Phase II Study of Pembrolizumab in Combination With Platinum-based Chemotherapy in Nonsmall Cell Lung Cancer Patients With Targetable Genetic Alterations Previously Treated With Appropriate Targeted Agents With Progressive Disease
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Sponsor: University of Michigan Rogel Cancer Center

ID: UMCC 
2017.057 
    Pembrolizumab in Combination With Platinum-Based 
Chemotherapy in Non-Small Cell Lung Cancer (NSCLC) 
Patients With Targetable Genetic Alterations, Previously 
Treated With Appropriate Targeted Agents, With 
Progressive Disease 
    NCT03242915 
 

 
UMCC 2017. 057 
 
 
1 
 
 
TITLE: UMCC 2017. 057: Phase II multi-center study of pembrolizumab in 
combination with platinum-based doublet chemotherapy in NSCLC (non-small cell 
lung cancer) patients with targetable genetic alterations in their tumor previously 
treated with appropriate targeted agents with progressive disease 
 
IND NUMBER: IND Exempt 
 
Principal Investigator 
Gregory Kalemkerian, MD 
1500 E. Medical Center Drive 
C350 Med Inn Building – SPC 5848 
Ann Arbor, MI 48109 
Tel: (734) 647-8921 
Fax: (734) 647-8792 
email: kalemker@med.umich.edu 
 
Coordinating Center 
University of Michigan 
 
Statistician 
 
Thomas Braun, PhD 
University of Michigan  
Cancer Center Biostatistics, Analytics and Bioinformatics Core, M4063 SPH II 
Ann Arbor, MI 48109 
P: (734) 936-9844 
Email: tombraun@umich.edu 
 
Version:  05/03/2021 
 
NOTE: The study was amended to address protocol-required items that the COVID-19 
pandemic may temporarily affect.  The potential changes are listed in Section 15.0 
(COVID-19 Addendum). 
 
 

 
UMCC 2017. 057 
 
 
2 
 
Index 
 
1.0 Trial Summary 
 
 
 
 
 
 
 
 
3 
 
2.0 Trial Diagram 
 
 
 
 
 
 
 
 
5 
 
3.0 Objectives and Hypothesis 
 
 
 
 
 
 
5 
 
4.0 Background and Rationale 
 
 
 
 
 
 
6 
 
5.0 Methodology (Inclusion & Exclusion Criteria)  
 
 
 
16 
 
6.0 Trial Treatments  
 
 
 
 
 
 
 
19 
 
7.0 Trial Flow Chart  
 
 
 
 
 
 
 
34 
 
8.0 Trial Procedures  
 
 
 
 
 
 
 
37 
 
9.0 Correlative Studies 
 
 
 
 
 
 
 
48 
 
10.0 Statistical Analysis Plan  
 
 
 
 
 
 
51 
 
11.0 Labeling, Packaging, Storage and Return of Clinical Supplies  
 
54 
 
12.0 Administrative & Regulatory Details 
 
 
 
 
 
55 
 
13.0 References 
 
 
 
 
 
 
 
 
59 
 
14.0 Appendices 
 
 
 
 
 
 
 
 
63 
 
15.0 Addendum 
 
 
 
 
 
 
 
 
65 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
UMCC 2017. 057 
 
 
3 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
A 
multi-center 
study 
of 
pembrolizumab 
with 
platinum-based 
chemotherapy in patients in NSCLC patients with targetable genetic 
alterations, previously treated with appropriate targeted agents with 
progressive disease 
Trial Phase 
II 
Clinical Indication 
Non-Small Cell Lung Cancer (NSCLC) 
Trial Type 
Single Arm Open Label Phase II with 2 cohorts 
Type of control 
N/A 
Treatment 
and 
Route 
of 
administration 
Pembrolizumab 200 mg with carboplatin at AUC 5 and pemetrexed at 500 
mg/m2 administered intravenously every 3 weeks 
Duration of Therapy 
All drugs will be administered for a maximum of 4 cycles followed by 
maintenance pemetrexed and pembrolizumab for a maximum of 24 
months.  
Trial Blinding 
N/A 
Treatment Groups  
Single Group 
Number of trial subjects 
31 EGFR and 31 NSCLC patients with other targetable genetic alterations 
Study Centers 
6 including University of Michigan as the lead site.  
Estimated enrollment period 
24 months 
Estimated duration of trial 
48 months 
Duration of Participation 
24 months 
Estimated average length of 
treatment per patient 
7 months 
Primary Objective 
To assess the response rate (RR) of the combination of pembrolizumab 
and chemotherapy in EGFR mutation or patients with NSCLC patients 
with other targetable genetic alterations, who have progressive disease 
following appropriate targeted therapy. 
Key Inclusion Criteria 
1. Cohort 1-Patients with EGFR mutation positive NSCLC 
previously treated with appropriate targeted therapy with 
measurable and progressive disease. Cohort 2- Other genetically 
altered NSCLC patients, previously treated with appropriate 
targeted therapy with measurable and progressive disease. 
Patients could have received more than one targeted therapy. 
Patients taken off an appropriate targeted therapy due to 
intolerance are eligible.  
2. Tumor to assess PD-L1 status should be available unless PD-L1 
status of the tumor is known.  
3.  ECOG PS of 0,1 
4. Defined hepatic, renal and hematologic laboratory results 

 
UMCC 2017. 057 
 
 
4 
 
Key Exclusion Criteria 
1. Has a diagnosis of immunodeficiency. Patient should not be on 
any immunosuppressive therapy or steroids > prednisone 
10mg/day or its equivalent on the day of the start of therapy. 
2. Has had targeted small molecule therapy, or palliative radiation 
therapy within 1 week 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. Some exceptions are allowed. 
3. Has symptomatic central nervous system (CNS) metastases 
and/or carcinomatous meningitis.  Subjects with asymptomatic 
brain metastases may participate provided they are clinically 
stable and are not using steroids equivalent to >10mg of 
prednisone day prior to trial treatment. 
4. Has active autoimmune disease that has required systemic 
treatment in the past 2 years (i.e. with use of disease modifying 
agents, 
corticosteroids 
or 
immunosuppressive 
drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic 
treatment.  
5. Has known history of non-infectious pneumonitis that required 
steroids or has current pneumonitis. Has known history of 
interstitial lung disease.  
Statistical Design 
The study design is a multi-site, single arm phase II trial with 2 parallel 
cohorts. To minimize the number of patients required the single arm two-
stage minimax Simon's design will be used for each cohort. The study will 
be conducted in two separate cohorts; EGFR mutation positive NSCLC 
cohort and NSCLC patients with other genetic alterations, previously 
treated with appropriate targeted therapy. The primary objective is to 
assess the treatment efficacy based on the response rate (RR), of 
combination pembrolizumab and platinum-based doublet in EGFR 
mutation positive or NSCLC patients with other genetic alterations 
patients who have progressed in the two study cohorts. The primary 
endpoint is RR defined by RECIST 1.1. 
For each cohort the sample size calculation is the same as we chose the 
same parameter settings. Sample size calculation: The combination 
treatment would be of clinical interest if the RR is > 0.55 and will not if 
the RR is <0.3. With 14 pts in stage I and 28 total pts, the 2-stage Simon’s 
minimax design has a 5% type I error and 85% power and a probability of 
early termination of 0.58. The cohort is to be terminated at stage I if ≤ 4 
pts respond. If the cohort goes on to stage II and total number of responses 
is ≤ 12, the treatment is rejected. Thus, if both cohorts go to stage II then 
each of the cohorts will require 28 evaluable patients. To be evaluable for 
efficacy, the patient has to have received at least one dose of 
pembrolizumab and doublet chemotherapy. We assume an ineligibility 
rate of 10% so we plan to enroll 31 patients in each cohort of the trial. 

 
UMCC 2017. 057 
 
 
5 
 
Due to slow enrollment on the study and changes in study personnel, 
the study enrollment will be terminated on December 31, 2020. We 
anticipate that we will enroll approximately 25 patients in Cohort 1 
and approximately 7 in Cohort 2.    
 
 
 
 
 
2.0  TRIAL DIAGRAM 
Trial Diagram 
 
 
 
 
 
The primary end point of the study is to assess response rate (RR) by RECIST 1.1.  
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 Primary Objective(s) & Hypothesis(es) 
Objective: To assess the response rate (RR) by RECIST 1.1 (Appendix 14.3) of the 
combination of pembrolizumab and chemotherapy in EGFR mutation or patients with NSCLC 
with other genetic alterations, who have progressive disease following appropriate targeted 
therapy.  
Hypothesis:  We hypothesize that addition of pembrolizumab will enhance the efficacy of 
carboplatin and pemetrexed in EGFR mutation and patients with NSCLC with other genetic 
alterations who have disease progression following appropriate targeted therapy.   
3.2 Secondary Objective(s) 
1. To assess the PFS (progression free survival defined by RECIST 1.1) (Appendix 
14.3), OS (Overall Survival) in these patients. 
 
Pembrolizumab 
+ 
Carboplatin/Pemetrexed 
Disease 
assessment 
every 6 
weeks.  
EGFR or patients 
with NSCLC with 
other genetic 
alterations 
previously treated 
with appropriate 
targeted therapy  

 
UMCC 2017. 057 
 
 
6 
 
3.3 Other Objectives 
1. To assess the toxicity of the combination.  
2. To correlate the RR with PD-L1 status of the tumor and the mutational load of the 
tumor. 
3. To assess the numerical changes in the CTCs (circulating tumor cells) count 
before the 1st and before 3rd cycles of therapy and correlate it with response to 
study therapy.  
4. To assess the ability to analyze PDL1 expression and assess the expression of 
EMT markers in CTCs.  
5. To assess the ability to extract tumor DNA from CTCs and conduct analysis of 
EGFR and other gene alterations.  
 
4.0 BACKGROUND & RATIONALE 
4.1 Background 
4.1.1 EGFR mutation positive NSCLC 
EGFR tyrosine kinase inhibitors (TKIs) are the standard first line therapy for advanced 
NSCLC patients (pts) with tumors that harbor activating EGFR mutations (1). For pts 
progressing on first line TKIs, the most common mechanism of resistance is presence of 
T790M mutation (2). Recently, T790M inhibitors, like osimertinib, have shown clinical 
benefit in these pts. However, almost all patients develop tumor progression even on 
these drugs (3,4). In addition, there are no approved targeted treatments for pts who have 
other mechanisms of resistance. Many of these patients will be considered for 
chemotherapy. The IMPRESS trial showed that continuation of gefitinib, an EGFR TKI, 
after disease progression did not prolong PFS in pts who received platinum-based doublet 
chemotherapy as subsequent therapy. Thus, platinum-based doublet chemotherapy 
remains a treatment option for patients with EGFR mutation positive cancer who have 
disease progression on a T790M inhibitor or have progression of disease following front 
line EGFR-TKI and don’t have the T790M mutation in their tumor. In the IMPRESS 
trial, the response rate (RR) to chemotherapy was 33% (5). Another combination 
evaluated in a similar population is the combination of afatinib and cetuximab. In a single 
arm multi-institutional study the response rate with this combination was 29% (6).  
 
4.1.2 Other genetically altered NSCLC 
 
Several ALK inhibitors are currently approved as front line therapy for ALK positive 
NSCLC (7). The median progression free survival with these drugs can range from   about 
11 months to 34 months. Two drugs are currently approved for the treatment of crizotinib 
resistant/refractory ALK positive NSCLC, ceritinib and alectinib (8, 9). The response 

 
UMCC 2017. 057 
 
 
7 
 
rate with these agents is about 50% and the median PFS is about 6-9 months. There are 
other agents, such as lorlatinib, that have shown activity in ALK positive patients 
following treatment with 2 prior ALK inhibitors (10). However, many patients eventually 
require chemotherapy. Though the response rate with chemotherapy in ALK positive 
patients who have received 2 prior ALK inhibitors is not known, it is expected to be 
around the same as observed in EGFR mutation positive NSCLC patients in the 
IMPRESS trial.    
 
