Clinical trial NCT03083808
Conditions: Non-Small-Cell Lung Cancer
Keywords: PD-1 PD-L1 Inhibitor Pembrolizumab Docetaxel Pemetrexed Gemcitabine
Sponsor: Greg Durm, MD
Start date: 2017-03-20; Completion date: 2022-03-03
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-arm phase II study of continuation immunotherapy with pembrolizumab following initial benefit (CR, PR, or SD ≥ 3 months) with a PD-1 or PD-L1 inhibitor.

Detailed description:
OUTLINE: This is a multi-center study.

Patients who have been treated with a PD-1 or PD-L1 inhibitor and experienced a PFS of ≥3 months will be enrolled within 6 weeks of last dose of PD-1 or PD-L1 inhibitor. On Day 1 of each 3-week cycle, subjects will first receive pembrolizumab at a dose of 200mg IV every three weeks in combination with chemotherapy. Partner chemotherapy will be either gemcitabine 1000mg/m2 IV D1 and D8 every three weeks, docetaxel 75mg/m2 IV D1 every three weeks, or pemetrexed 500mg/m2 IV D1 every 3 weeks (pemetrexed for non-squamous histologies only). Subjects will continue to receive this combination until progression or intolerable toxicity.

Administration Sequence: First Sequence

\- Pembrolizumab 200mg IV on Day 1 (cycle = 21 days)

Administration Sequence: Second Sequence

* Gemcitabine 1000mg/m\^2 IV on Days 1,8 (cycle = 21 days)
* Docetaxel 75mg/\^2 IV on Days 1,8 (cycle = 21 days)
* Pemetrexed 500mg/m\^2 IV on Day 1 (cycle -= 21 days)

Arms: arm 1: Patients who have been treated with a PD-1 or PD-L1 inhibitor and experienced a PFS of ≥3 months will be enrolled within 6 weeks of last dose of PD-1 or PD-L1 inhibitor. On Day 1 of each 3-week cycle, subjects will first receive pembrolizumab at a dose of 200mg IV every three weeks in combination with chemotherapy. Partner chemotherapy will be either gemcitabine 1000mg/m\^2 IV D1 and D8 every three weeks, docetaxel 75mg/m\^2 IV D1 every three weeks, or pemetrexed 500mg/m\^2 IV D1 every 3 weeks (pemetrexed for non-squamous histologies only). Subjects will continue to receive this combination until progression or intolerable toxicity.
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Pembrolizumab 200mg IV every 21 days

\+

Physician's choice chemotherapy with one of the following every 21 days:

* Docetaxel 75mg/m2 IV
* Pemetrexed 500mg/m2 IV (non-squamous only)
* Gemcitabine 1000mg/m2 IV on days 1 and 8

Protocol documents:
Prot_SAP_001.pdf: 
  
Clinical Study Protocol 
 
 
 
 
BTCRC-LUN15-029 
 
A Phase II Trial of Chemotherapy plus Pembrolizumab in patients with advanced 
NSCLC previously treated with PD-1 or PD-L1 Inhibitor: 
Big Ten Cancer Research Consortium BTCRC-LUN15-029 
 
Sponsor Investigator 
Greg Durm, MD 
Assistant Professor, Department of Medicine, IU School of Medicine 
Indiana University Health Simon Cancer Center 
 
 
Co-Investigators 
Nasser Hanna, MD 
Lawrence Einhorn, MD 
Shadia Jalal, MD 
Christina Ferreira, PhD 
Tiago Sobreira, PhD 
 
 
Statistician 
Susan Perkins, PhD 
 
 
Trial Management Provided by  
Big Ten CRC Administrative Headquarters at Hoosier Cancer Research Network, Inc. 
500 N. Meridian, Suite 100 
Indianapolis, IN 46204 
 
 
Trial Supported by  
Merck Sharp & Dohme Corp. 
(MISP 53940) 
 
 
Investigational New Drug (IND) Number: 
132237 
 
 
Initial Protocol Version Date:  
26JAN2017 
 
Protocol Amendment Version Date:  
22MAR2017 
26JUL2017  
24JAN2019  
07NOV2019 (current) 
 


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PROTOCOL SIGNATURE PAGE 
 
A Phase II Trial of Chemotherapy plus Pembrolizumab in patients with advanced NSCLC previously 
treated with PD-1 or PD-L1 Inhibitor: 
Big Ten Cancer Research Consortium BTCRC-LUN15-029 
 
VERSION DATE:  07NOV2019 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and to the 
ethical principles stated in the latest version of the Declaration of Helsinki, the applicable guidelines for 
good clinical practices, whichever provides the greater protection of the individual.  I will accept the 
monitor’s overseeing of the study.  I will promptly submit the protocol to applicable ethical review 
board(s). 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Site Investigator 
 
 
  
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PLASE E-MAIL COMPLETED FORM TO BIG TEN CRC  
ADMINISTRATIVE HEADQUARTERS 
 
 
 


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SYNOPSIS 
TITLE 
A Phase II Trial of Chemotherapy plus Pembrolizumab in patients with 
advanced NSCLC previously treated with PD-1 or PD-L1 Inhibitor: 
Big Ten Cancer Research Consortium BTCRC-LUN15-029 
SHORT TITLE 
Phase II Trial of Continuation Pembrolizumab in NSCLC: BTCRC-
LUN15-029
PHASE  
2 
OBJECTIVES 
Primary Objective:  
 To assess if continuation therapy with pembrolizumab in 
combination with next-line chemotherapy will improve PFS in 
patients who have previously benefitted from a PD-1/PD-L1 
inhibitor (CR, PR, or SD ≥ 3months) according to RECIST 1.1 
criteria as compared to historical controls 
Secondary Objectives: 
 To estimate PFS by immune-related RECIST (irRECIST) 
 To estimate objective response rate (ORR) by RECIST 1.1 and 
irRECIST 
 To estimate clinical benefit rate as defined by RECIST 1.1 and 
irRECIST 
 To estimate overall survival (OS) 
 Toxicity of pembrolizumab in combination with next-line 
chemotherapy (gemcitabine, docetaxel, or pemetrexed-non-
squamous only) 
Exploratory Objectives: 
 To assess tumor PD-L1 status at baseline (prior to initial treatment 
with PD-1 inhibitor), at time of progression on PD-1 or PD-L1 
inhibitor (study entry), and at time of progression on combination of 
pembrolizumab and chemotherapy (safety follow up visit) 
 To correlate ORR, PFS, and clinical benefit rate with the results of 
proteomic analysis and lipidomic profiling 
 To correlate ORR, PFS, and clinical benefit rate with the results of 
NeoTYPE Lung Tumor Profile Genetic Analysis 
STUDY DESIGN 
Single Arm Phase II 
KEY ELIGIBILITY 
CRITERIA  
 Histological or cytological evidence of stage IV non-small cell lung 
cancer (any histology) 
 Subjects must have progressed on or after receiving platinum-based 
chemotherapy. Chemotherapy may have previously been given with 
a PD-1 or PD-L1 inhibitor. They must also have progressed on or 
after any PD-1 or PD-L1 inhibitor (including pembrolizumab) as 
their most recent therapy and must have had at least a 3-month PFS 
on this therapy. 
 Subjects must be enrolled on the trial within 12 weeks of their last 
infusion of PD-1 or PD-L1 inhibitor therapy. 
 Demonstrates adequate organ function (as defined in Table 1) and 
performance status (PS 0 or 1)


