclitaxel) 
 
Product description: Paclitaxel is a natural product with antitumor activity. Taxol 
(paclitaxel) is obtained via a semi-synthetic process from Taxus baccata. The 
chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax- 
11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3- 
phenylisoserine. Taxol (paclitaxel) Injection is a clear, colorless to slightly yellow 
viscous solution. 
 
Solution preparation: It is supplied as a nonaqueous solution intended for 
dilution with a suitable parenteral fluid prior to intravenous infusion. Taxol is 
available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose 
vials. Each mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg 
of purified Cremophor® EL* (polyoxyethylated castor oil) and 49.7% (v/v) 
dehydrated alcohol, USP. Taxol should be diluted in 0.9% Sodium Chloride 
Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium 
Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final 
concentration of 0.3 to 1.2 mg/mL. 
Storage requirements and Stability: Unopened vials of Taxol (paclitaxel) 
Injection are stable until the date indicated on the package when stored between 
20°–25° C (68°–77° F), in the original package. Neither freezing nor refrigeration 
adversely affects the stability of the product. Upon refrigeration, components in 
the Taxol vial may precipitate, but will redissolve upon reaching room 
temperature with little or no agitation. There is no impact on product quality under 
these circumstances. If the solution remains cloudy or if an insoluble precipitate 
is noted, the vial should be discarded. Solutions for infusion prepared as 
recommended are stable at ambient temperature (approximately 25° C) and 
lighting conditions for up to 27 hours. Store the vials in original cartons between 
20°–25° C (68°–77° F). Retain in the original package to protect from light. 
 
Route of administration: Intravenous. Taxol should be administered through an 
in-line filter with a microporous membrane not greater than 0.22 microns. 
 
Drug interactions: The metabolism of Taxol is catalyzed by cytochrome P450 
isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when Taxol is 
concomitantly administered with known substrates (eg, midazolam, buspirone, 
felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors 
(eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (eg, 
rifampin and carbamazepine) of CYP3A4. Caution should also be exercised 
when Taxol is concomitantly administered with known substrates (eg, repaglinide 
and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers (eg, rifampin) of 
CYP2C8. 
 
Disposal: To minimize the risk of dermal exposure, always wear impervious 
gloves when handling vials containing paclitaxel. If paclitaxel contacts the skin, 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
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immediately wash the skin thoroughly with soap and water. If paclitaxel contacts 
mucous membranes, the membranes should be flushed immediately and 
thoroughly with water. 
 
10.5 Carboplatin 
 
Product description: The chemical name for Carboplatin is platinum, diammine 
[1,1-cyclobutanedicarboxylato(2-)-O,O’]-,(SP-4-2). It is supplied as a sterile, 
pyrogen-free, 10 mg/mL aqueous solution. 
 
Solution preparation: Carboplatin injection is a premixed aqueous solution of 10 
mg/mL Carboplatin. Carboplatin aqueous solution can be further diluted to 
concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% 
Sodium Chloride Injection, USP. Needles or intravenous administration sets 
containing aluminum parts that may come in contact with Carboplatin injection 
should not be used for the preparation or administration of the drug. Aluminum 
can react with Carboplatin causing precipitate formation and loss of potency. 
 
Storage requirements and Stability: When prepared as directed, Carboplatin 
aqueous solutions are stable for 8 hours at room temperature (25° C). Since no 
antibacterial preservative is contained in the formulation, it is recommended that 
Carboplatin aqueous solutions be discarded 8 hours after dilution. Unopened 
vials of Carboplatin injection are stable to the date indicated on the package 
when stored at 20° - 25° C (68° to 77° F) [see USP Controlled Room 
Temperature]. Protect from light. Carboplatin injection multidose vials maintain 
microbial, chemical, and physical stability for up to 14 days at 25° C following 
multiple needle entries. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration. 
 
Route of administration: Intravenous 
 
Drug interactions: The renal effects of nephrotoxic compounds may be 
potentiated by Carboplatin. 
 
Disposal: To minimize the risk of dermal exposure, always wear impervious 
gloves when handling vials containing Carboplatin injection. If Carboplatin 
injection contacts the skin, immediately wash the skin thoroughly with soap and 
water. If Carboplatin injection contacts mucous membranes, the membranes 
should be flushed immediately and thoroughly with water. 
 
 
11.1 Correlative Studies 
11.2 Tumor Correlative Studies 
Pre-therapy tumor that has been fixed with 10% buffered formalin solution and 
processed into paraffin embedded (FFPE) tissue blocks will be collected. The 


 
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Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
following infiltrating cells will be quantified (0 to 3+) using standing 
immunofluorescence techniques: 
CD4+, CD8+, CD68+ , PD 1+CD4+, PD 1+CD8+, PD-1+CD68+, PD-1L+, and 
CD4+Foxp3+. See Appendix M. 
 
Methods: Immunohistochemical staining will be carried out on 4μm-thick sections 
utilizing an Autostainer Plus (Dako - Agilent Technologies) with appropriate 
positive and negative controls. Sections are baked for 60 minutes at 60 °C in a 
dehydration oven and heat-induced epitope retrieved in the PT link (Dako – 
Agilent technologies) using EnVision FLEX target retrieval solution for 20 minutes 
at 97 °C then cooled to room temperature in TBST Wash buffer for 5 minutes. 
Slides are incubated with the following antibodies at the following dilutions: 
 
 
Dilution 
Source 
PD-1 
1:100 
Cell Marque NAT105 
PD-L1 
1:1000 
R&D Systems 
CD4 
1:100 
Cell Marque SP35 
CD8 
1:200 
Cell Marque SP16 
FOXP3 
1:200 
Abcam AB22510 
CD68 
1:1000 
Cell Marque KP-1 
 
Antibody detection will utilize the Envision FLEX kit (K8023) with a DAB 
chromagen for visualization according to the manufacturer’s instructions (Dako – 
Agilent technologies). Slides are then counterstained with hematoxylin. The 
percentage of tumor which have an infiltrate of lymphocytes or macrophages will 
be estimated and the average number of positive immune cells per high power 
field (HPF) in a minimum of 4 representative HPF areas will be determined 
utilizing a semi-quantitative four tiered scale used for scoring lymphocytes (0= no 
lymphocytes, 1= 1-10/HPF, 2= 11-50/HPF and 3= >50/HPF) and macrophages 
(0= no macrophages, 1= 1-50/HPF, 2= 50-100/HPF and 3=>100/HPF). 
Lymphocyte and macrophage infiltrate scores are obtained by multiplying these 
scores to attain a score from 0-300. 
 
 
11.3 Blood Correlative Studies 
Blood will be drawn prior to initiating treatment (C1D1), day 1 of cycle 2 (C2D1), 
day 1 of cycle 3 (C3D1), and End of Treatment (EOT). All blood samples are 
collected from the clinic and transported at room temperature within 3 hours after 
being drawn from each individual. Whole blood is collected in Vacutainer tubes 
containing EDTA (BD Vacutainer). Peripheral blood mononuclear cells (PBMC) 
are isolated from whole blood by density gradient centrifugation using 
Lymphocyte Separation Medium (Mediatech) and Leucosep tubes (Greiner Bio- 
one). Whole blood is centrifuged at 410 × g for 10 minutes and the plasma layer 
is collected, centrifuged for 10 minutes at 885 × g, and the supernatant frozen at 
−80°C for subsequent experiments. The whole blood is diluted 1:1 with RPMI 
(Mediatech) and the PMBCs isolated per manufacturer's guidelines. Cells at the 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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interface are harvested and washed once with RPMI, and red blood cells are 
lysed with ammonium chloride lysis buffer. Cells are washed, counted, and 
immediately used fresh for staining and flow cytometry analysis, or 10 million 
PBMCs are frozen per milliliter of freezing solution (10% DMSO 10% FBS- 
supplemented RPMI) per NUNC cryovial. PBMCs are frozen in a Nalgene Cryo 
1°C freezing container per manufacturer's instructions and stored in liquid 
nitrogen thereafter. 
 
See Appendix N. The following will be assessed: 
• 
Frequency (flow cytometry) of Lin−CD14+HLA-DRlow/− MDSC; CD4+, 
CD8+, ICOS+CD4+, ICOS+CD8+ effector and CD4+FoxP3+ regulatory T 
cells 
 
Method: Antibodies that will be used for flow cytometry analysis include CD4- 
BV421 (eBiosciences), CD8-PE (BD Pharmingen), CD14-APC 
(eBiosciences), HLA-DR-FITC (BD Pharmingen), lineage 
(CD3/CD16/CD19/CD20/CD56) cocktail FITC (BD Pharmingen), ICOS- 
efluro660 (eBiosciences), and FoxP3-Alexa480 (eBioscience). Isotype 
controls include the appropriate fluorochrome-conjugated mouse IgG1, IgG 
1k, IgG2a, or IgG2b k (BD Pharmingen; Beckman Coulter; R&D Systems). 
Triplicate samples will be analyzed using the FACSCanto II (Becton 
Dickinson). Data will be analyzed using the BD FACSDiva software. Gates 
are set according to appropriate isotype controls. Absolute lymphocyte counts 
will also be determined. Frequency (%) of the following phenotypes will be 
determined. 
 
Effector 
CD4+ 
CD8+ 
ICOS+CD4+ 
ICOS+CD8+ 
T regulatory 
CD4+FoxP3+ 
Myeloid derived suppressor 
Lin-CD14+HLA-DRlow/− 
 
• 
Peripheral blood mononuclear cell Th1/Th2/Th17 cytokine production in 
vitro (BD Cytometric Bead Array) in response to WT-1, p53, Mage-A3, 
Her2/neu, telomerase, and survivin peptide mixtures (Proimmune 
Promix), tumor-associated determinants implicated in NSCLC, and to 
anti-CD3 plus anti-CD28 antibody (BD) 
 
Methods: PBMC that have been separated by gradient centrifugation and 
cryopreserved are thawed at 37 ºC, diluted in 5 ml RPMI, and incubated at 37 
ºC for 1 hour. Cells are then pelleted at 200g, resuspended in complete 
medium, counted with trypan blue, and suspended at 4x106/ml and plated in 
100 µl in 96 well conical wells. PBMC are then cultured with 20 μg/ml of WT- 
1, p53, Her2/neu, Mage-A3, telomerase, and survivin peptide mixtures 
ProMix Peptide Pools (Proimmune Inc.). As a control PBMC are also 
stimulated with anti-CD3 plus anti-CD28 antibody (BD Pharmingen). After 3 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
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days, culture supernatants are collected and assayed using BD Cytometric 
Bead Array Human Th1/Th2/Th17 Cytokine Kit according to the 
manufacturer's instructions. Positivity criteria include a ≥3.0-fold increase over 
unstimulated background control, expressed as a stimulation index (SI), as 
well as a minimum concentration (pg/ml) over background as follows: IL-2, 
40; IL-4, 15; IL-6, 20; IL-10, 50; IFN-γ, 75; tumor necrosis factor-α, 30; and IL- 
17A, 20. 
 