Over the last few years targeted drugs for other genetically altered NSCLC have also 
received FDA approval. Crizotinib and entrectinib are now approved for the treatment of 
ROS1 positive NSCLC (11.12). Similarly, the combination of dabrafenib and trametinib 
is approved for the treatment of Braf mutation positive NSCLC and recently larotrecinib 
was approved for the treatment of NTRK gene rearranged cancers (13, 14). In addition, 
NCCN guidelines include treatment with crizotinib for patients with cMET amplification 
and exon 14 skip mutation and RET inhibitors for the treatment of RET altered NSCLC 
(15). Despite clinical efficacy of these agents, almost all patients eventually experience 
disease progression. Many of these patients are treated with platinum based 
chemotherapy. The efficacy of platinum based chemotherapy following targeted therapy 
in these patients is not well defined but is not expected to be any better than the efficacy 
of chemotherapy in EGFR or ALK positive patients.  
 
4.2 Immune Surveillance and PD-1 axis 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (16).  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies (17,18,19).  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 (20,21,22,23,24).  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.  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 

 
UMCC 2017. 057 
 
 
8 
 
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 
(MEL).  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 (Keytruda®) 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.  In the case of pembrolizumab the use is restricted to patients 
whose tumors express PD-L1. More recently pembrolizumab was approved for front line use 
in advanced NSCLC patients with tumors that have high PD-L1 expression. This approval was 
based on the results of the Keynote-24 trial (25). In this trial patients with tumors that had ≥ 
50% tumor proportion score (TPS score) for PD-L1 expression were randomized to 
pembrolizumab or platinum based chemotherapy. Patients with EGFR mutation and ALK 
positive NSCLC were excluded. The results of this study showed that pembrolizumab 
significantly improved survival and progression free survival compared to chemotherapy. Thus 
currently single agent pembrolizumab is approved for advanced NSCLC patients as front line 
therapy if their tumors have high PD-L1 expression and for patients who have had prior 
chemotherapy or targeted therapy if their tumor has any level of PD-L1 expression.   
4.2.1 Anti-PD-1 Therapy in patients with NSCLC with gene alterations 
PD1 inhibitors, such as pembrolizumab and nivolumab and PD-L1 inhibitor atezolizumab have 
been FDA approved for second line therapy in NSCLC (26,27,28). Activity of single agent 
anti-PD-1/PD-L1 drugs has been modest in EGFR mutated/ALK positive patients. 
Retrospective subset analysis of Checkmate 057 and atezolizumab trials showed that never 

 
UMCC 2017. 057 
 
 
9 
 
smokers and EGFR mutated pts did not derive greater benefit from these agents compared to 
docetaxel . Recently, Gainor, et al published the results of a retrospective analysis of the use 
of these agents in 28 patients with EGFR mutation (n=22 patients) or ALK translocations (n=6 
patients) (29). Of these patients, only 1 EGFR mutation positive patient had tumor response to 
a PD-1 directed agent. This response rate was far lower than the response rate of 23% among 
30 patients, treated at the same institution, who were EGFR and ALK wild type or ALK 
unknown.   Similar results have been reported in patients with other gene altered NSCLC (29). 
Previous studies have suggested that tumors with higher number of somatic mutations such as 
melanoma and lung cancer had higher RR to PD1-blockade (30, 32). This was also supported 
by the observation that in lung cancer cohorts, pts with smoking history had higher RR to PD1 
inhibition (31). In addition, anti-PD-1 drugs have shown clinical benefit in mismatch repair-
deficient colorectal cancer which are known to have 10 to 100 times as many somatic mutations 
as mismatch repair-proficient (34). The relative lack of benefit with anti-PD-1 agents in EGFR 
mutated or ALK positive patients may be a result of low mutation load, since most are 
never/light smokers.  
4.2.2 Combination of Pembrolizumab and Chemotherapy  
Since recurrent tumors are likely to have greater mutational load, it can be speculated that anti-
PD-1 drugs may be more beneficial in EGFR mutation and ALK positive NSCLC pts following 
recurrence, as compared to front line therapy. With the recognition that anti-PD-1 drugs have 
only modest activity in recurrent EGFR mutated and ALK positive patients, these drugs may 
have to be combined with other drugs in such patients. Chemotherapy is thought to cause 
release of tumor antigens through cell necrosis and activate the anti-tumor T cell response 
which can be further potentiated with the addition of anti-PD-1 drugs. Initial results evaluating 
the combination of pembrolizumab with chemotherapy have shown promising results (29). 
In the Keynote 021 trial (35), 74 advanced NSCLC patients were treated with one of 3 different 
chemotherapy regimens in combination with pembrolizumab. In cohort A, patients received 
carboplatin and paclitaxel; in cohort B, patients received carboplatin paclitaxel and 
bevacizumab and in cohort C patients received carboplatin (Parapatin®) and pemetrexed 
(Alimta®). The overall response rate was 57% (RR varied from 48%-71%). The response rate 
did not vary according to the PD-L1 status. The median PFS (progression free survival) was 
10.2 months in cohorts A and C and had not been reached at the time of analysis in cohort B. 
No unusual toxicities were reported. Immune related AEs were reported in 16%-38% of the 
patients.  
Subsequently over 120 patients with advanced non-squamous histology were randomized to 
carboplatin pemetrexed with or without pembrolizumab (36). The results of this randomized 
cohort demonstrated that the progression free survival (median 13mo vs. 8.9mo, HR- 0.53, 
p=0.0102) and response rate (55% vs. 29%) were significantly improved with the addition of 
pembrolizumab. These data suggest that the addition of pembrolizumab can enhance the 

 
UMCC 2017. 057 
 
 
10 
 
efficacy of chemotherapy regimens and this study also showed that the increase in efficacy can 
occur irrespective of tumor PD-L1 expression. Based on these data a randomized double blind 
phase III study Keynote 189 was initiated and reported similar results (37) initiated 
(NCT02578680). In this study treatment naïve advanced non-squamous NSCLC patients, that 
are EGFR and ALK negative were randomized in 2:1 fashion to chemotherapy and 
pembrolizumab. Based on the improved survival observed with combination of 
pembrolizumab and chemotherapy, the FDA has now approved the regimen for advanced 
NSCLC patients without EGFR or ALK gene alterations in their tumors.         
 
4.3 Preclinical and Clinical Trial Data 
Refer to the investigator’s brochure and package insert for preclinical and clinical data of 
pembrolizumab. Also please refer to package inserts of carboplatin (paraplatin®) and 
pemetrexed (Alimta®) for details of these drugs. 
4.4 Rationale 
4.4.1 Rationale for the Trial and Selected Subject Population 
EGFR tyrosine kinase inhibitors (TKIs) are the standard first line therapy for advanced 
NSCLC patients (pts) with tumors that harbor activating EGFR mutations. The most 
common mechanism of resistance in pts progressing on first line TKIs is presence of 
T790M mutation. T790M inhibitors, like osimertinib, have shown clinical benefit in 
these pts. However, almost all patients eventually develop tumor progression. In addition, 
there are no approved targeted treatments for pts who have mechanisms of resistance, 
other than T790M. All such patients will be considered for chemotherapy. The most 
commonly considered chemotherapy for such patients is the combination of carboplatin 
and pemetrexed.    
ALK inhibitors are now consistently utilized as front line and second line treatments for 
ALK positive NSCLC patients. Though there are ALK inhibitors in development that 
may have activity after patients that have received 2 ALK inhibitors, chemotherapy will 
be considered for many of these patients. As with EGFR mutated NSCLC patients, 
carboplatin and pemetrexed is the most commonly considered chemotherapy 
combination for ALK positive NSCLC patients who have progressed on 2 or more ALK 
inhibitors.  
Similarly, though targeted agents are used for other gene altered NSCLC patients such 
as Braf, ROS1 or RET, chemotherapy is considered in patients who have disease 
progression following targeted therapy.  

 
UMCC 2017. 057 
 
 
11 
 
Anti-PD-1 drugs may be more beneficial in EGFR mutation, ALK positive NSCLC and 
other gene altered NSCLC pts following recurrence, as compared to front line therapy, 
since recurrent tumors are likely to have greater mutational load. However, single agent 
anti-PD-1 drugs have not shown significant activity in these patients. Chemotherapy is 
thought to cause release of tumor antigens through cell necrosis and activate the anti-
tumor T cell response which can be further potentiated with the addition of anti-PD-1 
drugs. The trial Keynote 189 showed that the addition of pembrolizumab to the 
combination of carboplatin/pemetrexed enhanced the efficacy of chemotherapy in 
advanced NSCLC patients, irrespective of PD-L1 status of the patient’s tumor.    
Based on the above data, we hypothesize that the addition of pembrolizumab to the 
combination of carboplatin and pemetrexed will increase the response rate in EGFR 
mutation and other gene altered NSCLC patients who have had disease progression on 
appropriate targeted therapy. To test this hypothesis we propose to conduct a phase II 
clinical trial evaluating the addition of pembrolizumab to standard platinum based 
doublet chemotherapy in EGFR mutation and other gene altered NSCLC patients who 
have disease progression following treatment with appropriate targeted therapy.  
For this exploratory study, we believe that a single arm study with 2 cohorts one (EGFR 
mutated and other gene altered NSCLC cohorts) is acceptable design since efficacy of 
chemotherapy in these patients is well defined. If the results of the proposed trial 
demonstrate sufficient efficacy then a randomized study will be conducted in the future.    
 
4.4.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) has reported safety and clinical activity of single 
agent MK-3475 (20).  The dose escalation portion of this trial evaluated three dose levels, 1 
mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting 
toxicities were observed.  This first in human study of MK-3475 showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 
mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the 
highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and 
D of this protocol to test for initial tumor activity.  Recent data from other clinical studies 
within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 

 
UMCC 2017. 057 
 
 
12 
 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
Finally, in the Keynote 021 trial, cohort G this flat dose of 200mg of pembrolizumab 
administered every 3 weeks when combined with carboplatin/pemetrexed was found to be well 
tolerated and efficacious. So consistent with the schedule tested in cohort G of trial Keynote 
021, in this trial all eligible patients will be treated with pembrolizumab at a dose of 200mg in 

 
UMCC 2017. 057 
 
 
13 
 
combination with carboplatin AUC 5 and pemetrexed 500 mg/m2 every 3 weeks. Patients will 
receive combination chemotherapy for a maximum of 4 cycles. Following 4 cycles patients 
will receive maintenance therapy with pemetrexed and pembrolizumab for a maximum of 24 
months (from the start of trial therapy).  
 
4.4.3 Rationale for Endpoints 
4.4.3.1 Efficacy Endpoints 
We have selected Response Rates (RR) as defined by RECIST 1.1 criteria as the primary 
endpoint. RR with the combination of a platinum analogue and pemetrexed in a similar 
patient population, as being studied in this study, was found to be 33% in the recently 
reported IMPRESS trial. Another combination of afatinib+cetuximab examined in a 
similar population showed a RR of 29%. These two datasets provide the benchmark for 
EGFR mutation positive NSCLC patients. The response rate with second line and third 
line ALK inhibitors in ALK positive NSCLC is about 50% and this establishes the 
benchmark of ALK positive NSCLC patients. Though data with platinum based 
chemotherapy in other gene altered NSCLC patients is not well defined we speculate that 
efficacy will be no better than what has been observed in EGFR mutation positive 
NSCLC patients. We also wanted to select a relatively early endpoint for this exploratory 
trial.    
It is well recognized that in minority of patients treated with immune therapy may have 
pseudo progression or can have delayed response. In addition, there are patients who 
have isolated areas of progression, with control in other areas. Therefore, patients can 
continue on study therapy beyond progression, if felt to be in the best interest of the 
patient.      
In this trial we will also assess PFS by RECIST criteria and we will assess overall survival 
as well.  
 