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 Must be fit enough to receive next-line chemotherapy (either 
gemcitabine, docetaxel, or pemetrexed [non-squamous only]) 
according to the discretion of the treating physician. 
 Subjects whose tumors harbor a mutation in EGFR exon 19 or 21 or 
have gene rearrangements in ALK or ROS1 must have already been 
treated with standard targeted therapies. NOTE: Subjects must also 
have progressed on or after platinum-containing combination 
chemotherapy. 
 No evidence of active autoimmune disease requiring systemic 
treatment within the past 90 days or a documented history of 
clinically severe autoimmune disease, or a syndrome that requires 
systemic steroids or immunosuppressive agents. 
 No history of interstitial lung disease or pneumonitis related to the 
use of immunotherapeutic drugs. Subjects with a history of 
pneumonitis which is unrelated to the used of immunotherapeutic 
drugs may participate at the discretion of the treating physician 
 No history of an immune-related toxicity requiring treatment with 
corticosteroids during prior PD-1/ PD-L1 inhibitor treatment.
STATISTICAL 
CONSIDERATIONS 
When the sample size is 31, a non-parametric test of median survival 
with a one-sided 0.05 significance level will have 80% power to detect 
the difference between a median survival of 3 months vs 6 months 
assuming an accrual period of approximately 6 months (6 per month) and 
maximum follow-up of 1.5 years. To allow for replacement of patients 
who are not evaluable for efficacy (estimated to be 10%), up to 35 
patients will be enrolled.  
 The historical control is a median PFS of 3 months (in the 2nd/3rd 
line setting).  
 Null hypothesis - Pembrolizumab plus chemo will have a median 
PFS of 3 months.  
 Alternative hypothesis –Pembrolizumab plus chemo will have a 
median PFS of 6 months  
Median PFS will be estimated using Kaplan-Meier methodology and 
tested using a non-parametric test.  ORR and clinical benefit rate will be 
estimated with two-sided 95% exact binomial confidence intervals.  
Toxicities will be tabulated.  Change in tumor levels of PD-L1 will be 
descriptively summarized and compared over time using paired t-tests.  
Proportional hazards regression (for PFS) and logistic regression (for 
ORR and clinical benefit rate) will be used to correlate proteomic, 
lipidomic and genomic results with clinical outcomes. 
TOTAL NUMBER OF 
SUBJECTS 
N = 35 
ESTIMATED 
ENROLLMENT PERIOD 
12 months 
ESTIMATED STUDY 
DURATION  
30 months 
 
 


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TABLE OF CONTENTS 
 
Schema ........................................................................................................................................................ 7 
1. 
Background and Rationale .................................................................................................................. 8 
1.1 
Lung Cancer Background ........................................................................................................... 8 
1.2 
Current Standard of Care for Non-Small Cell Lung Cancer ....................................................... 8 
1.3 
Background for Pembrolizumab ................................................................................................. 9 
1.4 
Rationale ................................................................................................................................... 12 
2. 
Study Objectives and Endpoints ....................................................................................................... 14 
2.1 
Objectives ................................................................................................................................. 14 
2.2 
Endpoints .................................................................................................................................. 14 
3. 
Eligibility Criteria ............................................................................................................................. 15 
3.1 
Inclusion Criteria ...................................................................................................................... 15 
3.2 
Exclusion Criteria ..................................................................................................................... 16 
4. 
Subject Registration .......................................................................................................................... 18 
5. 
Treatment Plan .................................................................................................................................. 18 
5.1 
Pre-medication and Hydration .................................................................................................. 18 
5.2 
Chemotherapy + Pembrolizumab Administration .................................................................... 18 
5.3 
Concomitant Medications ......................................................................................................... 19 
5.4 
Supportive Care ........................................................................................................................ 21 
5.5 
Diet/Activity/Other Considerations .......................................................................................... 23 
6. 
Toxicities and Dose Delays/Dose Modifications .............................................................................. 24 
6.1 
Dose Delays/Dose Modifications ............................................................................................. 24 
6.2 
Dose Modifications ................................................................................................................... 25 
6.3 
Protocol Therapy Discontinuation ............................................................................................ 33 
6.4 
Protocol Discontinuation .......................................................................................................... 33 
7. 
Study Calendar & Evaluations .......................................................................................................... 34 
7.1 
Screening Evaluations ............................................................................................................... 36 
7.2 
On Treatment Evaluations ........................................................................................................ 37 
7.3 
Safety Follow-up Evaluations ................................................................................................... 38 
7.4 
Long Term Follow-up Evaluations ........................................................................................... 38 
8. 
Biospecimen Studies and Procedures ............................................................................................... 38 
8.1 
Tissue for assessment of PD-L1 status ..................................................................................... 38 
8.2 
Tissue for genetic analysis ........................................................................................................ 39 
8.3 
Blood for Somatic Baseline DNA ............................................................................................. 39 
8.4 
Blood for proteomic analysis and lipidomic profiling .............................................................. 39 
8.5 
Confidentiality of Biospecimens ............................................................................................... 39 
8.6 
Samples for future studies ......................................................................................................... 39 
9. 
Criteria for Disease Evaluation ......................................................................................................... 39 
9.1 
Measurable Disease .................................................................................................................. 39 
9.2 
Non-measurable Lesions ........................................................................................................... 40 
9.3 
Target Lesions ........................................................................................................................... 40 
9.4 
Non-target Lesions .................................................................................................................... 40 
9.5 
Evaluation of Target Lesions .................................................................................................... 40 
9.6 
Evaluation of Non-target Lesions ............................................................................................. 41 
9.7 
Evaluation of Best Overall Response ....................................................................................... 41 


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9.8 
Definitions for Response Evaluation – RECIST 1.1 ................................................................ 42 
9.9 
Immune- Related RECIST Criteria ........................................................................................... 43 
10. Drug Information .............................................................................................................................. 45 
10.1 
Pembrolizumab ......................................................................................................................... 45 
10.2 
Docetaxel .................................................................................................................................. 48 
10.3 
Pemetrexed Disodium Heptahydrate (Alimta) .......................................................................... 49 
10.4 
Gemcitabine .............................................................................................................................. 50 
11. Adverse Events ................................................................................................................................. 52 
11.1 
Definitions................................................................................................................................. 52 
11.2 
Reporting................................................................................................................................... 53 
12. Statistical Methods ............................................................................................................................ 56 
12.1 
Study Design ............................................................................................................................. 57 
12.2 
Endpoints .................................................................................................................................. 57 
12.3 
Sample Size and Accrual .......................................................................................................... 57 
12.4 
Analysis Datasets ...................................................................................................................... 57 
12.5 
Assessment of Safety ................................................................................................................ 58 
12.6 
Assessment of Efficacy ............................................................................................................. 58 
12.7 
Data Analysis Plans .................................................................................................................. 58 
12.8 
Interim Analysis/Criteria for Stopping Study ........................................................................... 59 
13. Trial Management ............................................................................................................................. 59 
13.1 
Data and Safety Monitoring Plan (DSMP) ............................................................................... 59 
13.2 
IUSCC Data Safety Monitoring Committee and Protocol Progress Committee ...................... 59 
13.3 
Data Quality Oversight Activities ............................................................................................. 60 
13.4 
Compliance with Trial Registration and Results Posting Requirements .................................. 60 
14. Data Handling and Record Keeping ................................................................................................. 61 
14.1 
Data Management ..................................................................................................................... 61 
14.2 
Case Report Forms and Submission ......................................................................................... 61 
14.3 
Record Retention ...................................................................................................................... 61 
14.4 
Confidentiality .......................................................................................................................... 61 
15. Ethics................................................................................................................................................. 62 
15.1 
Institutional Review Board (IRB) Approval ............................................................................. 62 
15.2 
Ethical Conduct of the Study .................................................................................................... 62 
15.3 
Informed Consent Process ........................................................................................................ 62 
16. References ......................................................................................................................................... 63 