 
• 
Plasma levels (ELISA) of TGF-β, VEGF, IL-6, IL-8, PGE2 (metabolite), 
and sPD-1L. 
 
Methods: Commercially available ELISA kits will be used according to the 
recommendation of the manufacturer. Results are expressed as a 
concentration. 
 
Manufacturer 
TGF-β 
R&D Systems 
VEGF 
R&D Systems 
IL-6 
R&D Systems 
IL-8 
R&D Systems 
PGE2 (metabolite) 
Abcam 
sPD-1L 
MyBiosource 
 
11.4 Quality of Life Correlative Studies 
EORTC QLQ-30 and EORTC QLQ-LC13 will be completed by the patient at 
baseline and then every 12 weeks (Appendices I – L).21 
 
The EORTC QLQ-C30 is reportedly the most frequently used QOL instrument in 
lung cancer clinical trials.22 The QLQ-30 is a 30-item multi-dimensional 
questionnaire designed for use in cancer populations.21  It contains nine multi- 
item scales: five functional scales (physical, role, cognitive, emotional, and 
social); three symptom scales (fatigue, pain, and nausea and vomiting); and a 
global health and quality-of-life scale, requested by 4-point Likert or visual 
analogue scales. Several single-item symptom measures are also included. The 
QLQ-LC13 is a lung cancer-specific module to be used in conjunction with the 
QLQ-30 and is 13 additional items. These questionnaires have been shown to be 
reliable and valid in over 60 languages, can be self or interviewer-administered 
and take approximately 11 minutes to complete.21,22  Both the QLQ-C30 and 
QLQ-LC13 will be available in Spanish for Spanish-speaking participants. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 44 of 83  
 
 
12.0  Data Management 
 
 
Informed consent document 
WISER 
Protocol registration form 
WISER 
Tumor measurement form 
REDCap 
Screening form 
REDCap 
Study data collection form 
REDCap 
Follow-up form 
REDCap 
EORTC QLQ-C30 & QLQ-LC13 
REDCap 
Tumor correlative study form 
REDCap 
Blood correlative study form 
REDCap 
 
 
13.1 Statistical Considerations 
13.2 Power, sample size, and accrual rate 
This is a pilot study and will accumulate useful preliminary data to compare whether a 
combination of immunotherapy and chemotherapy shows more promising efficacy data 
than immunotherapy alone. To achieve this goal a total of 40 patients will be 
randomized, 20 patients will be randomized to single agent and 20 to the combination. 
 
For the primary outcome of objective response rate, (ORR) patients will be dichotomized 
to being a success/failure based on whether they have a partial or complete response. 
Exact Clopper-Pearson 95% confidence intervals will be calculated for each group 
separately. With a sample size of 20 patients in a group, a two-sided 95% confidence 
interval (Exact Clopper-Pearson interval) will have a total width of 0.324 if the estimated 
proportion of successes is 50% (most conservative assumption for the confidence 
interval calculation). This level of precision will provide information (estimate and 95% 
confidence interval) as to whether this therapeutic approach is promising and worthy of 
future studies. 
 
Furthermore, a comparison between groups will be made using a Fisher’s Exact Test. If 
we observe a very large difference in ORR (greater than 43% in absolute percent if the 
ORR was 10%in the Control arm) we will have sufficient power to declare that difference 
statistically significant. However, since this is a pilot study it is not anticipated that a 
statistically significant difference will  necessarily be observed. 
 
Based on current projects, approximately 30 eligible patients will be enrolled in one 
year, so overall it is anticipated that the trial will take approximately 18 months to accrue 
40 patients followed by a 12-month follow-up period for the patients. 
 
13.3 Analysis of Primary Objective 
 
13.3.1 The effects of the treatments on immune markers will be analyzed using 
paired t-tests (possibly after transformation) or the non-parametric 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 45 of 83  
 
 
counterpart within each group separately. In addition, the two groups will 
be compared on these measures using two-sample t-tests for outcomes 
measured only post-randomization or analysis of covariance for 
measures that have an assessment made prior to randomization. If a 
measure is assessed a multiple post-randomization times then a 
longitudinal mixed model will be fit to examine the differences between 
groups over time accounting for the repeated measurements. 
 
13.3.2 This study will enroll patients with recurrent or metastatic NSCLC and PS 
of 2. In this group of patients, the ORR’s is approximately 10% with OS of 
about 2 to 4 months. With this pilot study, we would be able to conduct 
two hypothesis tests (one for each arm of the study) to determine whether 
there is evidence that the observed response rate, using RECIST criteria, 
is better than 10%. To do this, two one-sided binomial tests will be 
performed. For each test the null hypothesis is that the response rate is 
10% and the alternative hypothesis is that the response rate is higher 
than 10%. With 20 patients in each analysis there is 80% power to detect 
a difference of 0.2133 with alpha=0.05 (one sided). 
13.3.3 Duration of response will also be assessed in each group and compared 
using survival analysis methods. Furthermore, progression free and 
overall survival rates will be estimated in each group and compared using 
Kaplan-Meier curves. These comparisons will be for descriptive purposes 
since it is not anticipated that statistically significant differences will be 
observed with the small sample sizes. 
 
13.4 Analysis of Secondary Objectives 
 
13.4.1 Adverse events will be categorized by organ system and severity and 
summarized as frequency counts and percentages. A treatment will be 
considered too toxic if ≥6 of 20 patients in a cohort are removed from 
study because of toxicity. 
 
13.4.2 Two instruments the EORTC QLQ-30 and EORTC QLQ0LC13 will be 
administered to patients at baseline and every 12 weeks during the study, 
thus it is anticipated that patients will have up to 5 assessments made 
during the trial.  Summary scores from each instrument will be assessed 
at each time point and longitudinal comparisons will be made between 
groups using a repeated measure mixed model approach. 
 
 
13.4.3 The association of immune response with clinical response will also be 
explored. Treatment response will be grouped into 4 categories as 
defined earlier in the protocol (irCR, irPR, irSD, irPD). The immune 
responses for patients within each of these 4 groups will be examined to 
determine whether there is evidence of an association. This comparison 
will be primarily descriptive, however we will be examining whether there 
is evidence that immune response improves as patients go from PD to 
CR (i.e. it is expected that patients with irPD will have worse immune 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 46 of 83  
 
 
response than patients with irCR). For continuous measures of immune 
response the mean value within each response category will be 
compared. If we dichotomize the immune response assessment into 
responder yes/no then we will compare the proportion of responders in 
each category. As stated above, with a small sample size (n=20 per 
group) this examination will be exploratory since some categories may 
have less than 4 patients in them. 
 
 
 
13.5 Interim Analysis Plan 
 
There is no planned interim analysis for this study, however the DSMC will 
monitor this study and if there were to be an unexpected safety concern from 
unexpected Grade 4 or 5 events occurring on one or both arms of the study then 
the trial could be suspended or amended if necessary. However, this is not 
expected. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 47 of 83  
 
 
References 
 
1. 
Azzoli CG, Baker S, Jr., Temin S, et al. [American Society of Clinical Oncology Clinical 
Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer]. 
Zhongguo fei ai za zhi = Chinese journal of lung cancer. Mar 2010;13(3):171-189. 
2. 
Sculier JP, Chansky K, Crowley JJ, Van Meerbeeck J, Goldstraw P. The impact of 
additional prognostic factors on survival and their relationship with the anatomical extent 
of disease expressed by the 6th Edition of the TNM Classification of Malignant Tumors 
and the proposals for the 7th Edition. Journal of thoracic oncology : official publication of 
the International Association for the Study of Lung Cancer. May 2008;3(5):457-466. 
3. 
Bunn PA, Jr. Chemotherapy for advanced non-small-cell lung cancer: who, what, when, 
why? Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. Sep 15 2002;20(18 Suppl):23s-33s. 
4. 
Lilenbaum RC, Cashy J, Hensing TA, Young S, Cella D. Prevalence of poor 
performance status in lung cancer patients: implications for research. Journal of thoracic 
oncology : official publication of the International Association for the Study of Lung 
Cancer. Feb 2008;3(2):125-129. 
5. 
Tartarone A, Aieta M. Treatment of performance status 2 patients with advanced non- 
small-cell lung cancer: what we know and what we don't know. Future Oncol. Aug 
2009;5(6):837-841. 
6. 
Des Guetz G, Landre T, Westeel V, et al. Similar survival rates with first-line gefitinib, 
gemcitabine, or docetaxel in a randomized phase II trial in elderly patients with advanced 
non-small cell lung cancer and a poor performance status (IFCT-0301). Journal of 
geriatric oncology. Feb 16 2015. 
7. 
Jouveshomme S, Canoui-Poitrine F, Le Thuaut A, Bastuji-Garin S. Results of platinum- 
based chemotherapy in unselected performance status (PS) 2 patients with advanced 
non-small cell lung cancer: a cohort study. Medical oncology (Northwood, London, 
England). Jun 2013;30(2):544. 
8. 
Califano R, Griffiths R, Lorigan P, et al. Randomised phase II trial of 4 dose levels of 
single agent docetaxel in performance status (PS) 2 patients with advanced non-small 
cell lung cancer (NSCLC): DOC PS2 trial. Manchester lung cancer group. Lung cancer 
(Amsterdam, Netherlands). Sep 2011;73(3):338-344. 
9. 
American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer 
Society;2012. 
10. 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature 
reviews. Cancer. Apr 2012;12(4):252-264. 
11. 
Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and T(regs) in the 
melanoma tumor microenvironment is driven by CD8(+) T cells. Science translational 
medicine. Aug 28 2013;5(200):200ra116. 
12. 
Grosso J HC, Inzunza D, Cardona DM, Simon JS, Gupta AK, Sankar V, Park J, Kollia G, 
Taube JM, Anders R, Jure-Kunkel M, Novotny J Jr., Taylor CR, Zhang X, Phillips T, 
Simmons P, Cogswell J. Association of tumor PD-L1 expression and immune 
biomarkers with clinical activity in patients (pts) with advanced solid tumors treated with 
nivolumab (anti-PD-1; BMS-936558; ONO-4538). Journal of Clinical Oncology. 
2013;31(suppl):abstract 3016. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 48 of 83  
 