4.4.3.2 Biomarker Research 
Response rates to PD-1 and PD-L1 targeted agents indicate that a subset of patients derive 
greater benefit from this treatment strategy, whereas some patients have no benefit. To 
complement this study and increase its scientific yield, we are proposing scientific 
correlates in an attempt to identify potentially predictive biomarkers for pembrolizumab 
combined with chemotherapy. While these are unlikely to be definitive, based on the 
relatively small numbers of patients involved, the data collected will help guide the 
development of potential biomarkers in future studies as well as identify patients most 

 
UMCC 2017. 057 
 
 
14 
 
likely to benefit or not benefit from the combination of pembrolizumab and 
chemotherapy in these specific NSCLC patients.  
PD-L1 expression 
Emerging data suggests that expression of PD-L1 on the tumor may predict for benefit 
from pembrolizumab and other anti-PD-1. Benefit has also been observed in patients 
whose tumors don’t express PD-L1 but the percentage of such patients who benefit is far 
less. This difference in efficacy with anti- PD-1 drugs has been observed across tumor 
types.  
Preliminary data suggest that tumor PD-L1 expression is a predictive marker for 
pembrolizumab (20). In patients with recurrent NSCLC the drug is only approved in 
patients whose tumors have some level of tumor PD-L1 expression. In addition, recently 
the results of trial Keynote 024 showed that in patients with tumors that have high level 
of PDL1 expression (tumor proportion score of ≥ 50%) pembrolizumab demonstrated 
significantly greater response rate, PFS and overall survival compared to platinum based 
combination chemotherapy (22). Based on these data pembrolizumab is currently 
approved for front line treatment of advanced NSCLC patients whose tumors have high 
PDL1 expression. However, the relevance of PD-L1 expression in determining efficacy 
of the combination of pembrolizumab with chemotherapy is unclear. In Keynote-021 PD-
L1 expression did not correlate with response rate. Also what is not known is if PDL1 
expression defines activity of these agents in EGFR, ALK positive and other gene altered 
NSCLC patients. In an effort to characterize PD-L1 expression in tumors of these patients 
with progressive disease, we will analyze tumor specimens, for PD-L1 expression. 
PD-L1 expression will be correlated with response rate. 
Assessing PD-LI expression in NSCLC patients is considered standard of care and this 
information will be collected.  
Mutational Load  
In addition to PD-L1 expression, recent data has also shown that mutational load of 
tumors can correlate with efficacy from pembrolizumab (26). Mutational load in EGFR 
mutation positive and other gene altered NSCLCs is not well defined. We therefore 
propose to analyze the mutational load of the tumors of patients enrolling on the trial. 
This analysis will also be conducted on tumor tissue obtained via tumor biopsy following 
tumor progression on prior targeted therapy. This analysis will be conducted by Genomic 
Core of University of Michigan.     
Resistant mutation status 

 
UMCC 2017. 057 
 
 
15 
 
All available gene analysis data on the patient will be collected. An attempt will be made 
to assess efficacy of the study regimen in patients with specific resistant gene alterations.  
Circulating Tumor Cells 
Obtaining tumor tissue in advanced NSCLC can prove to be challenging. In addition, the 
tumor sample obtained can be small and this can limit the biomarkers that can be 
analyzed. Therefore, in recent years ‘liquid biopsies’ are being used increasingly both in 
clinical practice and in clinical research. One avenue that holds promise in developing 
accurate predictive tools and pharmacodynamic biomarker information is the analysis of 
circulating tumor cells (CTCs) (38). CTCs describe the subset of tumor cells that have 
genetically acquired the ability to disseminate from primary and metastatic sites and 
intravasate to the circulatory system. The full clinical potential of CTCs is not yet realized 
due to the limitation of existing technologies to measure and study these cells in patient 
blood samples.  
Dr. Sunitha Nagrath from the Department of Chemical Engineering at University of 
Michigan has developed the GO Chip technology which we propose to use in the current 
study (39). This technology takes the advantage of the novel nanomaterial graphene 
oxide for the sensitive capture of CTCs using the self-assembly of GO nano-arms on a 
flat substrate. Some researchers have used circular patterns to capture rare cells in 
microfluidic devices. However, to enhance the surface area and the hydrodynamic 
interactions, we used a flower-shaped architecture pattern instead of regular circular 
structures. Dr. Nagrath and her colleagues have evaluated this technology and the 
resulting CTC capture in early stage NSCLC patients and found that presence of CTCs 
can have prognostic import (40).  
 
In addition, her group has demonstrated the ability to assess PD-L1 expression in CTCs 
and also evaluate markers for epithelial mesenchymal transition (EMT) in CTCs. As 
previously mentioned PD-L1 expression does correlate with clinical efficacy with PD-1 
and PD-L1 inhibitors. In addition, EMT is a known resistance mechanism to EGFR-TKIs 
and ALK inhibitors. Recently tissue based data has suggested that presence of EMT 
features maybe associated with increased benefit from PD-1/PD-L1 inhibitors (42, 42).  
 
We therefore propose to collect and bank blood on all patients enrolled on the trial before 
the first cycle and before the third cycle. Apart from quantifying CTCs, we will also 
assess PD-L1 expression and presence of EMT markers. We will attempt to correlate 
CTC count, PD-L1 expression and presence of EMT markers to response rate from the 
study therapy. We also propose to isolate tumor DNA from the circulating tumor cells 
and analyze for EGFR and ALK gene alterations. 
 

 
UMCC 2017. 057 
 
 
16 
 
5. METHODOLOGY 
5.1 Inclusion Criteria 
1. Cohort 1- EGFR mutation positive NSCLC patients previously treated with 
appropriate targeted therapy with progressive and measurable disease per RECIST 
1.1 criteria tumor. Cohort 2- Other genetically altered NSCLC patients previously 
treated with appropriate targeted therapy with progressive and measurable tumor. 
Patients could have received more than 1 targeted therapy.   Patients taken off an 
appropriate targeted therapy due to intolerance are eligible. 
2. Tumor tissue for PD-L1 assessment should be available unless PD-L1 
assessment results are already available. 
3. Patients should not have received any systemic chemotherapy for advanced 
NSCLC Patients who received 1 cycle of systemic chemotherapy for 
advanced NSCLC while awaiting the results of tumor molecular analysis and 
subsequently were switched to appropriate targeted therapy will be eligible. 
Patients who have received neoadjuvant, adjuvant or as part of concurrent 
chemotherapy and radiation are eligible if they received the chemotherapy 12 
months or more before the start of study therapy.  
4. ECOG PS 0-1 (Appendix 14.1).  
5. Patients should have recovered to ≤ grade 1 from clinically meaningful 
(example alopecia is not considered clinically meaningful) adverse events 
related to prior treatments.   
6. Patients should be willing and able to provide written informed consent for the 
trial. 
7. Be ≥ 18 years of age on day of signing informed consent. 
8. Demonstrate adequate organ function as defined in Table 1, all screening labs 
should be performed within 14 days of treatment initiation.   
 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
≤1.5 X upper limit of normal (ULN) OR 
 
≥45 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 

 
UMCC 2017. 057 
 
 
17 
 
(GFR can also be used in place of 
creatinine or CrCl) 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
aCreatinine clearance should be calculated per institutional standard. 
 
9. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 1 week of enrollment. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required. Patients may 
need the pregnancy test repeated if the test done prior to enrollment is more 
than 1 week prior to receiving the first dose of study medication.  
10. Female subjects of childbearing potential must be willing to use an adequate 
method of contraception as outlines in section 6.3.2. Contraception for the 
course of the study through 120 days after the last dose of study medication. 
Note- Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception of the subject.  
11. Male subjects of child bearing potential must agree to use an adequate method 
of contraception as outlined in Section 6.3.2. Contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
5.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. If the half-life of the drug is known then 
starting therapy 5 half-lives after the end of the last therapy is acceptable.  
2. Has a diagnosis of immunodeficiency. Patient should not be on any 
immunosuppressive therapy or steroids > prednisone 10mg/day or its equivalent on the 
day of the start of therapy. 
 
3. Has a known history of active TB (Bacillus Tuberculosis) 
 

 
UMCC 2017. 057 
 
 
18 
 
4. Hypersensitivity to pembrolizumab, carboplatin or pemetrexed or any of its 
excipients.  
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier. 
6. Has had targeted small molecule therapy, or palliative radiation therapy within 1 week 
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. Patients who received 
stereotactic radiotherapy can start on therapy without any delay as long as they 
have recovered from any adverse events to ≤ grade 1. Also, it is well recognized 
that some EGFR and ALK patients after discontinuing their TKI can develop 
tumor flare. Therefore, if it is felt that in the best interest of the patient the prior 
TKI should be continued until the day prior to start of this study therapy it is 
acceptable.    
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Patients with grade 2 or greater toxicities from prior therapy, such as alopecia, 
that are not considered clinically meaningful and not likely to impact 
administration of study therapy may start study therapy. An approval from the 
Principal Investigator of the study is required for AEs related to prior therapies 
other than alopecia that are not grade 1.  
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
7. Has a known additional malignancy that is progressing or requires active treatment or 
the treating physician believes will require therapy within 1 year. Discussion with 
Principal Investigator is required before enrolling a patient with known history of 
another malignancy.   
8. Has symptomatic central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with asymptomatic brain metastases may participate provided 
they are clinically stable and are not using steroids equivalent to >10mg of prednisone 
day prior to trial treatment.  This exception does not include carcinomatous meningitis 
which is excluded regardless of whether it is symptomatic or not.   
9. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 

 
UMCC 2017. 057 
 
 
19 
 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
10. Has known history of non-infectious pneumonitis that required steroids or has current 
pneumonitis. Has known history of interstitial lung disease.  
11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
18. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
6. TRIAL TREATMENTS  
All patients deemed eligible and registered by the Multi-Site Coordinator of the Clinical Trials 
Support Unit (CTSU) at University of Michigan, will initiate study therapy within 5 days of 
registration. Due to logistical and administrative issues therapy maybe started within 48 hours 
of the 5 days limit. Please see section 7.0 for all required tests and assessments prior to 
registration. This is a single arm study so all eligible patients will receive the study treatment.  
The treatment to be used in this trial is outlined below in Table 2 

 
UMCC 2017. 057 
 
 
20 
 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Pembrolizumab 200 mg 
Every 3 
weeks 
IV infusion 
Carboplatin 
AUC 5 
Every 3 
weeks 
IV infusion 
Pemetrexed  
500 mg/m2 
Every 3 
weeks 
IV infusion 
 
Patients will receive combination chemotherapy for a maximum of 4 cycles. Following 4 
cycles patients will receive maintenance therapy with pemetrexed and pembrolizumab for a 
maximum of 24 months (from the start of trial therapy). Patients may receive carboplatin for 
a shorter number of cycles if felt to be in the best interest of the patient by the treating 
physician or if the patient so desires.    
Patients will continue therapy for maximum of 24 months as long as the patient is 
deriving clinical benefit and is not experiencing unacceptable adverse events and patients 
wants to continue therapy. Patients can continue therapy beyond progression if the 
treating physician believes that continuing therapy is in the best interest of the patient 
and patient is agreeable with it. See Section 6.4.  
6.1 Dose Selection/Modification/Timing of Administration 
6.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
6.1.2 Dose Modification  
The Common Terminology Criteria for Adverse Events version 4.0 (CTC AE 4.0) will utilized 
to grade toxicities.  
Appropriate dose and schedule modification should be considered for carboplatin and 
pemetrexed according to package inserts of both drugs and institutional guidelines. Guidelines 
for dose modification for hematologic toxicities are provided in Table 3 below. For grade 3-
4 non-hematologic toxicities both chemotherapy drugs should be held till the toxicity 