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SCHEMA 
 
A Phase II Trial of Chemotherapy plus Pembrolizumab in patients with advanced 
NSCLC previously treated with PD-1 or PD-L1 Inhibitor: 
Big Ten Cancer Research Consortium BTCRC-LUN15-029 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects with progressive disease on single-agent PD-1 or PD-L1 
inhibitor following at least 3 month PFS
Pembrolizumab 200mg IV every 21 days 
+ 
Physician’s choice chemotherapy with one of the 
following every 21 days: 
 Docetaxel 60-75mg/m2 IV  
 Pemetrexed 500mg/m2 IV (non-squamous only) 
 Gemcitabine 1000mg/m2 IV on days 1 and 8  
*Optional 
biopsy 
recommended 
Enroll on study within 12 weeks of last 
PD-1 or PD-L1 infusion* 
Continue therapy until progression or 
unacceptable toxicity* 
*Optional biopsy 
at discontinuation 
is recommended
Follow for overall survival 


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1. 
BACKGROUND AND RATIONALE 
1.1 
Lung Cancer Background 
Lung cancer remains the leading cause of cancer-related  mortality in the United States with an 
estimated 224,390 new cases and 158,080 deaths in 2016 (1). Non-small cell lung cancer makes 
up approximately 83% of these cases with several histologic subtypes including adenocarcinoma, 
squamous cell carcinoma, large cell carcinoma, and a few others which are much less common 
(2). While a number of new treatments have become available over the last decade, the 5-year 
overall survival (OS) rate for all lung cancer patients remains poor at 17% and the OS for 
patients with metastatic disease is only 4% (2). New treatment options and approaches are 
needed to improve upon these poor outcomes. 
1.2 
Current Standard of Care for Non-Small Cell Lung Cancer 
The current standard of care for non-squamous NSCLC depends in large part on whether 
targetable mutations exist which can be exploited. Initial biopsy specimens are sent for 
mutational analysis with particular attention to activating epidermal growth factor receptor 
(EGFR) mutations in exon 19 and 21or gene rearrangements in either anaplastic lymphoma 
kinase (ALK) or ROS1. Tumors which harbor sensitizing EGFR mutations are responsive to a 
number of EGFR tyrosine kinase inhibitors (TKI) including erlotinib, gefitinib, and afatinib, and 
use of one of these agents is recommended in the 1st line setting. ALK translocations should be 
treated with crizotinib in the 1st line setting and either ceritinib or alectinib in the 2nd line setting 
(3). ROS1 mutations can be treated with crizotinib in the 1st line setting, and there is some 
evidence that cabozantinib may be an active alternative when resistance develops to this therapy 
(4, 5). 
 
In the majority of patients, there are no mutations for which targeted therapies have been 
approved. In this setting, the standard of care remains chemotherapy with a platinum doublet for 
fit patients. These combinations produce response rates of approximately 25-35% and 1-year OS 
rates of 30-40%. In non-squamous histologies, bevacizumab may also be added to either 
cisplatin or carboplatin with pemetrexed or to carboplatin and paclitaxel in patients without 
contraindications. Maintenance therapy with pemetrexed, bevacizumab, or erlotinib can also be 
considered in eligible patients (3). 
 
In the 2nd line setting, the mainstay of therapy has previously been single-agent chemotherapy 
with an agent not used as part of initial therapy. The most commonly used medications include 
docetaxel, pemetrexed (only for non-squamous), and gemcitabine. Erlotinb was also previously 
approved in this setting though subsequent studies have shown the majority of its activity to be in 
patients harboring activating mutations in EGFR, and its use for EGFR wild-type patients has 
declined. Recently, a trial of ramucirumab, a monoclonal antibody against the vascular 
endothelial growth factor receptor 2 (VEGFR2), in combination with docetaxel showed a modest 
improvement in PFS and OS compared with docetaxel alone, though there was also a modest 
increase in toxicity (6). One of the most promising new therapeutic strategies for advanced and 
metastatic NSCLC is the emergence of immunotherapy, particularly programmed death-1 (PD-1) 
and programmed death ligand-1 (PD-L1) blockade. In two separate phase III trials, nivolumab, a 
PD-1 inhibitor, improved OS in both squamous and non-squamous populations when compared 
to single-agent docetaxel (7, 8). A second PD-1 inhibitor, pembrolizumab, also showed good 


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activity in advanced and metastatic NSCLC with >50% PD-L1 expression on tumor cells with 
superior OS when compared with Docetaxel (9). In addition to their efficacy, both nivolumab 
and pembrolizumab were well tolerated during these trials with side effect profiles that are 
generally considered more manageable than standard chemotherapy options. Most importantly, 
there is the potential for durable responses with these agents which gives hope for long-term 
survival in a patient population for which this has typically been rare (7-10). Given the 
improvements in OS, potential for durable responses, and favorable toxicity profiles, these drugs 
were approved by the FDA for the treatment of NSCLC following progression on a platinum 
doublet, and they are increasingly considered the best option for the 2nd line treatment of 
advanced and metastatic disease. 
 
Following progression on either nivolumab or pembrolizumab, 3rd line treatment for fit patients 
typically consists of single-agent chemotherapy. Typical regimens include docetaxel with or 
without ramucirumab, gemcitabine, or pemetrexed in patients with non-squamous histology. 
Erlotinib can also be considered as a single agent in this setting. For patients who initially 
respond or have stable disease on immunotherapies, it is currently unclear whether continuation 
of these medications at the time of progression has any benefit in the 3rd line setting. 
1.3 
Background for Pembrolizumab 
1.3.1 Pre-clinical Data 
The importance of intact functions of immune surveillance in controlling outgrowth of neoplastic 
transformations has been known for decades (11). Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-
cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating lymphocytes can 
be expanded ex vivo and re-infused, inducing durable objective tumor responses in cancers such 
as melanoma (12, 13). 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated Tcells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2) (14, 15). The structure of 
murine PD-1 has been resolved (16). PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable–type (IgV-type) domain responsible for ligand binding 
and a cytoplasmic tail 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, and an immunoreceptor tyrosine-based switch motif. Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor tyrosine-based 
switch 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 (15, 
17-19). The mechanism by which PD-1 down-modulates T-cell responses is similar to, but 


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distinct from, that of CTLA-4, because both molecules regulate an overlapping set of signaling 
proteins (20, 21). 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 (22, 23). Expression 
has also been shown during thymic development on CD4-CD8- (double negative) T-cells, as 
well as subsets of macrophages and dendritic cells (24).  The ligands for PD-1(PD-L1 and PD-
L2) are constitutively expressed or can be induced in a variety of cell types including 
nonhematopoietic tissues and in various tumors (11, 21, 25-27). Both ligands are type 1 
transmembrane receptors containing IgV-like and Ig constant–like (IgC-like) domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs. 
Binding of either PD-L1 or PD-L2 to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor. PD-L1 is expressed at low levels on various nonhematopoietic tissues, most notably on 
vascular endothelium; whereas PD-L2 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 (21). Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. High 
expression of PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found to correlate 
with poor prognosis and survival in various cancer types, including renal cell carcinoma (28), 
pancreatic carcinoma (29), hepatocellular carcinoma (30), and ovarian carcinoma (31). 
Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects 
with melanoma (32). 
 