 
13. 
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. 
14. 
Johnson DB, Rioth MJ, Horn L. Immune checkpoint inhibitors in NSCLC. Current 
treatment options in oncology. Dec 2014;15(4):658-669. 
15. 
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. 
Nature medicine. Nov 2013;19(11):1423-1437. 
16. 
Ralph P, Nakoinz I. Augmentation of macrophage antibody-dependent killing of tumor 
targets by microtubule inhibitors. Cellular immunology. Jul 1 1982;70(2):321-329. 
17. 
Chang CL, Hsu YT, Wu CC, et al. Dose-dense chemotherapy improves mechanisms of 
antitumor immune response. Cancer Res. Jan 1 2013;73(1):119-127. 
18. 
He Q, Li J, Yin W, et al. Low-dose paclitaxel enhances the anti-tumor efficacy of GM- 
CSF surface-modified whole-tumor-cell vaccine in mouse model of prostate cancer. 
Cancer immunology, immunotherapy : CII. May 2011;60(5):715-730. 
19. 
Lu L, Xu X, Zhang B, Zhang R, Ji H, Wang X. Combined PD-1 blockade and GITR 
triggering induce a potent antitumor immunity in murine cancer models and synergizes 
with chemotherapeutic drugs. Journal of translational medicine. 2014;12:36. 
20. 
Barbon CM, Yang M, Wands GD, et al. Consecutive low doses of cyclophosphamide 
preferentially target Tregs and potentiate T cell responses induced by DNA PLG 
microparticle immunization. Cellular immunology. 2010;262(2):150-161. 
21. 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international 
clinical trials in oncology. J Natl Cancer Inst. Mar 3 1993;85(5):365-376. 
22. 
Damm K, Roeske N, Jacob C. Health-related quality of life questionnaires in lung cancer 
trials: a systematic literature review. Health economics review. 2013;3(1):15. 
23. 
Garon BG, Rizvi NA, HuiR, et al. Pembrolizumab for the Treatment of Non–Small-Cell 
Lung Cancer. N Engl J Med 2015;372:2018-28 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 49 of 83  
 
 
 
 
Appendix A – Protocol Registration Form 
 
DEMOGRAPHICS 
Patient: Last Name:   
 
 
 
First Name:   
 
MRN: 
   
   
 
ZIPCODE:    
   
   
  
  
  
  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: 
 
/ 
_/  
  
 
ECOG Performance Status:   
   
  
  
Prior Chemotherapy?   Yes 
 No 
Prior Therapies/ 
Start / End Date of   Best Response 
Date of 
Date of 
Duration of 
Protocol # if applicable 
Prior Therapy 
(CR, PR, 
Best Response 
Relapse 
Best Response 
Treatment Failure) 
(in Months) 
#1   
 
#2   
 
  
/  
  
 
  
 
 
  
/  
  
 
  
 
 
 
#3   
 
  
/  
  
 
  
 
 
 
#4   
 
  
/  
  
 
  
 
 
 
COMMENT:  
 
 
 
 
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and 
performance status of 2 treated with a combination of pembrolizumab and low dose weekly 
carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 50 of 83  
 
 
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): 
 
 
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. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 
2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
Appendix B – Subject Eligibility Checklist 
 
Protocol Version Date 03/12/2021 
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IRB Protocol No. IRB00034830 
CCCWFU Protocol No. 62415 
Study Title: Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status 
of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Principal Investigator:  W. Jeff Petty, MD 
 
Inclusion Criteria 
(as outlined in study protocol) 
Criteri
a is 
Criteria is 
NOT met 
Source Used to Confirm * 
(Please document dates and lab results) 
Patients must have histologically or cytologically 
confirmed NSCLC that is advanced/metastatic 
(stage IIIB/IV) or recurrent (progression after 
surgery or radiation or chemo-radiation treatment 
for loco-regional disease). 
Patients with epidermal growth factor (EGFR) 
mutation, anaplastic lymphoma kinase (ALK) 
gene rearrangement or ROS1 translocation must 
have received an approved EGFR, ALK, or 
ROS1-directed therapy and have signs of disease 
progression prior to receiving pembrolizumab. 
□ 
□ 
Patients must be willing to provide tissue from a 
newly obtained core or excisional biopsy of a 
tumor lesion. Newly-obtained is defined as a 
specimen obtained up to 12 weeks (84 days) prior 
to date of signing consent. Subjects for whom 
newly-obtained samples cannot be provided (e.g. 
inaccessible or subject safety concern) may 
submit an archived specimen (up to 3 years) only 
upon agreement from the Sponsor. At least 4 mm 
of tumor tissue will be needed for PD-L1 staining. 
□ 
□ 
Patients who have received zero (0) to two (2) 
previous lines of systemic chemotherapy and are 
not currently receiving chemotherapy treatment 
(within 2 weeks of randomization). 
□ 
□ 
At least one measurable lesion as defined by 
RECIST v1.1 on screening CT or MRI 
□ 
□ 
Age >18 years. 
□ 
□ 
ECOG performance status of 2. 
□ 
□ 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated 
with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 52 of 83  
 
 
Patients must have normal organ and marrow 
functions as described below: 
-white blood cell count > 2,500 cells/mcL 
-absolute neutrophil count >1,500/mcL 
-platelets >100,000/mcL 
-hemoglobin ≥ 9 g/dL 
-total bilirubin ≤ 2.0 x upper limit of normal (ULN) 
-AST(SGOT)/ALT(SGPT) < 2.5 x ULN 
OR 
≤ 5 x ULN in presence of liver metastases 
-creatinine within normal institutional limits 
OR 
creatinine clearance > 50 mL/min for patients 
with creatinine levels above institutional normal 
- potassium ≥ lower limit of normal 
□ 
□ 
Women of child-bearing potential and men must 
agree to use adequate contraception (hormonal 
or barrier method of birth control; abstinence) for 
the duration of study participation and for 4 weeks 
after the final administration of study drugs. 
Should a woman become pregnant or suspect 
she is pregnant while participating in this study, 
she should inform her treating physician 
immediately. 
□ 
□ 
Ability to understand and the willingness to sign 
an IRB-approved informed consent document. 
□ 
□ 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria is 
present 
Source Used to Confirm * 
(Please document dates and lab results) 
Known active (untreated) central nervous system 
(CNS) metastases that require steroids. Subjects 
with CNS metastases who have completed a 
course of therapy would be eligible for the study 
provided they are clinically stable for at least 2 
weeks before study entry, defined as: 
• 
No evidence of new or enlarging CNS 
metastasis or new neurological symptoms 
attributable to CNS metastases. 
• 
Asymptomatic and receiving either no or 
stable doses of anticonvulsants and total 
doses of corticosteroids equivalent to 10 
mg of prednisone or less. 
□ 
□ 
Current or previous other malignancy within 2 
years of study entry, except cured basal or 
squamous cell skin cancer, superficial bladder 
cancer, prostate intraepithelial neoplasm, 
carcinoma in situ of the cervix, or other 
noninvasive or indolent malignancy without 
sponsor approval. 
□ 
□ 
History of previous exposure to an anti PD1/PD- 
L1 agent 
□ 
□ 
Patients receiving any other investigational 
agents and or more than two different 
chemotherapy regimens for treatment of 
metastatic disease. 
□ 
□ 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated 
with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 53 of 83  
 
 
Has had prior chemotherapy, targeted small 
molecule therapy, or radiation therapy within 2 
weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered 
agent. 
 
Note: Subjects with ≤ Grade 2 neuropathy are an 
exception to this criterion and may qualify for the 
study. 
 
Note:  If subject received major surgery, they 
must have recovered adequately from the toxicity 
and/or complications from the intervention prior to 
starting therapy. 
□ 
□ 
History of allergic reactions attributed to 
compounds of similar chemical or biologic 
composition to pembrolizumab, paclitaxel or 
carboplatin. 
□ 
□ 
Current uncontrolled cardiac disease such as 
angina or myocardial infarction, congestive heart 
failure including New York Heart Association 
functional classification of 3, or arrhythmia 
requiring treatment. 
□ 
□ 
History of pneumonitis or active lung infection. 
□ 
□ 
Chronic or current active infectious disease 
requiring systemic antibiotics, antifungals, or 
antivirals. 
□ 
□ 
Patients receiving chronic steroids and or 
immunosuppression 
□ 
□ 
Known HIV infection, Hepatitis B virus (HBV) or 
hepatitis C virus (HCV) viremia or at risk for HBV 
reactivation. HBV DNA and testing for HCV RNA 
must be undetectable. At risk for HBV reactivation 
is defined as hepatitis B surface antigen positive 
or anti-hepatitis B core antibody positive 
□ 
□ 
History of autoimmune disease(s). 
□ 
□ 
Psychiatric illness/social situations that would limit 
compliance with study requirements 
□ 
□ 
Any other condition or circumstance that could 
interfere with adherence to the study’s procedures 
or requirements, or otherwise compromise the 
study’s objectives such as history of, or any 
evidence of active, non-infectious pneumonitis 
□ 
□ 
Has an active infection requiring systemic 
therapy. 
□ 
□ 
Pregnant women are excluded from this study 
because of the potential for teratogenic or 
abortifacient effects. Because there is an 
unknown but potential risk for adverse events in 
nursing infants, breastfeeding should be 
discontinued prior to study entry. 
□ 
□ 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated 
with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 54 of 83  
 
 
 
 
 
 
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:    
 
 
* 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 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated 
with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 55 of 83  
 
 
Appendix C – Race & Ethnicity Verification Form 
 
Thank you so much for helping us to verify your race and ethnicity to ensure the quality of our information. As 
a brief reminder, the information you provide today will be kept confidential. 
 