 
UMCC 2017. 057 
 
 
21 
 
recovers to ≤ grade 1 and then restarted at next lower dose as in the table for hematologic 
toxicities (Table 3). If grade 3 toxicity is not felt to related to chemotherapy drugs and 
will not worsen with chemotherapy drugs (eg- serum sodium of 129mmol/L) 
chemotherapy treatment maybe continued after discussion with the PI. For grade 2 non-
hematologic adverse events chemotherapy drugs maybe continued without dose 
modification as long as the treating physician considers the toxicities not related to the 
chemotherapy drugs.  
Reduction in the dose of one chemotherapy drug does not require the reduction in the dose of 
the other chemotherapy drug if the other drug is not felt to be the cause of the toxicity that led 
to the dose reduction. Discontinuation of one of the chemotherapy drugs at any point during 
the therapy is acceptable if the treating physician considers it to be in the best interest of the 
patient or the patient so desires. If chemotherapy drugs are held for longer than 3 weeks for 
pembrolizumab related toxicities or for toxicities that cannot be definitively attributed to 
chemotherapy drugs, chemotherapy drugs could be restarted after a discussion with the PI 
(Principal Investigator).   
Table 3 Suggested dose modifications for chemotherapy drugs for hematologic toxicities1 
 
 
Pemetrexed 
Carboplatin 
Nadir Platelet count 
Nadir Neutrophil 
count 
Dose 
Dose 
≥50 AND 
≥0.5 
500 mg/m2 
AUC 5 
≥50 AND 
≤ 0.5 
400 mg/m2 
AUC 3.75 
≤ 50 without 
bleeding AND 
≥0.5 
400 mg/m2 
AUC 3.75 
≤ 50 with bleeding 
AND 
ANY 
400 mg/m2 
Don’t give 
≤ 25 
ANY 
400 mg/m2 
Don’t give 
ANY 
≤ 1.0 with fever of > 
38.3 degrees C once 
or sustained ≥ 38 
degrees C 
400 mg/m2 
Don’t give 
1. A treating physician may decide to reduce the dose of the chemotherapy drugs 
(one or both) more than suggested in the table above or not give one of the 

 
UMCC 2017. 057 
 
 
22 
 
chemotherapy drugs. Dosages different than the suggested doses may be used 
if consistent with local guidelines.  If a physician wants to give doses higher 
than recommended or wants to give both drugs in situations where it is 
recommended to only give pemetrexed, a discussion with and permission from 
the PI is required.  
Adverse events (both non-serious and serious) associated with pembrolizumab 
exposure, including coadministration with additional compounds may represent an 
immunologic etiology.  These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab/combination treatment 
must be withheld for drug-related toxicities and severe or life-threatening AEs as per 
Table 4 below. 
There is no dose reduction allowed for pembrolizumab on the protocol. If the 
schedule of concomitant chemotherapy is changed to every 4 weeks due to 
tolerability issues then pembrolizumab will be administered on the day of the 
chemotherapy. Patients should be monitored closely to maintain the schedule as 
close to every 3 weeks as possible. 
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-
threatening AEs as per Table 4 below. In addition, the drug can be held for any 
grade of toxicity by the treating physician if it is felt that it is in the best interest 
of the patient.  
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse event to 
a single component is likely to be difficult.  Therefore, while the investigator may attribute a 
toxicity event to the combination, or to pembrolizumab alone, for adverse events listed in 
Table 4, both interventions must be held according to the criteria in Table 4 Dose 
Modification and Toxicity Management Guidelines for Immune-Related Adverse Events 
Associated with Pembrolizumab. 
Holding Study Interventions: 
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications. 
Restarting Study Interventions: 

 
UMCC 2017. 057 
 
 
23 
 
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 4. 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions. 
• If the toxicities do resolve and conditions are aligned with what is defined in Table 4, the 
combination of chemotherapy and pembrolizumab may be restarted at the discretion of the 
investigator.  In these cases where the toxicity is attributed to the combination or to 
chemotherapy alone, re-initiation of pembrolizumab as a monotherapy may be considered 
at the principal investigator’s discretion. 
Table 4. Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab monotherapy and IP Combinations 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at 
least 4 weeks. 
2. For situations where study intervention has been withheld, study intervention can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Study intervention should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 
mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity 
grade or 
conditions 
(CTCAEv4.
0) 
Action taken to 
pembrolizuma
b 
irAE management 
with corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
Pneumonitis 
Grade 2 
Withhold 
•  Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
•  Add prophylactic 
antibiotics for 
opportunistic 
infections 
 • Monitor participants for signs and 
symptoms of pneumonitis 
 • Evaluate participants with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4 
Permanently 
discontinue 
Diarrhea/Colitis 
Grade 2 or 3 
Withhold 
•  Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
•  Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) 
and of bowel perforation (ie, 
peritoneal signs and ileus) 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 

 
UMCC 2017. 057 
 
 
24 
 
 
•  Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing 
endoscopy to rule out colitis 
•  Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid 
and electrolytes should be substituted 
via IV infusion 
AST or ALT 
Elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
•  Administer 
corticosteroids (initial 
dose of 0.5 to 1 mg/kg 
prednisone or 
equivalent) followed 
by taper 
•  Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable) 
Grade 3 b or 
4 c 
Permanently 
discontinue 
•  Administer 
corticosteroids (initial 
dose of 1 to 2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
T1DM or 
Hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglyce
mia 
associated 
with 
evidence of 
β-cell failure 
Withhold d 
•  Initiate insulin 
replacement therapy 
for participants with 
T1DM 
•  Administer 
antihyperglycemic in 
participants with 
hyperglycemia 
 • Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
•  Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated 
•  Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism  Grade 2 
Continue  
• Treat with non-
selective beta-blockers 
(eg, propranolol) or 
thionamides as 
appropriate  
•  Monitor for signs and symptoms of 
thyroid disorders.  
 
Grade 3 or 4  Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) per 
standard of care 
•  Monitor for signs and symptoms of 
thyroid disorders.  
 
Nephritis – 
grading 
Grade 2 
Withhold  
• Administer 
corticosteroids 
•  Monitor changes of renal function 

 
UMCC 2017. 057 
 
 
25 
 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 3 or 4  Permanently 
discontinue 
(prednisone 1-2 mg/kg 
or equivalent) 
followed by taper. 
 
Neurological 
Toxicities 
Grade 2 
Withhold 
•  Based on severity of 
AE administer 
corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology and/or exclude other 
causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1  
Withhold 
• Based on severity of 
AE administer 
corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology and/or exclude other 
causes 
 
Grade 2, 3 
or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected 
SJS, TEN, 
or DRESS 
Withhold 
•  Based on severity of 
AE administer 
corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Confirmed 
SJS, TEN, 
or DRESS 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Persistent 
Grade 2 
Withhold 
• Based on type and 
severity of AE 
administer 
corticosteroids  
•  Ensure adequate evaluation to 
confirm etiology and/or exclude other 
causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event e.   
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology 
Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-
oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic 
Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN 
if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, 
vasculitis and sclerosing cholangitis). 
 
 

 
UMCC 2017. 057 
 
 
26 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the PI. The reason for interruption 
should be documented in the patient's study record. 
With investigator and Principal Investigator agreement, subjects with a laboratory adverse 
event still at Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic 
and controlled. A patient who requires longer than 12 weeks but less than 24 weeks to 
recover from an adverse event that led to the withholding of pemetrexed and/or 
pembrolizumab and is still grade 2, the patient could be restarted on the drug/drugs IF 
the treating physician believes that it is in the best interest of the patient to restart the 
drug and the patient is agreeable. This has to be discussed with the Principal Investigator 
before restarting the drugs. This does not apply to toxicities that require discontinuation 
of one or more study drugs.  
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of study therapy drugs should be discontinue trial treatment. 
 
6.1.3 Timing of Dose Administration 
Subjects will receive pembrolizumab 200 mg together with pemetrexed 500mg/m2 (with 
vitamin supplementation) + carboplatin AUC 5 all on Day 1 Q3W for 4 cycles followed 
by pembrolizumab 200 mg together with pemetrexed 500 mg/m2 Q3W until 
progression/completion. Patients should receive appropriate nausea and emesis 
prophylaxis.  
 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart 
(Section 7.0).  Trial treatment may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons, including patient’s desire. 
It is understood that patients on a study with a planned therapy for 2 years may desire to 
take short breaks or travel. For patient’s desire, therapy may be delayed for up to 3 weeks. 
Such delays should not be done in the first 6 cycles. The number of such delays should 
be minimized.  
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab will be administered at least 30 minutes prior to premedication for  
chemotherapy (pemetrexed with or without carboplatin). 
 

 
UMCC 2017. 057 
 
 
27 
 
Pembrolizumab will be administered as a 30 minute IV infusion.  Sites should make 
every effort to target infusion timing to be as close to 30 minutes as possible.  However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 
minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Merck will provide Pharmacy Manual which contains specific instructions for 
pembrolizumab dose calculation, reconstitution, preparation of the infusion fluid, and 
administration. 
Carboplatin and pemetrexed will be administered according to package insert and 
institutional guidelines.  
Pemetrexed 500 mg/m2 will be administered as an IV infusion over approximately 10 
minutes Q3W until progression or unacceptable toxicity. All subjects should receive 
appropriate supplementation with vitamin B12 and folic acid and corticosteroid 
prophylaxis. 
 
Carboplatin AUC 5 mg/mL/min will be administered as an IV infusion over 
approximately 15-60 minutes Q3W for 4 cycles immediately after pemetrexed as per 
local practice and labels. 
 
All patients should have CBC with differential and a multiphasic profile before each 
cycle of therapy. Patients can only receive chemotherapy (carboplatin and/or 
pemetrexed) if  
Neutrophil count ≥1,500 /mcL  
Platelets ≥ 100,000/mcL 
In addition patients should meet criteria mentioned in tables 3 and 4 and should be 
dosed accordingly.   
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
6.1.4 Trial Blinding/Masking 
This is an open-label trial; therefore, the investigator and subject will know the treatment 
administered. 
6.2 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 

 
UMCC 2017. 057 
 
 
28 
 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the PI and/or Merck Clinical team.  The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the subject's primary treating physician.  
6.2.1 Acceptable Concomitant Medications 
Patients will receive vitamin B12 (1000 mcg intramuscularly) and folic acid (1 mg orally daily) 
supplementation at least 5 days before starting therapy with pemetrexed and continue to receive 
it at frequencies mentioned in the package insert or according to institutional guidelines. All 
patients should receive anti-nausea and other supportive measures according to institutional 
guidelines.  
Patients should receive appropriate anti-nausea medications and dexamethasone for 
management of chemotherapy related adverse events as per institutional guidelines and 
package insert. All treatments that the investigator considers necessary for patient’s welfare 
may be administered at the discretion of the investigator in keeping with the community 
standards of medical care. All concomitant medication will be recorded in the medical record 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included in the medical record. 
 
6.2.2 Prohibited Concomitant Medications 
Patients should not receive any other systemic therapy for cancer unless specified in the 
protocol. If a patient needs palliative radiation therapy or other such local therapy for the 
treatment of limited areas of symptomatic disease or limited areas of progression, such as 
painful bone lesions, study therapy will have to be interrupted. Study therapy may be re-
initiated after completion of such palliative therapy after discussion with the Principal 
Investigator (PI). Following are the prohibited medications.   
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note:  Radiation therapy to symptomatic lesions or to the brain may be allowed 
at the investigator’s discretion. This has to be discussed with the PI. It is 

 
UMCC 2017. 057 
 
 
29 
 
important that at least one target lesion remains untreated with treatment other 
than study therapy.    
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
immune related adverse event or for use as a pre-medication before chemotherapy or 
to treat contrast related allergy or for treatment of COPD/asthma exacerbation.  The 
use of replacement doses of corticosteroids while on study is allowed. 
Subjects may receive other medications that the investigator deems to be medically necessary 
to manage the patient’s cancer such as bone modifying agents in patients with bone metastases 
and growth factors for management of neutropenia. 
The Exclusion Criteria section 5.2 describes other medications which are prohibited in this 
trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
6.3 Contraception/Pregnancy/Nursing 
6.3.1 Contraception 
Pembrolizumab and chemotherapy may have adverse effects on a fetus in utero.  Furthermore, 
it is not known if pembrolizumab has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.);  
OR  

 
UMCC 2017. 057 
 
 
30 
 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 

 
UMCC 2017. 057 
 
 
31 
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
 ‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in that region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
6.3.2 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab and 
chemotherapy drugs, the subject will immediately be removed from the study.  The site will 
contact the subject at least monthly and document the subject’s status until the pregnancy has 
been completed or terminated.  The outcome of the pregnancy will be reported to the PI and to 
Merck without delay and within 24 hours to the Sponsor and within 2 working days to Merck 
if the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or 
other disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the PI and to Merck and followed as described 
above and in Section 8.2.2. 
6.3.3 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, including carboplatin and pemetrexed, and because of the potential 
for serious adverse reactions in the nursing infant, subjects who are breast-feeding are not 
eligible for enrollment. 