The observed correlation of clinical prognosis with PD-L1 expression in multiple cancers 
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. Therapeutic studies in mouse 
models show that administration of antibodies blocking PD-1/PD-L1 interaction enhances 
infiltration of tumor-specific CD8+ T-cells and leads ultimately to tumor rejection, either as a 
monotherapy or in combination with other treatment modalities. Anti–mouse PD-1 and anti–
mouse PD-L1 have demonstrated antitumor responses as a monotherapy in models of squamous 
cell carcinoma, pancreatic carcinoma, melanoma, and colorectal carcinoma. Blockade of the PD-
1 pathway effectively promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-
γ, granzyme B, and perforin, indicating that the mechanism of action involved local infiltration 
and activation of effector T-cell function in vivo (29, 33-36). In addition, the combination of 
gemcitabine and anti–PD-L1 mAb demonstrated synergy in the rejection of pancreatic mouse 
tumors (29). In-house experiments have confirmed the in vivo efficacy of PD-1 blockade as a 
monotherapy as well as in combination with chemotherapy in syngeneic mouse tumor models. 
1.3.2 Clinical Data in NSCLC 
The PD-1 pathway represents a major immune control switch, which may be engaged by tumor 
cells to overcome active T-cell immune surveillance. Pembrolizumab (KEYTRUDA®, MK-
3475; previously known as SCH 900475 and ORG 307488- is a potent and highly selective 
humanized monoclonal antibody (mAb) of the immunoglobulin G4(IgG4)/kappa isotype 
designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This 
blockade enhances functional activity of the target lymphocytes to facilitate tumor regression and 
ultimately immune rejection. 
 


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The clinical activity of Pembrolizumab in NSCLC was demonstrated in two clinical trials. In the 
initial phase I trial (KEYNOTE-001), patients with advanced NSCLC were treated with either 
2mg/kg or 10mg/kg every 3 weeks or 10mg/kg every 2 weeks. The treatment was well tolerated 
with the most frequent side effects including fatigue, pruritus, and decreased appetite. Among all 
patients, the objective response rate (ORR) was 19.4% and the median duration of response was 
12.5months. Median progression free survival (PFS) was 3.7 months and median OS was 12 
months. Among patients with >50% PD-L1 expression on tumor cells, the response rate was 
45.2% with a PFS of 6.3 months. Median OS in this group was not reached (10).  
 
In a subsequent phase II/III trial (KEYNOTE-010) of single-agent pembrolizumab versus 
docetaxel for PD-L1 positive (>1% PD-L1 staining on tumor cells) NSCLC, patients were 
randomized 1:1:1 to receive either pembrolizumab 2mg/kg, pembrolizumab 10mg/kg, or 
docetaxel 75mg/m2 intravenously (IV) every 3 weeks.  In the total population, median overall 
survival favored the pembrolizumab arms with 10.4 months in the 2mg/kg arm, 12.7 months in 
the 10mg/kg arm, and 8.5 months in the docetaxel arm.  PFS was not statistically improved in the 
pembrolizumab arms when considering all patients.  In the group of patients with >50% PD-L1 
staining, a more substantial benefit was seen for the pembrolizumab arms with a median OS of 
14.9 months in the 2mg/kg arm versus 8.2 months in the docetaxel arm (HR 0.54, =0.0002) and 
17.3 months in the 10mg/kg arm versus 8.2 months in the docetaxel arm (HR 0.50, p<0.0001).  
PFS was also statistically significantly longer in the pembrolizumab arms for patients with >50% 
PD-L1 staining. Pembrolizumab appeared to be much better tolerated than docetaxel with grade 
3-5 treatment-related adverse events (TRAEs) of 13% and 16% in the 2mg/kg and 10mg/kg 
pembrolizumab respectively versus 35% in the docetaxel arm (9).  Based on the data from these 
trials, pembrolizumab was FDA-approved for the 2nd line treatment of PD-L1 positive (>50% 
staining on tumor cells) NSCLC and is currently under review by the FDA for the tissue 
polypeptide-specific antigen (TPS) >1% population. 
1.3.3 Safety Data in Combination with Chemotherapy 
The safety of combining immunotherapy with chemotherapy has been demonstrated in several 
early phase trials in NSCLC, and larger trials are currently being conducted to assess the efficacy 
of these combinations.  In a phase I trial (KEYNOTE-021), pembrolizumab was added to 
platinum doublet chemotherapy in patients with treatment-naïve NSCLC. Subjects were 
randomized to receive either 2mg/kg or 10mg/kg of pembrolizumab in combination with either 
carboplatin (AUC 6) and paclitaxel (200mg/m2) or carboplatin (AUC 5) and pemetrexed 
(500mg/m2) IV every 3 weeks for 4 cycles followed by either pembrolizumab or pembrolizumab 
and pemetrexed maintenance. The carboplatin and paclitaxel arm demonstrated 15% grade 3-4 
TRAEs including anemia and rash in one patient each. The carboplatin and pemetrexed arm 
experienced 38% grade 3-4 AEs including reversible transaminase elevations (n=3), anemia 
(n=2), rash (n=1), and colitis (n=2). No grade3-4 febrile neutropenia was observed, and there 
were no treatment-related deaths on either arm. ORR were 30% in the carboplatin/paclitaxel arm 
and 58% in the carboplatin/pemetrexed arm at the time of analysis with the majority of patients 
remaining on therapy in both arms (37). This study suggests that the combination of 
pembrolizumab and platinum doublet chemotherapy with a taxane or pemetrexed has a 
reasonable safety profile, and therefore, it is likely that the combination of pembrolizumab with 
either single-agent taxane or pemetrexed will be well tolerated as well. 
 