1. Are you: 
Hispanic  or Latino/a  
Not Hispanic or Latino/a 
 
2. What is your race? One or more categories may be selected. 
White or Caucasian 
Black or African American 
American Indian or Alaskan Native 
Asian 
Native Hawaiian or Other Pacific Islander 
Other, Please Specify:   
 
 
 
 
 
 
 
 
 
Internal use only: 
 
Was the self-reported race and ethnicity of the participant verified at the time of consent? 
Yes 
No 
 
Was a discrepancy found? 
Yes 
No 
If yes, please provide what is currently indicated in the EMR: 
 
Ethnicity:   
 
Race:   
 
 
Additional comments:   
 
 
 
 
 
 
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance 
status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU) CCCWFU # 62415 
 
 
Protocol Version Date 03/12/2021 
Page 56 of 83  
 
Appendix D – Mandatory DSMC SAE Reporting Guidelines 
 
Data and Safety Monitoring Committee 
(DSMC) Serious Adverse Event (SAE) 
Date: 2/11/2021 
 
Mandatory DSMC SAE Reporting Requirements in WISER 
This document describes reporting requirements of adverse events from WFBCCC 
Investigator Initiated interventional trials to the Data and Safety Monitoring Committee 
(DSMC). A trial is considered a WFBCCC Investigator Initiated interventional trial if the 
following criteria are met: 
 
1) The Principal Investigator (PI) of the trial is a member of a department at the 
Wake Forest University Baptist Medical Center. 
2) WFBCCC is considered as the primary contributor to the design, implementation 
and/or monitoring of the trial. 
3) The trial is designated as “Interventional” using the Clinical Research 
Categories definitions provided by the NCI in the Data Table 4 
documentation. 
(https://cancercenters.cancer.gov/GrantsFunding/DataGuide#dt4) 
 
There are two distinct types of WFBCCC Investigator Initiated interventional trials based 
on where patient enrollment occurs.  These include: 
 
1) Local WFBCCC Investigator Initiated interventional trials defined as trials where all 
patients are enrolled from one of the WFBCCC sites. These include the main 
outpatient Cancer Center clinics (located in Winston-Salem) as well as WFBCCC 
affiliate sites located in Bermuda Run (Davie Medical Center), Clemmons, 
Lexington, High Point, or Wilkesboro. 
2) Multi-Center WFBCCC Investigator Initiated interventional trials defined as trials 
where patients are enrolled from other sites in addition to WFBCCC sites.   
There are three types of trials that are included in this category: 
a. Trials sponsored by the NCI Community Oncology Research Program 
(NCORP) that are conducted at multiple sites where the PI is a member of a 
department at the Wake Forest University Baptist Medical Center. 
b. Trials sponsored by Industry that are conducted at multiple sites and the 
PI is a member of a department at the Wake Forest University Baptist 
Medical Center. 
c. Trials sponsored by WFBCCC that are conducted at multiple sites and the 
PI is a member of a department at the Wake Forest University Baptist 
Medical Center. 
 
All Adverse Events (AEs) and Serious Adverse Events (SAEs) that occur on any patients 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance 
status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU) CCCWFU # 62415 
 
 
Protocol Version Date 03/12/2021 
Page 57 of 83  
 
enrolled on WFBCCC Investigator Initiated Interventional trials must be entered into the 
WISER system. The only exception to this requirement is for patients enrolled on NCORP 
trials at non- WFBCCC sites. AEs and SAEs for NCORP patients enrolled at WFBCCC sites 
must be entered into the WISER system. Once these AEs and SAEs are entered in WISER, 
certain actions must be taken regarding the reporting of specific Adverse Events to the 
DSMC. 
 
 
 
All Adverse Events that occur during protocol intervention (defined below) and are coded 
as either 1) unexpected grade 4, 2) unplanned inpatient hospitalization > 24 hours 
(regardless of grade), or grade 5 (death) must be reported to the DSMC using the using 
the SAE console in WISER. 
 
A research nurse or clinical research coordinator when made aware that an adverse event 
meets one of the above criteria has occurred on a WFBCCC Investigator Initiated 
interventional trial, is responsible for informing a clinical member of the DSMC by phone 
(or in-person) about the adverse event. The nurse/coordinator should contact the treating 
physician prior to calling the DSMC clinical member to obtain all details of the SAE, as well 
as all associated toxicities to be recorded along with the SAE. In addition, this nurse or 
coordinator is responsible for entering the adverse event information into the SAE console 
in WISER.  Once the adverse event has been entered into the SAE console an email 
informing the entire DSMC will be generated. 
 
THESE REPORTING REQUIREMENTS APPLY TO any staff member on the study team for a 
WFBCCC Institutional Interventional trial. Ultimately, the protocol PI has the primary 
responsibility for AE identification, documentation, grading and assignment of attribution 
to the investigational agent/intervention. However, when an AE event as described above 
is observed, it is the responsibility of the person who observed the event to be sure that it 
is reported to the DSMC. 
 
What is considered during protocol intervention? 
During protocol intervention is considered to be the time period while a patient is on study 
treatment or during the time period within 30 days of last study treatment (even if patient 
begins a new (non-study) 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. If it is a trial 
sponsored by Industry and the sponsor requires a longer window for monitoring of SAEs, 
then the longer window of time specified by the sponsor should be followed. 
 
What is considered as an Unexpected Grade 4 event? 
Any grade 4 event that was not specifically listed as an expected adverse event in the 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance 
status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU) CCCWFU # 62415 
 
 
Protocol Version Date 03/12/2021 
Page 58 of 83  
 
protocol should be considered as unexpected. A grade 4 adverse event can be considered to 
be unexpected if it is an event that would not be expected based on the treatment being 
received or if it is unexpected based on the health of the patient. In either case, if there is 
any uncertainty about whether a grade 4 adverse event is expected or unexpected it should 
be reported to DSMC. 
 
DSMC notification responsibilities of the person (e.g., nurse) handling the 
reporting/documenting of the SAE in WISER: 
1. Make a phone call (or speak in person) to the appropriate clinical member of the 
DSMC according to the schedule as listed below (page if necessary). 
2. Enter a new SAE into the SAE module that is located in the Subject>> CRA Console in 
WISER WITHIN 24 HOURS of first knowledge of the event. Information can be 
entered and saved, but the DSMC members will not be notified until a date is 
entered into the  DSMC Notification Date Field. This will ensure that all persons that 
need to be made aware of the event (i.e., PI, study team members and DSMC 
members) will be notified; remember to file a copy of the confirmation. 
3. Document that the appropriate person(s) on the DSMC has been contacted. Indicate 
the name of the DSMC clinician that was contacted and the date and time contacted 
in the Event Narrative field in the SAE console of the particular subject. 
4. Document whether or not the protocol should be suspended based on the 
discussion with the DSMC clinician. This is the major function of the email 
notification. Enter whether the protocol should be suspended in the Event Narrative 
Field. 
5. Follow up/update the clinical member(s) of DSMC regarding any new developments 
or information obtained during the course of the SAE investigation and reporting 
process. 
 
Elements needed to complete the SAE form in the Subject Console in WISER (see Screen Shot 
3): 
1. Event Date 
2. Reported Date 
3. Reported by 
4. If Grade 5, enter Death Date 
5. If Grade 5, enter Death occurred: within 30 days 
6. Event Narrative: Brief description (include brief clinical history relevant to this event, 
including therapies believed related to event). Begin narrative with the DSMC clinician 
who was notified and Date/Time notified. In addition, state attribution by DSMC 
clinician as either “Unrelated”, “Unlikely”, “Possibly”, “Probably”, or “Definitely”.  
Always include the following here: 
i. DSMC clinician name, date/time contacted and comments 
ii. Date of last dose before the event 
iii. Is suspension of the protocol needed? Y/N 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance 
status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU) CCCWFU # 62415 
 
 
Protocol Version Date 03/12/2021 
Page 59 of 83  
 
7. Treating Physician comments 
8. PI comments, if available 
9. Protocol Attribution after discussion with DSMC clinician 
10. Outcome (Fatal/Died, Intervention for AE Continues, Migrated AE, Not Recovered/Not 
Resolved, Recovered/Resolved with Sequelae, Recovered/Resolved without Sequelae, 
Recovering and Resolving) 
11. Consent form Change Required? Y/N 
12. SAE Classification *This is required in order for the email notification to be sent* 
13. Adverse Event Details – Enter all details for each AE associated with the SAE. 
a. Course start date 
b. Category 
c. AE Detail 
d. Comments 
e. Grade/Severity 
f. Unexpected Y/N 
g. DLT Y/N 
h. Attributions 
i. Action 
j. Therapy 
k. Click ADD to attach the AE Detail to the SAE. 
14. Enter Date Notified DSMC -- *This is required for the email notification to be sent* 
15. Click Submit. The auto-generated notification email will disseminate within 5 minutes. 
If you do not receive an email within 5 minutes, check that you have entered the 
“Date Notified DSMC” and the “SAE Classification”. If these have been entered and 
the email still has not been received, take a screen shot of the SAE in WISER and 
immediately email it out to all of the DSMC members listed in this SOP. In the subject 
line, indicate that this is a manual transmission of the SAE in lieu of the auto-
generated email. It is required that a notification goes to the DSMC members 
immediately so that their assessment can be obtained within the 24 hour period 
requirement. Contact the Cancer Center Programmer/Analyst to alert that there is an 
issue with the auto-generated email. 
 