 
UMCC 2017. 057 
 
 
32 
 
6.4 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the PI if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 8.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
• Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved. 
It is well recognized that in some patients despite radiologic evidence of 
disease progression the treating physician may want to continue therapy 
since the progression may not be clinically relevant. In addition certain 
patients may develop isolated areas of progression. The treating physician 
may consider treating such isolated areas of progression with local 
treatments such as radiation or surgery, as long as at least one target lesion 
is not treated with any other treatment than the study therapy. The patient 
may continue on study therapy after the patient has recovered to ≤ grade 
1 adverse events from such local treatments, as long as the treating 
physician considers that patient is still deriving clinical benefit from study 
therapy. CONTINUATION of study therapy in patients who have disease 
progression or after local therapy for limited areas of progression can only 
be done after discussing with the PRINCIPAL INVESTIGATOR.   
• Unacceptable adverse experiences. 
• Intercurrent illness that prevents further administration of treatment.  
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 

 
UMCC 2017. 057 
 
 
33 
 
• Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later.  
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided they 
meet the requirements detailed in Section 8.1.5.2 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 7 (Protocol Flow 
Chart) and Section 8.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 8.2.3).  Subjects who discontinue 
for reasons other than progressive disease will have post-treatment follow-up for disease status 
until disease progression, initiating a non-study cancer treatment, withdrawing consent or 
becoming lost to follow-up.  After documented disease progression each subject will be 
followed by telephone for overall survival until death, withdrawal of consent, or the end of the 
study, whichever occurs first. 
Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR and have been treated for at least 24 weeks, receiving two cycles of combination including 
2 doses of pembrolizumab and at least 80% of the planned dose beyond the date when the 
initial CR was declared. The decision to continue or discontinue pemetrexed in such patients 
is to be decided by the treating physician. Subjects who then experience radiographic disease 
progression may be eligible for up to one year of additional treatment with pembrolizumab 
with or without pemetrexed via the Second Course Phase at the discretion of the investigator 
if no cancer treatment was administered since the last dose of pembrolizumab, other than 
pemetrexed, the subject meets the safety parameters listed in the Inclusion/Exclusion criteria, 
and the trial is open.  Subjects will resume therapy at the same dose and schedule at the time 
of initial discontinuation.  Additional details are provided in Section 8.1.5.2. 
6.5 Subject Replacement Strategy 
Patients will only be replaced if the patient withdraws consent before the first dose of study 
therapy.  
6.6 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 

 
UMCC 2017. 057 
 
 
34 
 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made 

 
 
35 
 
7 TRIAL FLOW CHART 
Trial Period: 
Main Study 
Screening 
(Visit 2) 
Treatment Cycles  
(for initial combination treatment and 
retreatment phase start at cycle 1) 
  
  
  
  
  
  
Treatment Cycle/Title: 
1 
2 
3 
4 
To be repeated beyond 
8 cycles 
Safety Follow-Up/ 
EOT 
Progression Free     
Follow-Up Phase 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window 
(Days): 
-28 to -0 
  
±3 
±3 
±3 
±3 
±3 
±3 
±3 
30 days (+/- 7 days) 
after last dose/ 
before initiation of 
new tx  
Every 12 weeks  
+/- 2 weeks 
Every 12 
weeks  
+/- 2 weeks 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion 
Criteria 
X 
  
  
  
  
  
  
  
  
 
  
 
  
  
Medical History1 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
Medication Review2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
  
Trial Treatment 
Administration3 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
Survival Status 
  
  
  
  
 
  
  
  
  
 
  
 
  
X 
Review Adverse Events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Physical Examination1 
X 
  
  
  
 
  
  
  
  
 
  
 
  
  
Directed Physical 
Examination1 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
 
 
  
ECOG Performance 
Status4 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
 
 
  
Pregnancy Test – Urine or 
Serum β-HCG5 
X 
  
  
  
 
  
  
  
  
 
  
 
  
  
CBC with Differential6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Comprehensive Serum 
Chemistry Panel6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
  

 
 
36 
 
Trial Period: 
Main Study 
Screening 
(Visit 2) 
Treatment Cycles  
(for initial combination treatment and 
retreatment phase start at cycle 1) 
  
  
  
  
  
  
Treatment Cycle/Title: 
1 
2 
3 
4 
To be repeated beyond 
8 cycles 
Safety Follow-Up/ 
EOT 
Progression Free     
Follow-Up Phase 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window 
(Days): 
-28 to -0 
  
±3 
±3 
±3 
±3 
±3 
±3 
±3 
30 days (+/- 7 days) 
after last dose/ 
before initiation of 
new tx  
Every 12 weeks  
+/- 2 weeks 
Every 12 
weeks  
+/- 2 weeks 
Urinalysis (See Table 6) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
T3, FT4 and TSH7 
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
  
Tumor Imaging8 
X 
  
X 
  
X 
  
X 
  
  
  
  
X 
  
Research Blood 
Collection (CTC)10 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Research Blood 
(Mutational Load)11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Tissue Collection9 
X 
  
  
  
 
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
1. Patients should undergo a detailed history and physical examination during screening. A full examination, to be performed to 
determine eligibility, means detailed medical history is obtained and all relevant systems have been examined, include height at 
baseline and weight. All patients should undergo a focused (at the discretion of the managing health care provider) history and 
physical examination during each treatment day for the first 6 cycles. After the first 6 cycles history and physical examination 
can be performed every other cycle as per the discretion of the managing health care provider.  
2. All medications need to be reviewed at screening visit. During follow up visits any changes in medications should be 
documented. 
3. Pembrolizumab will be administered at a dose of 200 mg IV every 3 weeks for a maximum of 2 years. For the first 4 cycles 
patients will receive carboplatin AUC 5 and pemetrexed 500 mg/m2. After first 4 cycles patients will receive maintenance 
pemetrexed. Prior to each administration vital signs- heart rate, blood pressure, temperature, weight, respiratory rate should be 

 
 
37 
 
documented. Cycles can be administered +/- 3 days around the scheduled day of therapy. Please also see section 6.1.2. Patients 
can be retreated with pembrolizumab with or without pemetrexed. Please see section 8.1.5.2  
4. Performance status needs to be documented on the day of study drug administration for the first 6 doses. After the first 6 doses 
it should be documented as deemed appropriate by the treating physician.  
5. Pregnancy test should be performed within 1 week of the first dose of study therapy in appropriate women.  
6. Patients should undergo CBC with differential count, a multiphasic profile consisting of serum electrolytes, BUN, serum 
creatinine, AST, ALT, serum bilirubin, alkaline phosphatase, and calcium with each treatment. Baseline labs should be done 
within 2 weeks of the first dose of study therapy, unless patient was undergoing any cancer therapy within a week of starting 
study therapy. In that case patient should have repeat labs after the completion of such cancer therapy. During the trial, laboratory 
tests can be done within 72 hours of the administration of study therapy. 
7. Patients should undergo Thyroid tests within 2 weeks of the first dose. These should be repeated at least every 4 cycles.  
8. Patients should undergo appropriate scans, including brain scan, during screening, to document the status of the patient's cancer. 
The screening scans should be done within 4 weeks before the first dose of study therapy. Patients should undergo appropriate 
scans to restage the patient after every 2 cycles for the first 6 cycles. For the first 6 cycles the re-staging scans should be performed 
within 1 week of the next cycle. After the first 6 cycles, the scans can be done as often as necessary by the treating physician but 
should be done at least every 4 cycles. Brain imaging does not have to be repeated if patient does not have known brain metastases 
at baseline or has had prior treatment to brain metastases and is stable at baseline.  
9. Tumor tissue will be retrieved to assess tumor PD-L1 status and mutational load.  If PD-L1 status is not known and no archival 
tumor tissue is available to conduct such analysis a new tumor biopsy is necessary. Mutational load will be assessed on any 
tumor tissue available, with preference for the tissue from the most recent biopsy. See Section 9.0.   
10. Blood will be collected prior to the start of study therapy and before the third cycle in patients enrolled in this trial to identify 
and quantify CTCs.  Samples will not need to be re-drawn if a patient comes back on study for the re-treatment phase.  See  
Section 9.0. 
11. Blood for mutational load should be collected on all patients who undergo a biopsy or who have archival tissue.  The blood 
sample can be taken at any time while the patient is on study, however it is preferred to be taken prior to treatment on C1D1.

 
 
38 
 
8 TRIAL PROCEDURES 
8.1 Trial Procedures 
Patient registration for this trial will be centrally managed by the Coordinating Center of The 
Rogel Cancer Center as described below: 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log provided by the Coordinating Center. 
It is the responsibility of the local site investigator to determine patient eligibility prior to 
submitting patient registration request to the Coordinating Center. After patient eligibility has 
been determined, a copy of the completed Eligibility Worksheet together with all the pertinent 
de-identified source documents will be submitted by the requesting site to the Coordinating 
Center, by email to CTSU-Oncology-Multisite@med.umich.edu.   
The Multi-Site Coordinator, who acts as the registrar, will review the submitted documents 
and process the registration. Sites should inform the Multi-Site Coordinator of a potential 
registration by 5 p.m. on the day prior to registration.  Same day registrations cannot be 
guaranteed.   
An email will be sent by the registrar to the requesting site registrar to confirm patient 
registration and to provide the study identification number that has been assigned to the patient. 
In addition, a copy of the completed Eligibility Worksheet signed and dated by the registrar, 
will be sent back to the requesting site registrar. 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
have study identification number assigned to them, and will not receive study treatment. 
Once registration has occurred patient has to be treated within 5 days. If patient does not start 
therapy within 5 days of registration, the reasons for delay should be communicated to the 
Principal Investigator. He will then decide if the patient can continue on study therapy.  
The Trial Flow Chart - Section 7.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the PI and/or Merck 
for reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 

 
 
39 
 
8.1.1 Administrative Procedures 
8.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial or conducting any testing specifically to assess eligibility. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
8.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
8.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition that are considered to be clinically 
significant by the Investigator.   

 
 
40 
 
8.1.1.4 Concomitant Medications Review 
8.1.1.4.1 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial in the medical record.  All medications related to reportable SAEs and ECIs 
should be recorded as defined in Section 8.2. 
8.1.1.5 Disease Details and Treatments 
8.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
8.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. The number of prior treatments for the lung 
cancer will be recorded. Details of any radiation administered will be recorded. This will 
include site radiated, dose and dates.   
8.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
8.1.2 Clinical Procedures/Assessments 
8.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (Appendix 14.2). Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
Please refer to section 8.2 for detailed information regarding the assessment and recording of 
AEs.   

 
 
41 
 
8.1.2.2 Physical Exam/Vital Signs/Eastern Cooperative Oncology Group Performance 
Scale (ECOG PS) 
The investigator or qualified designee will perform physical exam, including vital signs 
(temperature, pulse, respiratory rate, weight and blood pressure) and assess ECOG PS during 
the screening period and subsequent visits as mentioned in Trial Flow Chart section 7.0.  
Clinically significant abnormal findings should be recorded.  A full physical exam should be 
performed during screening.  
8.1.2.3 Tumor Imaging and Assessment of Disease 
Patients will undergo scans to assess the status of the cancer within 4 weeks before the first 
dose of study therapy. All known areas of metastases should be imaged. Patients will undergo 
restaging scans every 2 cycles for the first 6 cycles. Subsequently they can be done as often as 
necessary, but should be done at least every 4 cycles. See section 7.0 
The treating physician will decide which scans need to be done to appropriately assess the 
status of the cancer.  
 