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There is no direct safety data with the combination of pembrolizumab and gemcitabine, however, 
there is a phase I trial of nivolumab (another PD-1 inhibitor) with platinum doublet 
chemotherapy that includes a gemcitabine arm. In this trial, treatment-naïve patients were 
randomized to one of 4 treatment regimens. The first three arms combined nivolumab 10mg/kg 
IV every three weeks with either cisplatin (75mg/m2) and gemcitabine (1250mg/m2), cisplatin 
(75mg/m2) and pemetrexed (500mg/m2), or carboplatin (AUC 6) and paclitaxel (200mg/m2). The 
last arm combined nivolumab 5mg/m2 with carboplatin (AUC 6) and paclitaxel (200mg/m2).  All 
regimens were given for 4 cycles followed by nivolumab maintenance. No dose-limiting 
toxicities (DLTs) were seen during the first 6 weeks of treatment, and there were no reported 
treatment-related deaths. Grade 3-4 AEs were seen in 45% of patients (range 25-73% across all 
arms) and most commonly included pneumonitis (grade 4, n=1; grade 3, n=3), fatigue (grade 3, 
n=3), and acute renal failure (grade 3, n=3). Grade 3 select AEs occurred in ≤7% of patients, and 
overall, 20% of patients discontinued any study medication because of treatment-related AEs 
(38). This study shows that the combination of nivolumab with platinum doublet chemotherapy 
including gemcitabine, pemetrexed, and paclitaxel has a manageable safety profile and reflects 
the additive toxicities of immunotherapy and chemotherapy. Based on this, the combination of 
immunotherapy with single agent gemcitabine, pemetrexed, or a taxane would be expected to 
have a reasonable safety profile as well. 
1.4 
Rationale 
1.4.1 Study Rationale 
While many patients who initially respond to immunotherapy have prolonged durations of 
response, the majority of patients will still ultimately progress on these therapies. Little is 
currently known about the resistance mechanisms responsible for this progression, and there is 
currently no data to suggest whether immunotherapy has any benefit or should be continued 
following clear progression. Previous studies in both NSCLC and other malignancies have 
shown differing results in the benefit of continuing targeted agents. A trial of continuation 
trastuzumab following progression in human epidermal growth factor receptor 2 (HER-2)-
positive early and advanced breast cancer shows a significant overall survival benefit for the 
combination of chemotherapy and trastuzumab compared with chemotherapy alone (39). 
Furthermore, treatment with bevacizumab, a monoclonal antibody (mAb) targeting vascular 
endothelial growth factor (VEGF) following progression on first line therapy suggests a 
significant OS advantage for the patients who were continued on bevacizumab (40). Lastly, 
androgen deprivation therapy (ADT) is routinely continued beyond progression in the treatment 
of metastatic prostate cancer (41). Conversely, continued treatment with the TKI erlotinib did not 
show benefit when continued beyond progression in patients with advanced EGFR-mutated 
NSCLC (42). Therefore, further study of continuation of immunotherapy at the time of 
progression is warranted. 
1.4.2 Dose Selection Rationale 
The dose regimen of 200 mg Q3W of pembrolizumab is planned for all urothelial cancer trials. 
Available PK results in subjects with melanoma, NSCLC, and other solid tumor types support a 
lack of meaningful difference in PK exposures obtained at a given dose among tumor types. An 
open-label Phase 1 trial (PN001) in melanoma subjects is being conducted to evaluate the safety 
and clinical activity of single agent pembrolizumab. 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 


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(Q2W) in subjects with advanced solid tumors. All three dose levels were well tolerated and no 
DLTs were observed. This first in human study of pembrolizumab 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 maximum tolerated dose (MTD) has been identified. 
 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed. The clinical 
efficacy and safety data demonstrate a lack of clinically important differences in efficacy 
response or safety profile at these doses. For example, in Cohort B2, advanced melanoma 
subjects who had received prior ipilimumab therapy were randomized to receive pembrolizumab 
at 2 mg/kg versus 10 mg/kg Q3W. The overall ORR was 26% (21/81) in the 2mg/kg group and 
26% (25/79) in the 10 mg/kg group (full analysis set (FAS)). The proportion of subjects with 
TEAEs, grade 3-5 drug-related AEs, serious drug-related AEs, death or discontinuation due to an 
AE was comparable between groups or lower in the 10 mg/kg group. 
 
Available pharmacokinetic (PK) results in subjects with melanoma, NSCLC, and other solid 
tumor types support a lack of meaningful difference in PK exposures obtained at a given dose 
among tumor types. Population PK analysis has been performed and has confirmed the 
expectation that intrinsic factors do not affect exposure to pembrolizumab to a clinically 
meaningful extent. Taken together, these data support the use of lower doses (with similar 
exposure to 2 mg/kg Q3W) in all solid tumor indications. 
 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation 
results indicating that 200 mg will provide exposures that are reasonably consistent with those 
obtained with 2 mg/kg dose and importantly will maintain individual patient exposures within 
the exposure range established in melanoma as associated with maximal clinical response. A 
population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed using available data from 476 subjects from PN001. 
The distribution of exposures from the 200 mg fixed dose are predicted to considerably overlap 
those obtained with the 2 mg/kg dose, with some tendency for individual values to range slightly 
higher with the 200 mg fixed dose. The slight increase in PK variability predicted for the fixed 
dose relative to weight-based dosing is not expected to be clinically important given that the 
range of individual exposures is well contained within the range of exposures shown in the 
melanoma studies of 2 and 10 mg/kg to provide similar efficacy and safety. 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 tumor types and indication settings. 
1.4.3 Rationale for Historical Control 
Previous studies evaluating single-agent chemotherapy following progression on a platinum 
doublet have shown consistently that the PFS or TTP in these studies is approximately 3 months.  
In a trial of docetaxel versus best supportive care (BSC), the chemotherapy arm demonstrated a 
TTP of 10.6 weeks (43), and in a trial of docetaxel versus vinorelbine or ifosfamide, the 
docetaxel arm showed a TTP of 8.5 weeks (44).  A more recent trial comparing single-agent 
docetaxel versus pemetrexed in the second-line setting demonstrated a PFS of 2.9 months for 
both arms (45).  Given the consistent findings in these studies, a PFS of 3 months appears to be 
an appropriate historical control arm.  


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Primary Objective 
 To assess whether continuation of pembrolizumab in combination with next-line 
chemotherapy (either gemcitabine, docetaxel, or pemetrexed [non-squamous only]) will 
prolong PFS by RECIST 1.1 criteria in patients who previously benefitted from a PD-1/ 
PD-L1 inhibitor (PFS ≥ 3 months) but now have progressive disease as compared to 
historical controls 
2.1.2 Secondary Objectives 
 To estimate PFS by immune-related RECIST (irRECIST) 
 To estimate ORR by RECIST 1.1 and irRECIST criteria  
 To estimate clinical benefit rate as defined by RECIST 1.1 and irRECIST 
 To estimate OS 
 Assess the toxicity of pembrolizumab in combination with next-line chemotherapy 
(gemcitabine, docetaxel, or pemetrexed [non-squamous only]) 
2.1.3 Correlative/Exploratory Objectives 
 To assess tumor PD-L1 status at baseline (prior to initial treatment with PD-1 inhibitor), 
at time of progression on PD-1 or PD-L1 inhibitor (study entry), and at time of 
progression on combination of pembrolizumab and chemotherapy (safety follow up 
visit) 
 To correlate ORR, PFS, and clinical benefit rate with the results of proteomic analysis 
and lipidomic profiling 
 To correlate ORR, PFS, and clinical benefit rate with the results of NeoTYPE Lung 
Tumor Profile Genetic Analysis 
2.2 
Endpoints 
2.2.1 Primary Endpoint 
 PFS as measured by RECIST 1.1 criteria 
2.2.2 Secondary Endpoints 
 PFS as measured by irRECIST criteria 
 Objective response rate (CR+PR) assessed via RECIST 1.1 and irRECIST 
 Clinical benefit rate - defined as any subject with stable disease (SD) for ≥ 3 months, 
partial response (PR), or complete response (CR) assessed via RECISIT 1.1 and 
irRECIST  
 OS  
 Toxicity will be graded according to the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.  
 


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3. 
ELIGIBILITY CRITERIA 
3.1 
Inclusion Criteria 
Subjects must meet all of the following applicable inclusion criteria to participate in this study: 
1. Written informed consent and HIPAA authorization for release of protected health 
information 
NOTE: HIPAA authorization may be included in the informed consent or obtained 
separately. 
 