The Clinical Members of DSMC to Notify by Phone or Page: 
 
Monday 
Tuesday 
Wednesday Thursday 
Friday 
Saturday Sunday 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed Porosnicu
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance 
status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU) CCCWFU # 62415 
 
 
Protocol Version Date 03/12/2021 
Page 60 of 83  
 
Glenn Lesser, MD – Hematology Oncology 
  
Mercedes Porosnicu, MD-- Hematology Oncology 
 
Ryan Hughes, MD – Radiation Oncology 
 
 
Michael Goodman, MD -- Hematology Oncology 
 
Daniel Reed, MD -- Hematology Oncology 
 
Mary Beth Seegars, MD -- Hematology Oncology 
 
 
 
Definition of Unavailable: 
As a general guideline if the first clinician that is contacted does not respond to the phone 
call or page within 30 minutes, then initiate contact with the next DSMC clinician listed in the 
table above on the particular day the SAE is being reported. Allow up to 30 minutes for the 
new DSMC clinician to respond to a phone call or page before contacting the next member in 
the table. These times (30 minutes) are a general guideline. Best judgment as a clinical 
research professional should be used giving considerations of 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 the DSMC notification form. It is important to take reasonable steps 
and to document that some type of contact has been initiated to one or more of the clinical 
members of DSMC. 
 
DSMC CLINICAN RESPONSIBILITY: 
It is the responsibility of the DSMC 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 DSMC. 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. DSMC reserves the right to disagree with the Investigator's assessment. If DSMC 
does not agree with the Investigator, DSMC reserves the right to suspend the trial pending 
further investigation. If there is any immediate danger or harm that could be present for a 
future patient based on the information provided in the DSMC report then an immediate 
suspension of enrollment should be considered. 
 
 
AMENDMENTS TO PREVIOUS REPORTS 
If all pertinent information is unavailable with the initial submission, once the additional 
information is available do not submit a new report. Rather, go to the original email that 
was sent to the DSMC and using that email “reply to all”. Entitle this new email 
“Amendment for (list date of event and patient ID)” this will avoid duplications of the same 
event. List the additional information being reported. This information needs to be entered 
into WISER as well. To do this, go to the Subject console and click SAEs on the left column. 
Click on the appropriate SAE number that needs updating. Then click Update. This will allow 
additional  information to be added. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance 
status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU) CCCWFU # 62415 
 
 
Protocol Version Date 03/12/2021 
Page 61 of 83  
 
 
 
Acronyms 
AE – Adverse Event 
DSMC-Data and Safety Monitoring Committee 
SAE-Serious Adverse Event 
WFBCCC – Wake Forest Baptist Comprehensive Cancer Center 
NCI-National Cancer Institute 
WISER –Wake Integrated Solution for Enterprise Research 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 
treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 61 of 83  
 
Screen Shots: 
 
The following screen shots come from the SAE Console within the Subject Console in WISER. 
 
Screen Shot 1: 
 
Screen Shot 2: 
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 
treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 62415 
 
 
Protocol Version Date 03/12/2021 
Page 62 of 83  
 
Screen Shot 3: 
 
 
 
Screen Shot 4: 
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a 
combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 63 of 83  
 
Appendix E - Tumor Response Worksheet 
 
Immune-Related Response Criteria (irRC) Measurement Form 
Patient Name:   
 MRN: 
Study:   
 
 
Measurable Sites 
Lesion 
Site 
Imaging 
(ie, CT, 
MRI) 
Baseline Date: 
(Se,Im) 
Evaluation Date: 
(Se,Im) 
Evaluation Date: 
(Se,Im) 
Size of 
Lesion 
(mm x mm) 
Product of 
Measurement 
s 
(mm2) 
Size of Lesion 
(mm x mm) 
Product of 
Measurement 
s 
(mm2) 
Size of Lesion 
(mm x mm) 
Product of 
Measurement 
s 
(mm2) 
1. 
2. 
3. 
4. 
5. 
6. 
7. 
8. 
9. 
10. 
11. 
12. 
13. 
14. 
15. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a 
combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 64 of 83  
 
Sum of Product Measurements (mm2) 
Non-Measurable Sites 
Lesion 
Site 
Imagin 
g 
(ie, CT, 
MRI) 
Baseline Date: 
(Se,Im) 
Evaluation Date: 
(Se,Im) 
Evaluation Date: 
(Se,Im) 
1. 
2. 
3. 
4. 
5. 
6. 
7. 
8. 
9. 
10. 
11. 
12. 
13. 
14. 
15. 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a 
combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 65 of 83  
 
New Sites 
Lesion 
Site 
Imaging 
(ie, CT, 
MRI) 
Baseline Date: 
(Se,Im) 
Evaluation Date: 
(Se,Im) 
Evaluation Date: 
(Se,Im) 
Size of 
Lesion 
(mm x mm) 
Product of 
Measurements 
(mm2) 
Size of Lesion 
(mm x mm) 
Product of 
Measurements 
(mm2) 
Size of Lesion 
(mm x mm) 
Product of 
Measurements 
(mm2) 
1. 
2. 
3. 
4. 
5. 
6. 
7. 
8. 
9. 
10. 
11. 
12. 
13. 
14. 
15. 
Sum of Product Measurements (mm2) 
% Change (difference/nadir) 
Response (irCR, irPR, irSD, irPD) 
Radiologist Signature/Date 
Treating Physician Signature/Date 
PI Signature/Date 
 
 
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a 
combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 66 of 83  
 
Appendix F - Screening form 
 
1. Medical history: 
Myocardial infarction 
Congestive heart failure 
Peripheral vascular disease 
Cerebrovascular disease 
Dementia 
Chronic pulmonary disease 
Connective tissue disease 
Peptic ulcer disease 
Liver disease – 
mild 
moderate  
severe 
Diabetes – end organ damage? Yes 
No 
Hemiplegia 
Other cancer – specify   
 
Prior anticancer interventions? Yes 
No 
If yes, specify 
Date: 
 
/ 
 
/   
  
  
AIDs 
Other medical condition – specify   
 
 
2. Concurrent medications:  
 
 
 
 
 
 
 
 
3. Physical exam: 
 
Derm – 
WNL 
Abnormal, specify   
 
HEENT – 
WNL 
Abnormal, specify   
 
CV – 
WNL 
Abnormal, specify   
 
Pulm – 
WNL 
Abnormal, specify   
 
GI – 
WNL 
Abnormal, specify   
 
Other – 
Specify   
 
 
 
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 
2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 67 of 83  
 
4. Vital signs: 
a. HR  
 
b.BP _/  
 
d. Temp   
 
e. Weight 
(kg) 
 
 
b. RR  
 
 
f. Height 
(cm) 
 
 
5. Performance Status: 
 
GRADE 
ECOG 
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 
5 
Dead 
6. Documentation of negative pregnancy test for women of child-bearing potential? 
Yes 
No 
N/A 
If N/A, specify:   
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 
2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 68 of 83  
 
Appendix G - Study Data Collection Form 
To be completed prior to each treatment and at the End of Treatment visit 
 
Study Visit: 
Cycle 1 
Cycle 8 
Cycle 2 
Cycle 9 
Cycle 3 
Cycle 10 
Cycle 4 
Cycle 11 
Cycle 5 
Cycle 12 
Cycle 6 
Cycle 13 
Cycle 7 
End of Treatment 
Other (specify below): 
 
 
1. Concurrent medications:  
 
 
 
 
 
 
 
 
2. Physical exam: 
 
Derm – 
WNL 
Abnormal, specify   
 
HEENT – 
WNL 
Abnormal, specify   
 
CV – 
WNL 
Abnormal, specify   
 
Pulm – 
WNL 
Abnormal, specify   
 
GI – 
WNL 
Abnormal, specify   
 
Other – 
Specify   
 
3. Vital signs: 
a. HR  
 
b. BP _/  
 
c. RR  
 
 
d. Temp_  
 
e. Weight   
 
 
4. ECOG performance status 
GRADE 
ECOG 
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 
5 
Dead 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance 
status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 69 of 83  
 
 
Appendix H - Follow-up Form 
 
To be completed for long-term follow-up after treatment has finished 
 
1. Vital status: Alive 
Dead 
If deceased, date of death: 
 
/ 
 
/   
  
 
 
2. Disease state (last known, if deceased):   
 
 
3. Initiation of any new anticancer interventions since last contact? 
Yes 
No 
If yes, specify   
 
 
 
  
Date: 
 
/ 
 
/   
  
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 
treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 70 of 83  
 
Appendix I - EORTC QLQ-C30 English 
 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. 
The information that you provide will remain strictly confidential. 
 
1. 
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
Not at 
All 
1 
A 
Little 
2 
Quite 
a Bit 
3 
Very 
Much 
4 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. 
Do you have any trouble taking a short walk outside 
of the house? 
1 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. 
Were you short of breath? 
1 
2 
3 
4 
9. 
Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 
treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 71 of 83  
 
 
 
 
For the following questions please circle the number between 1 and 7 that best 
applies to you 
 
29.  How would you rate your overall health during the past week? 
1 
2 
3 
4 
5 
6 
7 
Very poor 
 
 
 
 
 
Excellent 
 
30.  How would you rate your overall quality of life during the past week? 
1 
2 
3 
4 
5 
6 
7 
Very poor 
 
 
 
 
 
Excellent 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
During the past week: 
 
 
 
 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with you family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance 
status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 72 of 83  
 
 
Appendix J - EORTC QLQ-LC13 English 
 
Patients sometimes report that they have the following symptoms or problems. Please indicate 
the extent to which you have experienced these symptoms or problems during the past week. 
Please answer by circling the number that best applies to you. 
 
 
During the past week: 
 
31. How much did you cough? 
32. Did you cough up blood? 
33. Were you short of breath when you rested? 
34. Were you short of breath when you walked? 
35. Were you short of breath when you climbed stairs? 
36. Have you had a sore mouth or tongue? 
37. Have you had trouble swallowing? 
38. Have you had tingling hands or feet? 
39. Have you had hair loss? 
40. Have you had pain in your chest? 
41. Have you had pain in your arm or shoulder? 
42. Have you had pain in other parts of your body? 
If yes, where   
  
43. Did you take any medicine for pain? 
1 
No 
2 
Yes 
If yes, how much did it help? 
1 
2 
3 
4 
Not at 
All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status 
of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 73 of 83  
 
 
Appendix K - EORTC QLQ-C30 Spanish 
 
Estamos interesados en conocer algunas cosas sobre usted y su salud. Por favor, responda a 
todas las preguntas personalmente, rodeando con un círculo el número que mejor se aplique a 
su caso. No hay contestaciones "acertadas" o "desacertadas". La información que nos 
proporcione será estrictamente confidencial. 
 