8.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 6.   

 
 
42 
 
Table 6  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis (only at screening) 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
 
 
Red Blood Cell Count 
 
Microscopic exam (If abnormal)  
Total triiodothyronine (T3)α 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4)α 
 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH)α 
 
 
 
 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
  
 
 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
α These tests are to be conducted at baseline. Once the patient is on trial therapy tests to be conducted at least every 4 cycles. 
Baseline labs should be done within 2 weeks of the first dose of study therapy, unless patient was undergoing any cancer therapy within a week of starting 
study therapy. In that case patient should have repeat labs after the completion of such cancer therapy. After cycle 1 pre-dose laboratory procedures can be 
conducted up to 72 hours prior to dosing. Results must be reviewed by the investigator or qualified designee and found to be acceptable to proceed with 
treatment.  

 
 
43 
 
8.1.4 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 8.2 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 8.1.5.2.  After discontinuing treatment following assessment 
of CR, these subjects should return to the site for a Safety Follow-up Visit (described in Section 
8.1.5.1) and then proceed to the Follow-Up Period of the study (described in Section 8.1.5.1). 
 
8.1.5 Visit Requirements 
Visit requirements are outlined in Section 7.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 8.1 - Trial Procedures. 
8.1.5.1 Follow-up Visits Including Safety Follow Up Visit 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed at least every 12 weeks (by radiologic 
imaging) to monitor disease status.  Every effort should be made to collect information 
regarding disease status until the start of new anti-neoplastic therapy, disease progression, 
death, end of the study or if the subject begins retreatment with pembrolizumab with or without 
pemetrexed as detailed in Section 8.1.5.2.  Information regarding post-study anti-neoplastic 
treatment will be collected if new treatment is initiated. 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first. It is recognized that in some NSCLC patients such a visit may not be possible and 
inability to conduct such a visit will not be considered a protocol deviation.  All AEs that occur 
prior to the Safety Follow-Up Visit should be recorded.  Subjects with an AE of Grade > 1 will 
be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new anti-
neoplastic therapy, whichever occurs first.  SAEs that occur within 90 days of the end of 
treatment or before initiation of a new anti-cancer treatment should also be followed and 
recorded.  If the investigator or a member of the study team becomes aware of SAEs that 
occurred 90 days after end of treatment and they were considered to be treatment related then 
they should be recorded as the other SAEs. Subjects who are eligible for retreatment (as 
described in Section 8.1.5.5) may have up to two safety follow-up visits, one after the 
Treatment Period and one after the Second Course Phase. 
Subjects who are eligible to receive retreatment according to the criteria in Section 8.1.5.2 will 
move from the follow-up phase to the Second Course Phase when they experience disease 
progression.    

 
 
44 
 
8.1.5.1.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone or 
other mode of communication every 12 weeks to assess for survival status until death, 
withdrawal of consent, or the end of the study, whichever occurs first.  
8.1.5.2 Second Course Phase (Retreatment Period) 
Subjects who stop therapy with SD or better may be eligible for up to one year of additional 
pembrolizumab therapy with or without pemetrexed if they progress after stopping study 
treatment.  This retreatment is termed the Second Course Phase of this study and is only 
available if the study remains open and the subject meets the following conditions: 
• Either  
o Stopped initial treatment after attaining an investigator-determined confirmed CR 
according to RECIST 1.1, and 
 Was treated for at least 24 weeks with pembrolizumab with or without either 
of the chemotherapy drugs before discontinuing therapy 
 Received at least two treatments with pembrolizumab with or without 
chemotherapy beyond the date when the initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
o Patients who stopped therapy earlier than 24 months and had SD, PR or CR can 
also be considered for re-treatment after discussion with the PI.  
 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab. 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 5.1  

 
 
45 
 
• Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  
• Male subject should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.   
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab. The investigator can decide to either start pembrolizumab 
alone or with pemetrexed. For the retreatment patients will not receive carboplatin again.  
Treatment will be administered for up to one additional year. Therapy beyond one year may 
be considered after discussing with the PI.  
Visit requirements will be the same as done with the first treatment on the study. See section 
7.0 – Trial Flow Chart. 
 
8.2 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of the underlying lung cancer that is temporally associated with the 
study therapy, is also an adverse event.  
Adverse events may occur during the course of the use of any of the study therapy drugs in 
clinical trials, or as prescribed in clinical practice, from overdose (whether accidental or 
intentional), from abuse and from withdrawal. 
All adverse events that occur after the start of study treatment allocation must be reported by 
the investigator  

 
 
46 
 
From the time of treatment start through 90 days following cessation of treatment, or 30 days 
after the cessation of treatment if the patient starts on another therapy, whichever is earlier, all 
adverse events must be reported by the investigator. Such events will be recorded at each 
examination on the Adverse Event case report forms/worksheets.  The reporting timeframe 
for adverse events meeting any serious criteria is described in section 8.2.3.1 The investigator 
will make every attempt to follow all subjects with non-serious adverse events for outcome. 
 
8.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the PI 
(Principal Investigator) and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of pembrolizumab, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the PI and Coordinating Center. The Coordinating Center within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
Overdose of carboplatin and pemetrexed should be addressed according to institutional 
guidelines and should be documented in patient’s study records.  
8.2.2 Reporting of Pregnancy and Lactation to the PI and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator. Pregnancies and lactations that 
occur from the time of treatment allocation/randomization through 120 days following 
cessation of any study therapy, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, must be reported by the investigator.  
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 

 
 
47 
 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
Such events must be reported within 24 hours to the PI and Coordinating Center. The 
Coordinating Center will report within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 
8.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
8.2.3.1 Serious Adverse Events (SAEs) 
A serious adverse event is any adverse event occurring during study therapy that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; Hospitalization related to 
patient convenience (eg. Transportation issues) will not be considered a SAE.  
• Is a congenital anomaly/birth defect; 
• Is any other important medical event 
  
Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
Events not considered to be serious adverse events are hospitalizations for:  
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures  
• Elective or pre-planned treatment for a pre-existing condition that did not worsen, or 
that is required per protocol  
• Emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission  
• Respite care  
• Death due to disease progression unless attributable to the study drug(s)  
• 
A hospitalization due to an expected adverse event (e.g., hospitalization due to expected 
febrile neutropenia).  
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless of causality 
to study drug, will be reported to the Study Principal Investigator and also to the Coordinating 
Center.  All SAEs and UPs must be reported to the Coordinating Center within 24 hours of 

 
 
48 
 
first awareness of the event.  Events should be reported using the Coordinating Center SAE 
form as available in the study database.  A copy of the Coordinating Center SAE form should 
be sent to the Coordinating Center via email to CTSU-Oncology-Multisite@med.umich.edu 
within 24 hours of the site’s knowledge of the event.  
Follow-up information must also be reported within 24 hours of receipt of the information by 
the investigator. 
All SAEs and UPs should be reported to the local IRBs per current local institutional standards. 
The Coordinating Center will disseminate information regarding SAEs and UPs to the 
participating sites within 5 days of review of the information by the Coordinating Center’s 
Principal Investigator (or designee in the event of extended absence) only in the case that the 
event(s) is believed to be related (i.e., possibly, probably, or definitely) to the study drug. The 
Coordinating Center will be responsible for reporting of events to the FDA and Merck, as 
appropriate (outlined below). 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to study therapy that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the PI, the Coordinating Center and to Merck 
Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
In this trial, serious unexpected adverse events believed to be definitely, probably or possibly 
related to the study treatment will be reported to the Food and Drug Administration via the 
MedWatch 3500A.  The Coordinating Center will be responsible for correspondence regarding 
adverse events with the FDA for all participating sites. 
The Coordinating Center will be responsible for sending SAE reports and any other 
relevant safety information 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, 
or other local regulators. 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 the Coordinating Center 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. 
8.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the PI and within 2 working days after the 
University of Michigan Multi-Site Coordinator becomes aware of the event to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 

 
 
49 
 
For the time period beginning at start of study therapy through 30 days following cessation of 
treatment, any ECI, or follow up to an ECI, whether or not related to study therapy, must be 
reported within 72 hours to the PI and within 2 working days after the University of Michigan 
Multi-Site Coordinator becomes aware of the event to Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 8.2.1 - Definition of an Overdose for 
this Protocol and Reporting of Overdose to the Sponsor, 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.*This is not required if the elevation is deemed to be related to 
progression of underlying cancer.  
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  
 
8.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician or an appropriate designee will evaluate all 
adverse events according to the NCI Common Terminology for Adverse Events (CTCAE), 
version 4.0. The investigator or sub-investigator will assess the grade, duration of the AE, 
management of the AE and the relatedness to the study therapy. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets.  
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
8.2.5 Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable local laws and regulations.  
8.3 Study Closure 
 At this amendment (dated 10/27/2020) the enrollment rate has been significantly slower than 
anticipated when this study was developed. We therefore may close the study earlier than 
planned since planned enrollment is not feasible. The current plan is to close the study to 
enrollment on December 31st 2020. Based on current enrollment, we anticipate that we will 
enroll approximately 25 patients in the EGFR cohort (Cohort 1) and 7 patients in the other 
cohort (Cohort 2). 

 
 
50 
 
9 CORRELATIVE STUDIES 
Response rates to PD-1 and PD-L1 targeted agents indicate that a subset of patients derive 
greater benefit from this treatment strategy, whereas some patients have no benefit. To 
complement this study and increase its scientific yield, we are proposing scientific correlates 
in an attempt to identify potentially predictive biomarkers for the study therapy. While these 
are unlikely to be definitive, based on the relatively small numbers of patients involved, the 
data collected will help guide the development of potential biomarkers in future studies as well 
as identify patients most likely to benefit or not benefit from the study therapy.  
 
PD-L1 expression 
The available data suggests that NSCLC patients with tumors that express PD-L1, particularly 
at a high level, have a greater probability of deriving benefit from anti-PD-1 drugs such as 
pembrolizumab (20,22). In addition, the FDA has recently approved the use of pembrolizumab 
as single agent for upfront therapy in patients with advanced NSCLC with high PD-L1 
expressing tumors (22).  
Although the predictive relevance of tumor PD-L1 expression in patients receiving 
pembrolizumab in combination with chemotherapy is unclear, the data from Keynote-021 trial 
suggests that benefit with the addition of pembrolizumab to chemotherapy maybe irrespective 
of tumor PD-L1 expression (30,31). In an effort to characterize PD-L1 expression in tumors of 
EGFR mutation or other genetically altered NSCLC patients with progressive disease, we will 
analyze tumor specimens, for PD-L1 expression analyses, unless these results are already 
available. If these results are not available and there is no tumor tissue available, then a fresh 
tumor biopsy will have to be obtained.  
PD-L1 expression can be conducted locally and the results and methodology reported to the 
Coordinating Site. It is highly encouraged that the test be performed on the tumor tissue 
obtained with the most recent biopsy procedure.  
 
Mutational Load  
In addition to PD-L1 expression, recent data has also shown that mutational load of tumors can 
correlate with efficacy from checkpoint inhibitors (26). Mutational load is higher in tumors of 
patients who have a history of smoking for many years. It is speculated that lung cancers that 
arise in patients with chronic smoking history are a result of chronic exposure to carcinogens 
that leads to accumulation of several genetic changes and higher mutational load in such 
tumors. It is also suggested that higher mutational load may cause more neo-antigens to be 
expressed on the surface of cancer cells and therefore these cancers maybe more susceptible 
to immunogenic attack. It is possible that one of the reasons single agent anti-PD-1 and anti-
PD-L1 agents are not very effective in patients with EGFR/ALK NSCLCs is that almost all of 

 
 
51 
 
these patients are never or light smokers and therefore the tumors in these patients have a low 
mutational load.  
We therefore propose to analyze the mutational load of the tumors of patients enrolling on the 
trial, as reported by Rizvi, et al and classify tumors as high or low mutational load tumors (a 
blood sample will be utilized to conduct genomic analysis in order to assess if the mutations 
identified in the tumor are somatic or germline. We will then attempt to correlate mutational 
load of the tumor with the response rate observed with the study therapy. This analysis will be 
conducted by Genomic Core of University of Michigan. It is recognized that tissue for both 
PD-L1 expression and mutational load may not be available. PD-L1 expression is considered 
mandatory and mutational load will only be assessed if tissue remains available.      
 