2. Age ≥ 18 years at the time of consent 
 
3. Histological or cytological evidence of stage IV NSCLC (any histology) 
 
4. Subjects must have progressed on or after previous platinum-based chemotherapy. 
Chemotherapy may have previously been given with a PD-1 or PD-L1 inhibitor. Subjects 
must have also progressed on or after receiving any PD-1 or PD-L1 inhibitor (including 
pembrolizumab) as their most recent therapy and must have had at least a 3-month PFS 
on this therapy. 
 
5. Subjects must be enrolled on the trial within 12 weeks of their last infusion of PD-1 or 
PD-L1 inhibitor therapy. 
 
6. Subjects whose tumors harbor a mutation in EGFR exon 19 or 21 or have gene 
rearrangements in ALK or ROS1 must have already been treated with standard targeted 
therapies. NOTE: Subjects must also have progressed on or after platinum-containing 
combination chemotherapy. 
 
7. ECOG Performance Status of 0 or 1 within 28 days prior to registration for protocol 
therapy. 
 
8. Must be fit enough to receive next-line chemotherapy (either gemcitabine, docetaxel, or 
pemetrexed [non-squamous only]) according to the discretion of the treating physician. 
 
9. Adequate laboratory values obtained within 28 days prior to registration for protocol 
therapy (as defined in table 1 below).  
 
Table 1 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 K/mm3 
Platelets 
≥100,000 K/mm3 
Hemoglobin without transfusion or EPO 
dependency (within 7 days of assessment) ≥9 g/dL or ≥5.6 mmol/L  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine 
levels > 1.5 X institutional ULN 


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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  
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT); Activated Partial 
Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy. In the case of 
anticoagulants, PT/INR/PTT must be 
within therapeutic range of intended use of 
anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
10. Women of childbearing potential (WOCBP) must have a negative urine or serum 
pregnancy test within 7 days prior to study registration and/or within 72 hours of first 
dose of study drugs. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
Female subjects will be considered of childbearing potential unless 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 
(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) have a congenital or acquired condition that prevents childbearing. 
 
11. Women of childbearing potential must be willing to use two methods of contraception 
(see section 5.5.2) or abstain from heterosexual activity from the point of registration 
through 120 days after the last dose of study drug.  
 
12. Male subjects capable of fathering a child must agree to use an adequate method of 
contraception (see section 5.5.2) starting with the first dose of the study drug through 120 
days after the last dose of the study drug. 
Male subjects will be considered to be capable of fathering a child unless they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. 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. 
 
2. Active central nervous system (CNS) metastases.  


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NOTE: Subjects who are symptomatic and have not undergone prior brain imaging must 
undergo a head computed tomography (CT) scan or brain MRI within 28 days prior to 
registration to exclude brain metastases.  
NOTE: A subject with prior brain metastasis may be considered if they have completed 
their treatment for brain metastasis at least 4 weeks prior to study registration, have been 
off corticosteroids for ≥ 2 weeks, are asymptomatic, and there is no evidence of 
progression on brain imaging (CT or MRI). 
 
3. Treatment with any investigational agent within 28 days prior to registration for protocol 
therapy with the exception of PD-1 or PD-L1 inhibitors.  
 
4. No active second cancers with the exception of localized non-melanoma skin cancer, in-
situ cervical or in-situ bladder cancer. 
 
5. Evidence of active autoimmune disease requiring systemic treatment within the past 90 
days or a documented history of clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents.  
NOTES: Subjects with vitiligo or resolved childhood asthma/atopy would be an 
exception to this rule. Subjects that require intermittent use of bronchodilators or local 
steroid injections would not be excluded from the study. Subjects with hypothyroidism 
stable on hormone replacement or Sjögren’s syndrome will not be excluded. 
 
6. Prior solid organ or stem cell transplant. 
 
7. History of interstitial lung disease or pneumonitis related to the use of immunotherapeutic 
drugs. Subjects with a history of pneumonitis which is unrelated to the use of 
immunotherapeutic drugs may participate at the discretion of the treating physician. 
 
8. History of an immune-related toxicity requiring treatment with corticosteroids during 
prior PD-1/ PD-L1 inhibitor treatment. 
 
9. Diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy or 
other immunosuppressive therapy (excludes inhaled corticosteroids) within 7 days of 
study registration 
 
10. History of psychiatric illness or social situations that would limit compliance with study 
requirements 
 
11. Clinically active infection (≥ Grade 2) as judged by the site investigator.  
 
12. Known history of human immunodeficiency virus (HIV) infection or chronic hepatitis B 
or C. NOTE: HIV, HBV or HCV testing is not required. 
 
13. 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 site investigator. 
 
14. Known history of active TB (Bacillus Tuberculosis). 
 


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15. History of hypersensitivity to pembrolizumab, docetaxel, gemcitabine, pemetrexed or any 
of their excipients. 
 
16. Has received a live vaccine within 30 days prior to 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. 
 
4. 
SUBJECT REGISTRATION 
All subjects must be registered through Big Ten CRC Administrative Headquarters’ (AHQ) 
electronic data capture (EDC) system OnCore. A subject is considered registered when an ‘On 
Study’ date is entered into OnCore. 
 
5. 
TREATMENT PLAN 
This is a single-arm phase II study of continuation immunotherapy with pembrolizumab 
following initial benefit with a PD-1 or PD-L1 inhibitor.  Patients who have been treated with a 
PD-1 or PD-L1 inhibitor and experienced a PFS of ≥3 months will be enrolled within 12 weeks 
of last dose of PD-1 or PD-L1 inhibitor.  On Day 1 of each 3-week cycle, subjects will first 
receive pembrolizumab at a dose of 200mg IV every three weeks in combination with 
chemotherapy. Partner chemotherapy will be either gemcitabine 1000mg/m2 IV D1 and D8 every 
three weeks, docetaxel 60-75mg/m2 IV D1 every three weeks, or pemetrexed 500mg/m2 IV D1 
every 3 weeks (pemetrexed for non-squamous histologies only).  Subjects will continue to 
receive this combination until progression or intolerable toxicity.  
5.1 
Pre-medication and Hydration 
Premedication and hydration will be administered as per institutional standards based on the 
partner chemotherapy selected (gemcitabine, docetaxel, or pemetrexed).  Pembrolizumab does 
not require any premedication.  
5.2 
Chemotherapy + Pembrolizumab Administration 
Partner chemotherapy will be administered as per institutional standards at the doses outlined 
below in Table 2.   
 
 
 


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Table 2 Drug Administration 
Drug 
Administration
Sequence 
Dose1 
Route 
Schedule2 
Cycle 
Length 
Pembrolizumab 
1st 
200mg 
Intravenously 
Day 1 
21 days
 
 
 
Gemcitabine 
2nd 
1000mg/m2 
Intravenously 
Days 1, 8 
21 days
Docetaxel 
60-75mg/m2
Intravenously 
Day 1 
Pemetrexed3 
500mg/m2 
Intravenously 
Day 1 
1 Body surface area (BSA) should be recalculated per institutional standards for weight changes. The 
starting dose of docetaxel within this range will be at the discretion of the treating physician. 
2 A window of ±3 days may be applied to all study visits to accommodate observed holidays, 
inclement weather, scheduling conflicts etc. Date and time of each drug administration should be 
clearly documented in subject’s chart and electronic case report forms (eCRFs). 
3 Cyanocobalamin (vitamin B12) should be given at a dose of 1000mcg intramuscularly every 3 cycles 
(9 weeks), and folic acid should be given at a dose of 1mg PO daily while on pemetrexed. 
5.2.1 Pembrolizumab Administration 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  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). 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.3 
Concomitant Medications 
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 or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The site investigator should discuss any questions regarding this 
with the Big Ten CRC project manager who will communicate with the sponsor-investigator and 
Merck Clinical team regarding the situation.  The final decision on any supportive therapy or 
vaccination rests with the site investigator and/or the subject's primary physician. There are no 
prohibited therapies during the Post-Treatment Follow-up Phase. 
5.3.1 Docetaxel Subjects 
Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of docetaxel 
may be modified by the concomitant administration of compounds that induce, inhibit, or are 
metabolized by cytochrome P450 3A4. 
 