1. 
¿Tiene alguna dificultad para hacer actividades 
que requieran un esfuerzo importante, como 
En 
absoluto 
Un 
poco 
Bastante 
Mucho 
llevar una bolsa de compra pesada o una 
maleta? 
2. 
¿Tiene alguna dificultad para dar un paseo 
1 
2 
3 
4 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 
treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 74 of 83  
 
largo? 
1 
2 
3 
4 
3. 
¿Tiene alguna dificultad para dar un paseo 
corto fuera de casa? 
1 
2 
3 
4 
4. 
¿Tiene que permanecer en la cama o sentado/a 
en una silla durante el día? 
1 
2 
3 
4 
5. 
¿Necesita ayuda para comer, vestirse, asearse o ir 
al servicio? 
Durante la semana pasada: 
 
6. 
¿Ha tenido algún impedimento para hacer su 
trabajo u otras actividades cotidianas? 
7. 
¿Ha tenido algún impedimento para realizar sus 
aficiones u otras actividades de ocio? 
8. 
¿Tuvo sensación de "falta de aire" o dificultad 
para respirar? 
9. 
¿Ha tenido dolor? 
10. ¿Necesitó parar para descansar? 
11. ¿Ha tenido dificultades para dormir? 
12. ¿Se ha sentido débil? 
13. ¿Le ha faltado el apetito? 
14. ¿Ha tenido náuseas? 
 
 
 
Durante la semana pasada: 
absoluto 
poco 
Bastante 
Mucho 
15. ¿Ha vomitado? 
1 
2 
3 
4 
16. ¿Ha estado estreñido/a? 
1 
2 
3 
4 
17. ¿Ha tenido diarrea? 
1 
2 
3 
4 
18. ¿Estuvo cansado/a? 
1 
2 
3 
4 
19. ¿Interfirió algún dolor en sus actividades 
diarias? 
1 
2 
3 
4 
20. ¿Ha tenido dificultad en concentrarse en cosas 
como leer el periódico o ver la televisión? 
1 
2 
3 
4 
1 
En 
absoluto 
2 
3 
Un 
poco 
Bastante 
4 
Much
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
En 
Un 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 
treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 75 of 83  
 
21. ¿Se sintió nervioso/a? 
1 
2 
3 
4 
22. ¿Se sintió preocupado/a? 
1 
2 
3 
4 
23. ¿Se sintió irritable? 
1 
2 
3 
4 
24. ¿Se sintió deprimido/a? 
1 
2 
3 
4 
25. ¿Ha tenido dificultades para recordar cosas? 
1 
2 
3 
4 
26. ¿Ha interferido su estado físico o el tratamiento 
médico en su vida familiar? 
1 
2 
3 
4 
27. ¿Ha interferido su estado físico o el tratamiento 
médico en sus actividades sociales? 
1 
2 
3 
4 
28. ¿Le han causado problemas económicos su 
estado físico o el tratamiento médico? 
1 
2 
3 
4 
 
Por favor en las siguientes preguntas, ponga un círculo en el número del 1 al 7 
que mejor se aplique a usted 
 
29.  ¿Cómo valoraría su salud general durante la semana pasada? 
1 
2 
3 
4 
5 
6 
7 
Pésima 
Excelente 
30.  ¿Cómo valoraría su calidad de vida en general durante la semana pasada? 
1 
2 
3 
4 
5 
6 
7 
Pésima 
Excelente 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status 
of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 76 of 83  
 
Appendix L - EORTC QLQ-LC13 Spanish 
 
Los pacientes a veces dicen que tienen los siguientes síntomas o problemas. Por favor Indique 
hasta qué punto ha experimentado usted estos síntomas o problemas durante la semana 
pasada. Por favor responda rodeando con un círculo el número que mejor se aplique a su caso. 
 
Durante la semana pasada: 
En 
Un 
 
31. ¿Cuánto tosió? 
32. ¿Escupió sangre al toser? 
33. ¿Le faltó la respiración cuando descansaba? 
34. ¿Le faltó la respiración al caminar? 
35. ¿Le faltó la respiración al subir las escaleras? 
36. ¿Ha tenido algún dolor en la boca o en la 
lengua? 
37. ¿Ha tenido problemas para tragar? 
38. ¿Ha tenido hormigueos en las manos o en los 
pies? 
39. ¿Ha perdido cabello? 
40. ¿Ha tenido dolor en el pecho? 
41. ¿Ha tenido dolor en el brazo o en el hombro? 
42. ¿Ha tenido dolor en otras partes de su cuerpo? 
En caso afirmativo, ¿dónde?   
 
 
43. ¿Tomó alguna medicina para el dolor? 
1 
No 
2 
Si 
En caso afirmativo, ¿cuánto le alivió? 
1 
2 
3 
4 
absoluto 
1 
poco 
2 
Bastante 
3 
Mucho 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance 
status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 77 of 83  
 
Appendix M – Tumor Correlative Studies Form 
(Pre-Study) 
 
 
1. Percentage of tumor with an infiltrate of lymphocytes:   
 
 
2. Percentage of tumor with an infiltrate of macrophages:   
 
 
3. Average number of positive immune cells per high power field (HPF) in a minimum of 4 
representative HPF areas: 
a. Lymphocytes 
0 = no lymphocytes 
1 = 1-10/HPF 
2 = 11-50/HPF 
3 = >50/HPF 
b. Macrophages 
0 = no macrophages 
1 = 1-50/HPF 
2 = 50-100/HPF 
3 = >100/HPF 
 
4. Lymphocyte infiltrate score:   
 
 
5. Macrophage infiltrate score:   
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 
treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 78 of 83  
 
Appendix N – Blood Correlative Studies Form 
 
Study Visit (circle one): 
C1D1 
C2D1 (Pembro) 
C3D1(Pembro) 
EOT 
 
Cellular regulators 
 
1. Absolute lymphocyte count:   
 
 
2. Frequency (%) of the following phenotypes: 
 
Frequency (%) 
Effector 
CD4+ 
CD8+ 
ICOS+CD4+ 
ICOS+CD8+ 
T regulatory 
CD4+FoxP3+ 
Myeloid derived suppressor 
Lin-CD14+HLA-DRlow/− 
 
 
Soluble regulators 
 
[Concentration] 
TGF-β 
VEGF 
IL-6 
IL-8 
PGE2 (metabolite) 
sPD-1L 
 
 
Antigen specific response 
 
PBMC response: 
Positivity criteria 
Stimulation index 
[concentration] (pg/mL) 
IL-2, 40 
IL-4, 15 
IL-6, 20 
IL-10, 50 
IFN-γ, 75 
TNF-α, 30 
IL-17A, 20 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low 
dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University (CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 79 of 83  
Appendix O – Adverse Event Log 
 
WFBCCC Adverse Event (AE) Log 
 
PI:   
 
Subject PID:   
 
MRN:   
 
Cycle #: 
Cycle Start Date: 
Cycle Start Time: 
Cycle End Date: 
Cycle End Time: 
 
 
 
Adverse Event CTC 
Term 
Lab 
Value 
Grade 
(2-5) per 
CTC 
Start 
Date 
Attribution 
DEF= Definite 
PROB= Probable 
POSS= Possible 
UNLK= Unlikely 
UNRL= Unrelated 
Treating MD 
Initials + 
Date 
End Date 
Expected 
N= No 
Y= Yes 
*Serious Adverse 
Event Detail: 
NO= No 
LT= Life Threatening 
DTH= Death 
DIS= Disability HOS= 
Hospitalization CA= 
Caused congenital 
anomaly               
RI= Required 
intervention to prevent 
impairment 
Dose 
Limiting 
Toxicity 
(DLT) 
N= No 
Y= Yes 
Action Taken 
NO= None 
DR= Dose 
Reduced 
RI= Regimen 
Interrupted 
TD= Therapy 
discontinued 
INTR= Interrupted 
then reduced 
Therapy 
Given 
NO= None 
Reportable? 
SYM= 
IRB= IRB 
Symptomatic DSMC= DSMC 
SUP= 
FDA= FDA 
Supportive 
SPON= Sponsor 
VSUP= 
(Mark all that 
Vigorous 
apply) 
Supportive 
Advers
e Event 
Report 
(AER) 
filed? 
N= No 
Y= Yes 
Outcome  
R= Recovered 
TX= Still under 
treatment or 
observation 
A= Alive with 
Sequalae 
D= Died 
 
 
 
 
 
 
 
 
 
 
 
 
 
*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 DSMC = Data and Safety Monitoring CommitteeVersion 10/30/17 
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status 
of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 80 of 83  
 
 
 
 
 
Appendix P – Pembrolizumab Guidance Document 
 
Please refer to the package insert PDF for Pembrolizumab, available from 
www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf 
Last updated December 2018 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 
2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
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Appendix Q – ECOG Performance Status 
 
 
 
 
 
ECOG PERFORMANCE STATUS 
GRADE Description 
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 
5 
Dead 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status 
of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 82 of 83  
 
 
Appendix R: Response Criteria 
 
Study Visit: 
Pre-Study 
Week 8 ( ± 3 days) 
Week 20 ( ± 7 days) 
Week 32 ( ± 7 days) 
End of Treatment Visit 
Other visit: (please specify)   
 
 
Evaluation of target lesions 
 
Complete Response (irCR): Complete disappearance of all target and new, 
measurable lesions, with the exceptions of lymph nodes which must decrease to < 10 
mm in short axis. 
 
Partial Response (irPR): Decrease in total measured tumor burden (TMTB*) >30% 
relative to baseline. 
 
Stable Disease (irSD):  Not meeting criteria for irCR or irPR, in absence of irPD. 
 
Progressive Disease (irPD):  Increase in TMTB >20% relative to nadir. 
 
Evaluation of non-target lesions 
 
Complete Response (irCR): Complete disappearance of all non-target lesions. 
 