T790M Status 
All eligible EGFR mutation positive NSCLC patients’ tumors will be analyzed for EGFR 
mutations in exons 18-21, including T790M. About 60% of the EGFR mutation positive 
NSCLC patients have T790M as the primary mechanism of resistance to EGFR-TKIs. We 
propose to evaluate the efficacy of pembrolizumab administered with chemotherapy in these 
patients based on presence or absence of T790M mutation. This assessment will be considered 
standard of care. If patients have a positive T790M result from a circulating cell free tumor 
DNA test, then a tissue test will not be mandatory.  
Circulating Tumor Cells (CTCs)  
Dr. Nagrath, et al at University of Michigan have developed a unique technique of identifying 
and quantifying CTCs. In addition, they can assess several biomarkers including PDL1 and 
markers associated with EMT (epithelial mesenchymal transition). Dr. Nagrath has 
demonstrated that CTCs can provide prognostic information in NSCLC patients. 
 
We propose to collect and bank blood from prior to the start of study therapy and before the 
third cycle in patients enrolled in this trial to identify and quantify CTCs by the method 
developed by Dr. Nagrath. In addition, we propose to assess PD-L1 expression and correlate 
it with tumor tissue PD-L1 expression where possible. We also plan on assessing markers for 
EMT in the isolated CTCs. EMT has been recognized as a resistance mechanism to both 
EGFR-TKIs in EGFR mutation positive NSCLC patients and to ALK TKIs in ALK positive 
NSCLC patients. We also propose to isolate tumor DNA from the CTCs to conduct EGFR and 
other gene analysis.   
 
We also propose to correlate the number of CTCs at baseline and the change in the CTC count 
before and after 2 cycles with response rate from the study therapy. 
Blood sample collection 

 
 
52 
 
Whole blood will be obtained for the CTC analysis.  All samples will be labeled with a unique 
specimen ID.  The specimen ID will not contain names, MRN, or other identifiers.   
 
Circulating tumor cell isolation 
Circulating tumor cells will be isolated from whole blood using a CTC chip as previously 
described (Nagrath 2007).  Isolated tumor cells will be confirmed by morphology using 
microscopy and/or immunostaining for tumor cell and nucleated blood cell surface markers. 
 
CTC quantification protocol 
Patient blood will be run over the CTC chip.  The chips containing bound CTCs are then 
washed with PBS and fixed with PFA.  Fixed chips can be stored in a refrigerator.  The number 
of tumor cells is determined by microscopy. 
 
CTC RNA and DNA isolation 
DNA and RNA will be extracted from the isolated CTCs. 
 
 
 
CTC staining protocol 
The CTC-chip containing patient sample is treated with buffer then washed with PBS.  The 
CTC-chip is then incubated with serum and the appropriate antibodies are added (e.g. CK, 
CD45) for a specific period of time.  CTC-chips are then washed with PBS and the appropriate 
secondary antibody are added. 
 
9.1. Shipping of tissues and blood samples to University of Michigan 
Tumor tissue for biomarker analysis from formalin fixed paraffin embedded tumor tissue 
sample or newly obtained formalin fixed biopsy of a tumor lesion not previously irradiated 
must be provided in the form of a tissue block or at least ten unstained slides. If new 
scientific data emerge that indicate that an existing biopsy or surgical specimen is suboptimal 
for identification of subjects, then only new biopsies will be acceptable for determination of 
PD-L1 status. A fine needle aspirate or cytologic specimen will not be acceptable. Needle or 
excisional biopsies, or resected tissue is required. Newly obtained formalin fixed specimens 
are encouraged. Refer to the Laboratory Manual for details.  
 
Blood samples for CTC and mutational load analysis should collected, handled and shipped 
to the University of Michigan as outlined in the Laboratory Manual.  
 

 
 
53 
 
10 STATISTICAL ANALYSIS PLAN 
10.1 Definition of Endpoints 
Primary Endpoint 
As cited in Appendix 14.3, RECIST 1.1 will be used to define response rates as: 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Secondary Endpoints- 
RECIST 1.1 defined Progression Free Survival (PFS)- PFS is defined as the duration of 
time from registration to time of progression. Patients who die without reported prior 
progression will be considered to have progressed on the day of their death. Patients who did 
not progress will be censored at the day of last tumor assessment. 
Overall Survival- Overall survival is defined as the time from registration to time of death. 
If the patient is lost to follow-up, survival will be censored on the last date the patient was 
known to be alive. 
10.2 Statistical Analysis Plan 
10.2.1 Study Design and Primary Endpoint 
The study design is a multi-site, single arm phase II trial with 2 parallel cohorts. To 
minimize the number of patients required the single arm two-stage minimax Simon's 
design will be used for each cohort. The study will be conducted in two separate cohorts; 
EGFR mutation positive NSCLC cohort and other genetically altered NSCLC cohort. 
The primary objective is to assess the treatment efficacy based on the response rate (RR), 
of combination pembrolizumab and platinum-based doublet in EGFR mutation positive 
or ALK positive NSCLC patients who have progressed on prior TKIs. The primary 
endpoint is RR defined by RECIST 1.1.   

 
 
54 
 
Secondary objectives include the evaluation of toxicity, overall survival (OS) duration, 
and Progression Free Survival (PFS). OS is defined as the time from the initiation of 
study therapy to death from any cause, see 10.2. PFS is defined as the time from the 
initiation of pembrolizumab to disease progression or death due to any cause, whichever 
occurs first. PFS as defined by RECIST 1.1 (Section 10.1).  
Exploratory endpoints include correlating tumor PD-L1 expression positive or negative 
and tumor mutational load as high or low with the primary endpoint of response rate. In 
addition, the study will assess toxicity from the study therapy.  
10.2.2 Sample Size and Accrual Rate:  
 
With chemotherapy in these patients, both EGFR mutation positive NSCLC patients and 
other genetically altered NSCLC patients are expected to demonstrate a response rate of 
about 30%. We hypothesize that the study regimen will be higher than 30% in both 
cohorts. A RR of 55% with the study regimen for this patient population will be 
considered of interest in both cohorts.  The accrual rate of both cohorts should be similar.  
For each cohort, the combination treatment would be of clinical interest if the RR is > 
0.55 and will not if the RR is <0.3. With 14 pts in stage I and 28 total pts, the 2-stage 
Simon’s minimax design has a 5% type I error and 85% power and a probability of early 
termination of 0.58. The cohort is to be terminated at stage I if ≤ 4 pts respond. If the 
cohort goes on to stage II and total number of responses is ≤ 12, the treatment is rejected.  
Thus, if both cohorts go to stage II then each of the cohorts will require 28 evaluable 
patients. To be evaluable for efficacy, the patient has to receive at least one dose of 
pembrolizumab and doublet chemotherapy. We assume an ineligibility rate of 10% so 
we plan to enroll 31 patients in each cohort of the trial.  
Assuming accrual duration of 12-24 months and minimum follow up of 12 months for 
OS, the duration of this trial will be 24-36 months.  Although the accrual rate will not 
affect the primary endpoint RR, the total study duration might be different for each 
cohort. 
For each cohort, once the 14th patient has been enrolled, further enrollment for that 
cohort will be halted until a decision has been reached from the interim analysis.  The 
interim analysis for each cohort will be done after the first 14 patients in the cohort have 
all completed at least six weeks of follow-up and have been assessed for CR/PR. 
 
10.2.3 Analysis plan for primary and secondary endpoints 
The primary analysis is response rate and will include reporting the response count and 
proportion with the associated exact 95% binomial confidence interval in the response 
evaluable population in each cohort.  If stage 2 is initiated for a cohort then the efficacy 
analysis methods will be as described by Koyama and Chen (43). 

 
 
55 
 
 
Secondary endpoint analysis will include Kaplan-Meier methods to describe OS and 
PFS.  Descriptive analysis including counts and proportions will be used to describe 
toxicity. Expression of PD-L1 by IHC will be categorized into positive (≥1% of cells) or 
negative. Mutation load will be high/low (Rizvi, et al) (32).  A description of the 
association of each with the response rate will be described using counts and percentages 
and tested using fisher’s exact chi-square test.  
   
Counts of CTC before the first cycle and before the third cycle will be summarized across 
all patients with sample means and standard deviations, or sample medians and ranges if 
the distribution of CTC levels is skewed.  We will also summarize counts of CTC before 
the first cycle and before the third cycle separately for responders and non-responders.  
All other data collected from the blood samples, such as EGFR and ALK expression, will 
be summarized in similar fashion and Pearson’s correlation coefficient will be used to 
summarize the association of PD-L1 expression in CTCs and in tumor tissue. 
 
11 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
11.1 Investigational Product  
Each of the site investigators shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and usage of 
pembrolizumab in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. Carboplatin and 
pemetrexed will sourced from commercial sources.  
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
11.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 

 
 
56 
 
11.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
11.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
11.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
12 
ADMINISTRATIVE AND REGULATORY DETAILS 
12.1 Confidentiality 
All efforts will be made at each participating site to maintain the confidentiality of patients 
enrolled on the trial according to institutional, local and federal guidelines.   
12.2 Compliance with Financial Disclosure Requirements 
All participating staff will disclose any financial conflicts of interest to respective institutional 
review boards or applicable compliance authorities.  
12.3 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Principal Investigator of the 
trial is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  

 
 
57 
 
Information posted will allow subjects to identify potentially appropriate trials for their disease 
conditions and pursue participation by calling a central contact number for further information 
on appropriate trial locations and trial site contact information.     
12.4 Data Safety Monitoring 
This study will be monitored in accordance with the NCI approved University of Michigan 
Rogel Cancer Center Data and Safety Monitoring Plan, with oversight by the Rogel Cancer 
Center Data and Safety Monitoring Committee (DSMC). 
The Study Principal Investigator will provide ongoing monitoring of data and patient safety in 
this trial and conduct regular data review with participating sites. 
The Study Principal Investigator and/or the Project Manager/Delegate will review data and 
patient safety issues with participating sites per a defined quarterly meeting cadence. 
Depending on the protocol activity, the meeting cadence may be more frequent. This data 
review meeting may be achieved via a teleconference or another similar mechanism to discuss 
matters related to: 
 Enrollment rate relative to expectations, characteristics of participants 
 Safety of study participants (SAE reporting, unanticipated problems) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
 
Similarly, protocol deviations are to be documented using the Notice of Protocol Deviation 
Form and requires the signatures of both the sites data manager or study coordinator and the 
site principal investigator or co-investigator. These reports are to be sent to the University of 
Michigan Coordinating Center within 7 calendar days of awareness of the event. 
Participating sites are required to ensure all pertinent data for the review period are available 
in the database at the time of the discussion. 
Participating sites unable to participate in the data review meeting are required to provide 
written confirmation that their site has reviewed the relevant data and patient safety issues for 
the review period and their site’s data are in alignment with the data reported in the database. 
Written confirmation is to be provided to the Project Manager/Delegate within the timeline 
requested to retain compliance with monitoring timelines. 
Documentation of the teleconference or alternate mechanism utilized to review items above is 
to be retained in the Trial Master File.  
The Project Manager/Delegate is responsible for collating the data from all participating sites 
and completing the Protocol Specific Data and Safety Monitoring Report (DSMR) form to 
document the data review meeting discussion.  