In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was co-
administered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly 
ritonavir, may increase the exposure of docetaxel. Concomitant use of docetaxel and drugs that 
inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients receiving 


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treatment with docetaxel, close monitoring for toxicity and a docetaxel dose reduction could be 
considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided. 
5.3.2 Pemetrexed subjects 
Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can 
be administered with pemetrexed in patients with normal renal function (creatinine clearance 
≥80 mL/min). No dose adjustment of pemetrexed is needed with concomitant NSAIDs in 
patients with normal renal function. 
 
Caution should be used when administering NSAIDs concurrently with pemetrexed to patients 
with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). NSAIDs 
with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period 
of 2 days before, the day of, and 2 days following administration of pemetrexed. 
 
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with 
longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt 
dosing for at least 5 days before, the day of, and 2 days following pemetrexed administration. If 
concomitant administration of NSAIDs is necessary, patients should be monitored closely for 
toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. 
5.3.3 Allowed Concomitant Medications 
All treatments that the site investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the site investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF 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 on the CRF. 
 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered more than 30 days after the last dose of trial treatment should be recorded for 
serious adverse events (SAE) and events of clinical interest (ECI) as defined in Section 11.2.4. 
5.3.4 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
throughout the Treatment Phase of this trial: 
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab  
 Radiation therapy- palliative radiation can be permitted per guidelines in section 5.3.5  
 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, chicken pox, yellow fever, rabies, 
BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-
Mist®) are live attenuated vaccines, and are not allowed. 


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 Systemic glucocorticoids for any purpose other than to modulate symptoms from an ECI 
(see section 11.2.4) of suspected immunologic etiology or for use as anti-emetic 
prophylaxis per standard chemotherapy protocols. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Big Ten CRC project 
manager and the sponsor-investigator.  
 
Subjects who, in the assessment by the site investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. The 
Exclusion Criteria describes other medications which are prohibited in this trial. 
5.3.5 Concomitant Palliative Radiotherapy 
The potential for overlapping toxicities with radiotherapy and pembrolizumab currently is not 
known. Therefore, palliative radiotherapy is not recommended while receiving pembrolizumab. 
If palliative radiotherapy is required, pembrolizumab should be withheld for at least 1 week 
before, during, and 1 week after radiation. Subjects should be closely monitored for any potential 
toxicity during and after receiving radiotherapy, and AEs should resolve to Grade ≤ 1 prior to 
resuming pembrolizumab.  
 Non-target bone lesions without lung tissue included in the planned radiation field may 
receive palliative radiotherapy.  
 Patients would also be permitted to continue on trial if they undergo palliative radiation 
to brain metastases if 1) this is their only site of progressive disease (no non-CNS 
progression) and 2) their treating physician feels restarting trial therapy is safe and in the 
best interest of the patient.   
Details of palliative radiotherapy should be documented in the source records and eCRF. Details 
in the source records should include: dates of treatment, anatomical site, dose administered and 
fractionation schedule, and adverse events. If warranted, symptoms requiring palliative 
radiotherapy should be evaluated for objective evidence of disease progression. 
5.4 
Supportive Care 
Subjects should receive appropriate supportive care measures as deemed necessary by the site 
investigator. Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include the use of 
oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory agents 
(please see section 5.3.2 for guidelines on concomitant administration of NSAIDS and 
pemetrexed) if symptoms do not improve with administration of corticosteroids.   Note that 
several courses of steroid tapering may be necessary as symptoms may worsen when the steroid 
dose is decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive care. 
The treatment guidelines are intended to be applied when the investigator determines the events 
to be related to pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). It may be necessary to perform 
conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of 
evaluation of the event.  
 


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Management of Pembrolizumab Infusion Related Reactions 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. 
 
Table 3 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
 
Table 3: Pembrolizumab Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Pembrolizumab Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable 
in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include 
but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable 
in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 50% 
of the original infusion rate (e.g., from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further pembrolizumab 
administration (chemotherapy can continue per 
section 6.2.1)
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine** 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable 
in the opinion of the investigator. 
Hospitalization may be indicated. 
No subsequent dosing 


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NCI CTCAE Grade 
Pembrolizumab Treatment 
Premedication at 
subsequent dosing 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Subject is permanently discontinued from further 
pembrolizumab (chemotherapy can continue per 
section 6.2.1).
Appropriate resuscitation equipment should be available and a physician readily available during the period of drug 
administration. 
5.4.1 Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving pembrolizumab and 
have an evaluation. The evaluation may include bronchoscopy and pulmonary function tests to 
rule out other causes such as infection. If the subject is determined to have study drug associated 
pneumonitis, the suggested treatment plan is detailed in Table 4. 
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules should 
apply: 
 First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles (permanent change) 
 Second episode of pneumonitis – permanently discontinue pembrolizumab if upon 
rechallenge subject develops pneumonitis  Grade 2 
o Partner chemotherapy may continue per physician discretion 
5.5 
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.5.2 Contraception 
Pembrolizumab 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.  
 
Non-pregnant, non-breast-feeding women of childbearing potential (see section 3.1.10) may be 
enrolled if they are willing to use 2 methods of birth control. The two methods of birth control 
can be either two barrier methods or a barrier method plus a hormonal method to prevent 
pregnancy. Subjects should start using birth control from the screening visit, throughout the 
study period, and up to 120 days after the last dose of study drug.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
 
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 


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study they must adhere to the contraception requirement (described above) for the duration of the 
study and during the follow-up period defined in section 11.2.3. If there is any question that a 
subject will not reliably comply with the requirements for contraception, that subject should not 
be entered into the study. 
5.5.3 Use in Pregnancy 
If a subject becomes pregnant while on treatment with pembrolizumab, the subject will 
immediately be removed from all study treatment and followed up per protocol. The site 
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 Big Ten CRC AHQ who will report to Merck. 
The site will report the outcome of the pregnancy to Big Ten CRC AHQ within 1 working day of 
discovery of event. Big Ten CRC will notify the sponsor-investigator and Merck within 1 
business day if the outcome is a SAE (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn). See also Section 11.2.3.  
 
If a male subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to Big Ten CRC AHQ who will report the event to 
Merck and followed as described above and in Section  11.2.3. 
5.5.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment. 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4 will be used to grade 
adverse events. 
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Study 
Calendar & Evaluations. 
 
Subjects will be evaluated for AEs (all grades), SAEs, and AEs requiring study drug interruption 
or discontinuation as specified in Study Calendar & Evaluations.   
6.1 
Dose Delays/Dose Modifications 
6.1.1 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be withdrawn from the trial at the 
discretion of the site investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the sponsor-investigator or Big Ten CRC AHQ 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 below.  
 