Non-irCR/Non-irPD: Non-target lesions do not meet the criteria for irCR or irPD. 
 
Progressive Disease (irPD): Unequivocal increase in the number or size of non- 
target lesions. To achieve unequivocal progression of non-target lesions, there must be 
a substantial worsening of non-target disease of a magnitude that, according to the 
treating physician, warrants a change in anticancer therapy. 
NOTE: Equivocal findings of progression of non-target lesions (e.g., small and 
uncertain new lesions; cystic changes or necrosis in existing lesions) should be 
considered irSD and treatment may continue until the next scheduled assessment. 
 
*TMTB=sum of the longest diameters (SOD) + SOD new, measureable lesions. 
 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. 
 
Treating Physician Signature:   
 Date: 
 
/ 
 
/   
  
 
 
PI Signature:   
 
Date: 
 
/ 
 
/   
  
 


Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status 
of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel 
Comprehensive Cancer Center of Wake Forest University 
(CCCWFU)  
CCCWFU # 62415 
 
Protocol Version Date 03/12/2021 
Page 83 of 83  
 
 
BEST OVERALL Response Criteria 
 
Study Visit: 
Pre-Study 
Week 8 ( ± 3 days) 
Week 20 ( ± 7 days) 
Week 32 ( ± 7 days) 
End of Treatment Visit 
Other visit: (please specify)   
 
 
 
Evaluation of Best Overall Response 
 
The overall response according to irRECIST is derived from the responses in TMTB as 
well as the presence of any non-target lesions as follows: 
 
Complete Response (irCR): Complete disappearance of all lesions (whether 
measureable or not);  lymph nodes must decrease to < 10 mm in shortest dimension. 
 
Partial Response (irPR): Decrease in TMTB >30% relative to baseline. 
 
Disease (irSD): Not meeting criteria for irCR or irPR, in absence of irPD. 
 
Progressive Disease (irPD): Increase in TMTB >20% relative to nadir. 
 
Confirmatory Measurement 
 
Confirmation: If there is suspicion of tumor progression at eight weeks, a second 
CT/MRI study 4 weeks after will need to be done as a confirmatory test. 
 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for irCR or irPR (if irCR is never met) until the first 
date that irPD is confirmed by independent radiology review or death, whichever comes 
first. 
 
Duration of disease control: The duration of time from the date measurement criteria are 
first met for irCR, irPR, or irSD, until the first date that irPD is confirmed by independent 
radiology review or death, whichever comes first. 
 
 
Treating Physician Signature:   
 Date: 
 
/ 
 
/   
  
 
 
 
PI Signature:   
 
Date: 
 
/ 
 
/   
  
 

ICF_001.pdf: 
Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU #62415
Page 1 of 10
Adult Consent Form
Version: 07/17/2019
Section of Hematology and Oncology
IMMUNE RESPONSE IN PATIENTS WITH RECURRENT OR METASTATIC 
NON-SMALL CELL LUNG CANCER AND PERFORMANCE STATUS OF 2 
TREATED WITH A COMBINATION OF PEMBROLIZUMAB AND LOW DOSE 
WEEKLY CARBOPLATIN/PACLITAXEL
 Informed Consent Form to Participate in Research
W. Jeff Petty, MD, 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 a type of cancer called non-small cell carcinoma of the lung (NSCLC) 
that is either recurrent, meaning you have previously received treatment for your NSCLC, or 
metastatic, meaning the cancer has spread to other parts of your body, and you have a 
performance status of 2, meaning that you are ambulatory, capable of all self-care, up and about 
more than 50% of waking hours, but unable to carry out any work. 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 compare the effects (good and bad) of pembrolizumab 
given every three weeks with or without low dose carboplatin and paclitaxel. The drug 
pembrolizumab is in a class of medications called monoclonal antibodies. It works by helping 
your immune system to slow or stop the growth of cancer cells.  Carboplatin and paclitaxel are 
chemotherapy drugs approved by the US Food and Drug Administration (FDA) for treatment of 
your disease. Pembrolizumab has been approved for the treatment of melanomas and, as of 
October 2016, for the treatment of patients with NSCLC.  The goal of this study is to determine 
if carboplatin and paclitaxel can improve the anti-tumor activity of pembrolizumab by improving 
the activity of your immune system against the tumor, and if it is useful for the treatment of 
patients with lung cancer who have a performance status of 2.  
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
43 people will take part in this study.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00034830
Meeting Date Approved 3/10/2021          
Version Valid Until: 3/9/2022


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU #62415
Page 2 of 10
Adult Consent Form
Version: 07/17/2019
WHAT IS INVOLVED IN THE STUDY?
Screening
During the first study visit, called a screening visit, you will have medical tests and procedures 
performed to help the study doctor decide if you meet the requirements to be in the study. These 
are all considered routine-care procedures (meaning they would be done regardless of your 
participation in this research study) and include: 

An assessment of your medical history, 

A physical examination, 

Blood chemistry lab tests measuring your red and white blood cells, platelets, liver and 
thyroid functions, 

A routine-care tumor biopsy, done at or within 12 weeks (84 days) of screening for this 
study (and with your consent to have your leftover tumor samples stored for future 
research at the Wake Forest Baptist Health Tumor Tissue Bank.) A portion of your tumor 
will be collected and checked for different types of immune cell markers to determine 
your eligibility for study entry.
o
If you already have a sample of tumor tissue stored at the Wake Forest Baptist 
Health Tumor Tissue Bank that is older than 12 weeks (84 days) at the time of 
this screening, you will be able to participate only if the sponsor considers that 
your ‘archived’ biopsied tumor tissue sample is useful for specific immune 
staining.  

Tumor assessments, which will be done by imaging studies such as computerized 
tomography (CT) or Positron emission tomography–computed tomography  (PET/CT) 
and magnetic resonance imaging (MRI scan).  
Before your treatment begins, you will be randomized into one of the study groups described 
below. Randomization means that you are put into a group by chance. It is like flipping a coin. 
You will have an equal chance of being placed in either group. 
Treatment
The two treatment groups are:

Single agent treatment: Pembrolizumab every three weeks as 30 minute intravenous 
infusion 
or 

Combination agent treatment: Pembrolizumab every three weeks as a 30 minute 
intravenous infusion plus low-dose weekly carboplatin and paclitaxel administered as 1-
hour intravenous infusions.
Study visits

Patients in the combination agent treatment group will be seen on a weekly basis for a 
physical exam, labs, and to receive treatment. Patients in the single agent treatment group 
will be seen every 3 weeks for a physical exam, labs, and to receive treatment. 

At the initial visit, at 8 weeks after you started treatment, and then every 12 weeks 
thereafter you will have an examination of your tumor(s) by computed tomography 
(CT)—like an x ray that uses radiation to produce pictures of your body, including 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00034830
Meeting Date Approved 3/10/2021          
Version Valid Until: 3/9/2022


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU #62415
Page 3 of 10
Adult Consent Form
Version: 07/17/2019
tumors, or magnetic resonance imaging (MRI)—which uses a magnetic field to produce 
an image of your body, including tumors. Your study doctor will determine which type of 
test (either CT or MRI) is best to assess your cancer.

Prior to your first treatment with pembrolizumab (Cycle 1, Day 1), then again on Day 1 
of Cycles 2 and 3 of pembrolizumab, and at the end-of-treatment visit (EOT), blood 
samples will be drawn to examine immune response. 

At the initial visit and then every 12 weeks you will complete a study questionnaire 
asking about how you are feeling.
Tumor Assessments
Tumor size assessment by imaging studies such as computerized tomography (CT scan), 
magnetic resonance imaging (MRI scan), or other methods (x-rays or physical exam) will be 8 
weeks after you started treatment and then approximately every 12 weeks thereafter.  It is 
possible that you will receive contrast dye injections during these time points, unless you are 
allergic to it.
Blood drawing
Samples of your blood and urine will be collected throughout the study. In the combination agent 
treatment group, these samples will be taken once a week. In the single agent treatment group, 
blood and urine samples will be taken every three weeks. Blood will be taken from a vein in your 
arm using a needle. For the immune studies, about 2 tablespoons of blood will be collected on 
the day you receive your first treatment (Cycle 1 Day 1), after 3 weeks (Cycle 2 Day 1 of 
pembrolizumab), after 6 weeks (Cycle 3 Day 1 of pembrolizumab), and then at the End of 
Treatment Visit. 
Study participant responsibilities
If you agree to participate in this study, you have certain responsibilities to help ensure your 
safety. These responsibilities are listed below.

Complete all required visits

Take the study medications as prescribed

Report all side effects and medical problems to the study personnel

Inform the study doctor or staff if you decide to discontinue your participation. You will 
be asked to complete an end of treatment visit
HOW LONG WILL I BE IN THE STUDY?
The active chemotherapy treatment period for this study can be up to 2 years. However, we will 
cap your treatment with carboplatin at 12 weeks (~3 months) if you are still getting treatment on 
the study at that time. You may continue to receive treatment with pembrolizumab and paclitaxel 
until your cancer progresses (gets worse), you can no longer tolerate the treatment, your doctor 
believes it is no longer in your best interest to continue the study treatment, or you decide to 
withdraw from the study. After you finish receiving treatment on this study, you will have an 
End of Treatment study visit with a physical exam, blood chemistry lab tests measuring your red 
and white blood cells, platelets,  liver and thyroid functions, and a tumor biopsy. You will be 
contacted by a member of your study doctor’s research team about every 8 weeks to see how you 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00034830
Meeting Date Approved 3/10/2021          
Version Valid Until: 3/9/2022