 
 
58 
 
The DSMR will be signed by the Study Principal Investigator or designated Co-Investigator 
and submitted to the DSMC on a quarterly basis for independent review. 
12.4.1 Quality Assurance and Audits 
The Data and Safety Monitoring Committee can request a ‘for cause’ quality assurance audit 
of the trial if the committee identifies a need for a more rigorous evaluation of study-related 
issues.  
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during 
its conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the Coordinating Center that such a 
request has been made. 
12.4.2 Clinical Monitoring Procedures 
Clinical studies coordinated by The Rogel Cancer Center must be conducted in accordance 
with the ethical principles that are consistent with Good Clinical Practices (GCP) and in 
compliance with other applicable regulatory requirements. 
This study will be monitored by a representative of the Coordinating Center. Monitoring visits 
will be made during the conduct of the study and at study close-out. 
Prior to subject recruitment, a participating site will undergo site initiation meeting to be 
conducted by the Coordinating Center. This will be done as an actual site visit; teleconference, 
videoconference, or web-based meeting after the site has been given access to the study 
database and assembled a study reference binder.  The site’s principal investigator and his 
study staff should make every effort in attending the site initiation meeting. Study–related 
questions or issues identified during the site initiation meeting will be followed-up by the 
appropriate personnel until they have been answered and resolved. 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source 
documents at the Coordinating Center and ‘On-site Monitoring’, an actual site visit.  The first 
‘Centralized’ visit should occur after the first subject enrolled completes first treatment cycle.  
The study site will send the de-identified source documents to the Coordinating Center for 
monitoring.  ‘Centralized’ monitoring may be requested by the Coordinating Center if an 
amendment requires changes to the protocol procedures. The site will send in pertinent de-
identified source documents, as defined by the Coordinating Center for monitoring.  
The first annual ‘On-site’ monitoring visit should occur after the first five study participants 
are enrolled or twelve months after a study opens, whichever occurs first.  The annual visit 
may be conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the study 
site.  The type of visit is at the discretion of the Coordinating Center.  At a minimum, a routine 
monitoring visit will be done at least once a year, or once during the course of the study if the 
study duration is less than 12 months. The purpose of these visits is to verify: 
 Adherence to the protocol 

 
 
59 
 
 Completeness and accuracy of study data and samples collected 
 Proper storage, dispensing and inventory of study medication 
 Compliance with regulations 
 
During a monitoring visit to a site, access to relevant hospital and clinical records must be 
given by the site investigator to the Coordinating Center representative conducting the 
monitoring visit to verify consistency of data collected on the CRFs with the original source 
data.  While most patient cases will be selected from patients accrued since the previous 
monitoring visit, any patient case has the potential for review.  At least one or more 
unannounced cases will be reviewed, if the total accruals warrant selection of unannounced 
cases.  
The Coordinating Center expects the relevant investigational staff to be available to facilitate 
the conduct of the visit, that source documents are available at the time of the visit, and that a 
suitable environment will be provided for review of study-related documents. Any issues 
identified during these visits will be communicated to the site and are expected to be resolved 
by the site in a timely manner.  For review of study-related documents at the Coordinating 
Center, the site will be required to ship or fax documents to be reviewed.   
Participating site will also undergo a site close-out upon completion, termination or 
cancellation of a study to ensure fulfillment of study obligations during the conduct of the 
study, and that the site Investigator is aware of his/her ongoing responsibilities. In general, a 
site close-out is conducted during a site visit; however, site close-out can occur without a site 
visit.  
12.5 Data Management 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the 
web-based electronic data capture (EDC) system of the University of Michigan. Online access 
will be provided to each site by the Coordinating Center.  
CRFs will be reviewed and source verified by the MSC during annual monitoring visits and 
prior to and between visits. Discrepant, unusual and incomplete data will be queried by the 
MSC. The investigator or study coordinator will be responsible for providing resolutions to the 
data queries, as appropriate. The investigator must ensure that all data queries are dealt with 
promptly.  
The data submission schedule is as follows:  
• At the time of registration   
o Subject entry into EDC 
 Subject Status 
 Demographics 
• During study participation 
o All data should be entered online within 10 business days of data acquisition. 
[Information on dose limiting toxicity events must be entered within one 

 
 
60 
 
business day.] Information on Serious Adverse Events must be entered within 
the reporting timeframe specified in Section 8.2.3 of the protocol.  
All study information should be recorded in an appropriate source document (e.g. clinic chart). 

 
 
61 
 
13 
REFERENCES 
 
1. Mok T, Yang JJ, Lam KC. Treating patients with EGFR-sensitizing mutations: first line 
or second line- is there a difference? J Clin Oncol:2013;31:1081-88. 
 
2. Jackman D, Pao W, Reily GJ, et al. Clinical definition of acquired resistance to 
epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung 
cancer. J Clin Oncol 2010;28:357-60. 
 
3. Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-Mutated Non–Small-
Cell Lung Cancer. N Engl J Med 2015;372:1700-9. 
 
4. Jänne PA, Chih-Hsin Yang JC, Kim D, et al. AZD9291 in EGFR Inhibitor–Resistant 
Non–Small-Cell Lung Cancer. N Engl J Med 2015;372:1689-99. 
 
5. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus 
chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression 
on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol 
2015;16:990-98. 
 
6. Janjigian YY, Smit EF, Groen HJ, et al. Dual inhibition of EGFR with afatinib and 
cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without 
T790M mutations. Cancer Discov:2014;9:1036-45. 
 
7. Peters S, Camidge R, Shaw A, et al. , et al. Alectinib versus crizotinib in intreated ALK-
positive non-small-cell lung cancer. N Engl J Med 2017;377:829-38. 
 
8. Kim DW, Mehra R, Tan D, et al. Activity and safety of ceritinib in patients with ALK 
rearranged non-small cell lung cancer (ASCEND-1): updated results from the 
multicenter, open label, phase I trial. Lancet Oncol 2016;17:452-63. 
 
9. Ou S, Ahn JS, Petris LD, et al. Alectinib in crizotinib refractory ALK rearranged non-
small cell lung cancer: A phase II global study. J Clin Oncol 2016;34:661-8. 
 
10. Solomon BJ, Bauer TM, Felip E, et al. Safety and efficacy of lorlatinib (PF-06463922) 
from the dose escalation component of a study in patients with advanced ALK + or 
ROS1+ non-small cell lung cancer (NSCLC). J Clin Oncol 2016;34(supplement, 
abstract 9009).    
 
11. Shaw AT, Ou SI, Bang Y, et al. Crizotinib in ROS-1 rearranged non-small-cell lung 
cancer. N Engl J Med 2019;371:1963-71.  
 
12. Doebele RC, Ahn MJ, Siena S, et al. Efficacy and safety of entrectinib in locally 
advanced or metastatic ROS-1 positive non-small cell lung cancer; Abstract presented 

 
 
62 
 
at World Conference of Lung Cancer, September 2018; abstract 13903.  
 
13. Planchard D, Smit EF, Groen HJ, et al. Dabrafenib plus trametinib in patients with 
previously untreated Braf V600E mutant metastatic non-small-cell lung cancer: an 
open-label, phase 2 trial. Lancet Oncol 2017;18:1307-16. 
 
14. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-
positive cancers in adults and children. N Engl J Med 2018;378:731-39. 
 
15. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf, 
MS-66; 
accessed 
October 27th , 2019. 
 
16. Disis ML.  Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8.  
 
17. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400.  
 
18. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. 
Clin Cancer Res 2008;14(16):5220-7.  
 
19. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010;37(Suppl 1):48-53.  
 
20. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune 
evasion. Nat Med 2002;8(8):793-800.   
 
21. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
 
22. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42. 
 
23. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-
1 expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.   
 
24. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of 
positive selection in the thymus of PD-1-d 
 
25. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus 
chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 
2016;375:1823-33. 
 

 
 
63 
 
26. Garon E, Leighl NB, Rizvi NA, et al. Safety and clinical activity of MK-3475 in 
previously treated patients with non-small cell lung cancer. N Engl J Med 
2015;372:2018-28. 
27. Borghaei H, Paz‑Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non–Small-Cell Lung Cancer. N Engl J Med 2015;373:1627-39. 
 
28. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in 
patients with previously treated non-small cell lung cancer (OAK): a phase 3, open-
label, multicenter randomised controlled trial. Lancet 2017;389:255-65.  
 
29. Gainor J, Shaw AT, Sequist LV, et al. EGFR mutations and ALK rearrangements are 
associated with low response rates to PD-1 pathway blockade in non-small cell lung 
cancer: A retrospective analysis. Clin Cancer Res 2016;22:4585-93. 
 
30. Mazieres J, Drilon AE, Mhanna L, et al. Efficacy of immune checkpoint inhibitors in 
non-small cell lung cancer patients harboring activating molecular alterations. J Clin 
Oncol 2018;36:15 suppl, abstract 9010.   
 
31. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, Activity, and Immune Correlates of 
Anti–PD-1 Antibody in Cancer. N Engl J Med 2012;366:2443-54. 
 
32. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology: mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015; 
348: 124-8. 
 
33. Cancer Genome Atlas Network. Comprehensive molecular characterization of human 
colon and rectal cancer. Nature 2012; 487: 330-7. 
 
34. Timmermann B, Kerick M, Roehr C, et al. Somatic mutation profiles of MSI and 
MSS colorectal cancer identified by whole exome next generation sequencing and 
bioinformatics analysis. PLoS One 2010; 5(12): e15661. 
 
35. Gadgeel SM, Stevenson J, Langer CJ, et al. Pembrolizumab plus chemotherapy as 
front-line therapy for advanced NSCLC: Keynote-021 cohorts A-C. J Clin Oncol 
2016;34:abstract 9016. 
 
36. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or 
without pembrolizumab for advanced non-squamous non-small-cell lung cancer: a 
randomised, phase 2 cohort of the open-label Keynote-021 study. Lancet Oncol 
2016;17:1497-1508.   
 
37. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy 
in metastatic non-small-cll lung cancer. N Engl J Med 2018;378:2078092.   
 

 
 
64 
 
38. Gallo M, DeLuca A, Maiello MR, et al. Clinical utility of circulating tumor cells in 
patients with non-small cell lung cancer. Transl Lung Cancer Res 2017;6:486-98. 
 
39. Yoon HJ, Kim TH, Zhang Z, et al. Sensitive capture of circulating tumour cells by 
functionalized graphene oxide nanosheets. Nat Nanotechnology 2013;8:735-741 
 
40. Murlidhar, V, Reddy RM, Fouladdel S, et al. Poor Prognosis Indicated by Venous 
Circulating Tumor Cell Clusters in Early-Stage Lung Cancers. Cancer Res 
2017;77:5194-5206. 
 
41. Zhang Z, Shiratsuchi H, Palanisamy N, et al. Expanded Circulating Tumor Cells from 
a Patient with ALK-Positive Lung Cancer Present with EML4-ALK Rearrangement 
Along with Resistance Mutation and Enable Drug Sensitivity Testing: A Case Study. J 
Thorac Oncol 2017;12:397-402. 
 
42. Zhang Z, Shiratsuchi H, Lin J, et al. Expansion of CTCs from early stage lung cancer 
patients using a microfluidic co-culture model. Oncotarget 2014;5:12383-97. 
 
43. Koyama T, Chen H. Proper inference from Simon’s two-stage designs. Statistics in 
Medicine 2008;27:3145-54. 
 
 

 
 
65 
 
14 
APPENDICES 
14.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
14.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
14.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 

 
 
66 
 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
 
 

 
 
67 
 
15.0 
COVID-19 Addendum 
Purpose 
The purpose of this addendum is to address protocol-required items that the COVID-19 pandemic may 
temporarily affect. 
 
A. Study Visit Schedule: 
• 
Visits:  Where participants cannot be seen at the site, the use of telemedicine and 
adaptation of schedule of assessments will be implemented, where feasible to 
ensure patient safety. 
• 
Treatment:  Per physician discretion, 1-2 cycles of treatment may be omitted once 
a patient completes 4 cycles of therapy. 
 
B. Correlative Samples: 
• 
PD-L1 testing:  Per physician discretion, a new biopsy is not required if a patient 
does not have PD-L1 results or archival tissue 
• 
CTC samples:  Samples will not be collected while the lab is closed due to COVID-
19. 
• 
Mutational Analysis samples:  Blood and tissue will not be collected or shipped 
while the lab is closed due to COVID-19.