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU #62415
Page 4 of 10
Adult Consent Form
Version: 07/17/2019
are doing and ask for an update on other anti-cancer therapies you have taken. This will most 
likely be done by telephone, but may also overlap with a routine clinic visit with your doctor.
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. If you decide to stop participating in 
the study please contact Dr. Petty at 
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. One risk is that you may get a drug or dose of a drug that does not help treat 
your disease or that makes your condition or disease worse. Another risk is that there may be 
side effects. Risks and side effects related to the drugs we are studying include: fatigue, cough, 
nausea/vomiting, itchy skin, rash, decreased appetite, constipation, muscle aches, diarrhea, 
mouth sores, hair loss, and low blood counts. Uncommon adverse effects include pain with 
breathing, pneumonia, infections, and kidney dysfunction.
Pembrolizumab: Most common adverse reactions (reported in ≥20% of patients) included 
fatigue, fever, cough, dyspnea (shortness of breath), nausea and/or vomiting, skin rash or itching, 
muscle aches, back pain, decreased appetite, constipation, and diarrhea. 
Uncommon but serious adverse drug reactions (reported in 2% -10% of patients) were 
hyperthyroidism (overactive thyroid), and inflammation in the lungs (pneumonitis) or skin 
(cellulitis). Most of the reported side effects are reversible with steroids or hormone therapy, and 
no deaths due to undesirable effects of the drug have been reported with the use of 
Pembrolizumab for the treatment of lung cancer patients.
Very rarely (less than 2% of patients), and reported in other  clinical studies involving 
Pembrolizumab, serious adverse reactions have included inflammations in various areas of the 
body including the colon, liver, pituitary gland, kidneys, heart wall, even a severe skin 
inflammation known as Stevens-Johnsons syndrome, which includes painful blistering and 
peeling of the skin and can give you flu-like symptoms.  These inflammation disorders have been 
reported to cause hospitalization and, in one extreme case, reported to lead to death.  The study 
sponsor, Merck, continues to monitor the safety profile of this drug and inform all study doctors 
of new risks. 
Paclitaxel: The most common adverse reactions (incidence ≥25%) include bone marrow 
suppression and overall low blood counts (neutropenia, leukopenia, anemia, thrombocytopenia), 
blood/bone marrow infections, bleeding, increased need for blood transfusions, hypersensitivity 
reactions, abnormal ECG, other heart problems, low blood pressure, nerve pain, joint pain, 
nausea/vomiting, diarrhea, mouth inflammation, hair loss, liver dysfunction, and injection site 
reactions.
Carboplatin: Bone marrow suppression is the dose-limiting toxicity of carboplatin. The most 
common adverse reactions (incidence ≥20%) during therapy with carboplatin as a single agent 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00034830
Meeting Date Approved 3/10/2021          
Version Valid Until: 3/9/2022


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU #62415
Page 5 of 10
Adult Consent Form
Version: 07/17/2019
were the same as for paclitaxel described above, but to include kidney dysfunctions as seen in 
rising creatinine or blood urea elevation, electrolyte depletion, and generalized pain.  There is 
also a risk of allergic reaction to carboplatin.
Regarding the combination of pembrolizumab with low dose carboplatin and paclitaxel, we do 
not anticipate any potentiation of side effects. Studies done with similar drug combinations, 
confirm that the treatment seems to be tolerable with manageable toxicity. If you are randomized 
to the combination treatment, the study team will perform weekly physical exams and blood tests 
to monitor your tolerance to the treatment.  
Possible risks from study procedures
Blood tests: 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 occasions.  Frequent donation of blood can result in low iron in your blood (iron deficient 
anemia).  
Tumor Biopsy (Standard of Care):  The possible risks associated with removal of a piece of your 
cancer (a biopsy) depend on the part of the body where the biopsy will be performed. You may 
experience pain from the biopsy and you may have bruising, soreness or scarring at the biopsy 
site. Rarely, a patient who has had a biopsy may experience infection and/or internal bleeding 
and depending on the location of the biopsy, ‘punctured lung’ and/or ‘collapsed lung’ (due to an 
abnormal collection of air or gas in the space that separates the lung from the chest).
CT scans (Standard of Care): Participation in this research study will involve exposure to 
radiation from the CT scan. The amount of radiation exposure that you will receive from each 
CT scan is considered minimal. The more radiation received over the course of your life 
increases the risk of cell changes in your body or having cancerous tumors.  The radiation from 
this study is not expected to greatly increase these risks, but the exact increase of such risks is 
unknown.
Some CT scans require you to take a “contrast solution” either by mouth, enema, or injection 
into a vein. Although rare, the contrast solution may cause an allergic reaction such as nausea, 
vomiting, itching, skin rash, or in very rare instances a swelling of the throat and difficulty in 
breathing. If you feel any of these symptoms of an allergic reaction you must tell the staff 
immediately so that you can be treated without delay.  In addition, because you must lie with 
your head and neck inside the narrow scanner tube, you may become anxious and frightened 
inside the enclosed space (claustrophobic).
MRI (Standard of Care): When having an MRI (Magnetic Resonance Imaging) scan, you will lie 
still on a table that slides into a tunnel slightly wider than your body. People who feel 
uncomfortable in confined spaces (claustrophobia) may feel uncomfortable in the narrow 
cylinder. If you feel uncomfortable in confined spaces, please tell your study doctor. Your study 
doctor may give you a medication to make you feel more comfortable in a confined space. 
MRIs use powerful magnets to make images. Therefore, persons with certain metal implants, 
WFU School of Medicine 
Institutional Review Board 
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Meeting Date Approved 3/10/2021          
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Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU #62415
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Adult Consent Form
Version: 07/17/2019
such as pacemakers, should not have an MRI. If you have an implant or any metal in your body, 
please check with your study doctor to see whether you can have an MRI or not. For people 
without metal implants, there are no known health risks associated with exposure to the magnet. 
As images are taken, a loud banging noise will be produced. Earplugs or headphones may be 
available if needed. The MRI can be stopped at any time at your request, but the scan may not be 
complete.
Taking part in this research study may involve providing information that you consider 
confidential or private. We will do our best to protect your confidential information. 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. 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.
Reproductive Risks and other Issues to Participating in Research
Due to unknown risks and potential harm to the unborn fetus, sexually active women of 
childbearing potential and men whose female partner can have children must use a reliable 
method of birth control while participating in this study and for 4 weeks after your last dose of 
study drug. 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. If you suspect that you or your partner 
may have become pregnant during the study, contact the study doctor immediately. Your study 
doctor will want to follow you and the progress of your pregnancy until the baby is born. 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 prior to study entry, if you are a 
sexually active woman of childbearing potential.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
You may not receive any direct benefit from participating in this study. In some patients, the 
cancer may stop spreading, may shrink in size, or may become undetectable. Even if you do not 
receive any personal benefit from this study, your participation may benefit future patients by 
helping develop a new therapy for others with similar conditions.
WHAT OTHER CHOICES ARE THERE?
If you do not wish to participate in this study, you may continue to be treated by your doctor and 
your care will not be jeopardized in any way. Your doctor will discuss other treatment options 
available to you. For example, you may receive the treatment weekly carboplatin and paclitaxel 
without participating in this study.  
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00034830
Meeting Date Approved 3/10/2021          
Version Valid Until: 3/9/2022


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU #62415
Page 7 of 10
Adult Consent Form
Version: 07/17/2019
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you and/or 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 results from 
your blood tests, physical examinations, gender, demographics, and other tests. It also includes 
identifying information such as your name and date of birth. 
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 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. Only the following people or organizations will be granted access to your 
Protected Health Information:
1) The study investigator and his/her staff, or others at Wake Forest University Health 
Sciences who oversee research
2) Other people or laboratories providing services for this research project on behalf of 
Wake Forest University Health Sciences and Wake Forest University Baptist Medical 
Center 
3) Federal agencies with regulatory oversight, such as the FDA and the Department of 
Health and Human Services (DHHS)
4) 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.
5) The study sponsor and those that they have designated to work on this research study
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 an indeterminate period of time. This authorization does not 
expire. You will not be able to obtain a copy of your Protected Health Information in the 
research records until all activities in the study are completely finished. The results of this study 
may be presented at meetings or in publications; however, your identity will not be disclosed in 
these presentations. Individual results from tumor biopsy analysis will not be provided to you or 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00034830
Meeting Date Approved 3/10/2021          
Version Valid Until: 3/9/2022


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU #62415
Page 8 of 10
Adult Consent Form
Version: 07/17/2019
your study doctor and will not be placed in your medical chart considering that all this data is 
still investigational and not part of the standard of care procedures.
You can tell W. Jeff Petty, MD 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:
W. Jeff Petty, MD
Wake Forest Baptist Health
Section on Hematology and Oncology
Medical Center Blvd.
Winston-Salem, NC  27157
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.  
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.
WHAT ARE THE COSTS?
There are no costs to you for taking part in this study. You or your insurance company will be 
charged for any portion of your care that is considered standard. You will not need to pay for any 
tests or procedures that are done for the sole purpose of this study. You may be responsible for 
any co-payments and deductibles that are standard for your insurance coverage. There will be no 
additional cost to you to participate in this research study.  All study costs, including 
Pembrolizumab and procedures related directly to the study will be paid for by the study. Costs 
for your regular medical care, which are not related to this study, will be your own responsibility.
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00034830
Meeting Date Approved 3/10/2021          
Version Valid Until: 3/9/2022


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU #62415
Page 9 of 10
Adult Consent Form
Version: 07/17/2019
WILL YOU BE PAID FOR PARTICIPATING?
Your involvement in this research study is voluntary and you will not be paid for your 
participation. Parking validation will be provided for all study-related visits.
The findings from this research may result in the future development of products that are of 
commercial value. There are no plans to provide you with financial compensation or for you to 
share in any profits if this should occur.
WHO IS SPONSORING THIS STUDY?
Merck & Co., Inc. is providing investigational drug, money or other support to Wake Forest 
University Health Sciences to help conduct this study. The researchers do not, however, hold a 
direct financial interest in the sponsor or the product being studied.
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,
.
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 Dr. Petty, or study personnel 
.
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. To ensure your safety, you will be asked to undergo a final evaluation visit. 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00034830
Meeting Date Approved 3/10/2021          
Version Valid Until: 3/9/2022


Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU #62415
Page 10 of 10
Adult Consent Form
Version: 07/17/2019
The investigators also have the right to stop your participation in the study at any time. This 
could be because it is in your best medical interest, your condition worsened, new information 
becomes available, you had an unexpected reaction, you failed to follow instructions, or because 
the entire study has been stopped. 
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, Dr. Petty, or study personnel 
.
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 
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
    
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00034830
Meeting Date Approved 3/10/2021          
Version Valid Until: 3/9/2022