A subject must be discontinued from the trial treatment for any of the following reasons: 
 Confirmed radiographic disease progression by RECIST 1.1 criteria 
 Unacceptable AEs as described in Section 6.2.1 


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 Intercurrent illness that prevents further administration of treatment 
 Site investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 Subject refuses further treatment 
 
A subject must be discontinued from the trial (no follow up) for any of the following reasons: 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 The subject is lost to follow-up 
 
After the end of treatment, each subject will be followed for 30 days for AE monitoring (SAEs 
will be collected for 90 days after the end of treatment as described in Sections 11.2.4 and 
11.2.5). 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 for overall survival until death, withdrawal of consent, 
or the end of the study, whichever occurs first. See also Section 7.4. 
 
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 AEs 
which are present at the time of discontinuation/withdrawal should be followed in accordance 
with the safety requirements outlined in Section 11.2.1.  
6.1.2 Treatment Delay 
If either Day 1 pembrolizumab or Day 1 of the partner chemotherapy agent is delayed, all study 
drugs must be delayed until treatment can resume.  If the toxicity is clearly attributable to one 
agent, the other agent can be resumed alone at a normal dose and schedule after one week.  If the 
toxicity resolves, the combination should be resumed at the next scheduled dosing interval (the 
drugs should not be on differing schedules).  If it is unclear which drug is causing the toxicity, all 
drugs must be delayed until the toxicity resolves to meet treatment parameters. 
 Delays of greater than 6 weeks secondary to toxicity from chemotherapy agents should 
result in permanent discontinuation of chemotherapy  
 Delays of greater than 12 weeks secondary to toxicity from pembrolizumab should result 
in permanent discontinuation of pembrolizumab 
 In either case, treatment with the other agent may continue at the discretion of the treating 
physician as long as the patient meets criteria for continued therapy 
 
If D8 gemcitabine requires a delay, this dose can be omitted or alternatively given on D15 per 
the treating physician’s discretion.  Delays for D8 gemcitabine should not prolong a cycle and 
cycles should continue every 21 days if subjects meet criteria for continued therapy. 
6.2 
Dose Modifications 
6.2.1 Pembrolizumab 
The dose of pembrolizumab will not be modified.  


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Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These immune-related AEs (irAEs) may occur shortly after 
the first dose or several months after the last dose of pembrolizumab treatment and may affect 
more than on body system simultaneously. Therefore, early recognition and initiation of 
treatment is critical to reduce complications. Based on existing clinical study data, most irAEs 
were reversible and could be managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to 
confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of 
irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab are 
provided in Table 4 below. 


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Table 4: Dose modification and toxicity management guidelines for immune-related adverse events associated with 
pembrolizumab 
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 pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has 
been tapered. Pembrolizumab 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 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis  
Grade 2 
Withhold  
 Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 Monitor participants for signs and 
symptoms of pneumonitis 
 Evaluate participants with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment 
 Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2 
Permanently discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
 Administer corticosteroids (initial 
dose of 1-2 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). 
 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.
Grade 4 
Permanently discontinue 
AST / ALT elevation or 
Increased bilirubin 
Grade 2 
Withhold 
 Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone 
or equivalent) followed by taper
 Monitor with liver function tests 
(consider weekly or more frequently 


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Grade 3 or 4  
Permanently discontinue  Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
until liver enzyme value returned to 
baseline or is stable 
Type 1 diabetes mellitus 
(T1DM) or 
Hyperglycemia 
Newly onset T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with evidence 
of -cell failure 
Withhold 
 Initiate insulin replacement 
therapy for participants with 
T1DM  
 Administer anti-hyperglycemic 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 
discontinue1  
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 and Renal 
dysfunction 
Grade 2 
Withhold  
 Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
 Monitor changes of renal function 
Grade 3 or 4  
Permanently discontinue 
Myocarditis 
Grade 1 or 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 
All other immune-
related AEs 
Intolerable/ 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.  Events that 
require discontinuation 
include and not limited 
to:  Gullain-Barre 
Syndrome, encephalitis
Grade 4 or recurrent 
Grade 3  
Permanently discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 


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If toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, pembrolizumab 
should be discontinued after consultation with the Big Ten CRC project manager and the 
sponsor-investigator. With site investigator and sponsor-investigator agreement, subjects with a 
laboratory AE still at Grade 2 after 12 weeks may continue treatment in the trial only if 
asymptomatic and controlled. If a subject has more than 3 delays in pembrolizumab dosing due 
to other toxicities specific to this medication, they will be discontinued from pembrolizumab. 
 
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of pembrolizumab should be discontinued from 
pembrolizumab.  
 
Subjects who permanently discontinue pembrolizumab due to toxicity but who have not 
progressed may remain on single-agent chemotherapy per physician discretion until progression 
or intolerable toxicity. 
6.2.2 Partner Chemotherapy  
6.2.2.1 Gemcitabine 
 Gemcitabine should be given at an initial dose of 1000mg/m2 IV day 1 and 8 every 3 
weeks.  
 Dose delays of >6 weeks will result in permanent discontinuation of gemcitabine. 
 Subjects who permanently discontinue gemcitabine due to toxicity but who have not 
progressed may remain on single-agent pembrolizumab until progression or intolerable 
toxicity. 
 
Dose Level 
Dose Modification 
Full dose gemcitabine 
1000 mg/m2 
75% of full dose 
750 mg/m2 
50% of full dose 
500 mg/m2 
 
If hematologic toxicity develops, dose reductions should be per drug label guidelines or as 
follows at discretion of site investigator: 
 
Hematologic Toxicity 
Gemcitabine dose 
modification 
ANCa ≥1000/mm3 and platelet count ≥100,000/mm3 
Administer 100% full dose 
ANCa 500-999/mm3 or platelet count 50,000-99,999/mm3 
Administer 75% of full dose 
ANCa <500/mm3 or platelet count <50,000/mm3 
Hold dose 
a=absolute neutrophil count 
 
Day 1 gemcitabine may resume when ANC is ≥ 1000/mm3 and platelet count ≥100,000/mm3. 
Day 8 gemcitabine may be given when the platelet count is ≥75,000/mm3. If platelets are 
<75,000, Day 8 gemcitabine may be given on Day 15 if the platelet count has improved to 


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≥75,000/mm3, at the discretion of the treating physician. If the platelet count has not improved, 
gemcitabine may be completely omitted during that cycle. 
 
For non-hematologic toxicity, dose reductions should be per drug label guidelines or as follows 
at discretion of site investigator: 
 
Non-Hematologic Toxicity 
Gemcitabine dose 
modification 
Severe (grade 3 or 4) non-hematologic toxicity (excludes 
nausea, vomiting, or alopecia- no dose modifications 
recommended) 
Hold until resolved and then 
resume at 50% dose 
Unexplained dyspnea (or other evidence of pulmonary 
toxicity), severe hepatotoxicity, hemolytic uremic syndrome 
(HUS), capillary leak syndrome (CLS), posterior reversible 
encephalopathy syndrome (PRES) 
Permanently discontinue 
gemcitabine 
6.2.2.2 Docetaxel 
 Docetaxel should be given at an initial dose of 60-75mg/m2 IV Day 1 every 3 weeks.  If 
dose reduction is required, recommend restarting at a 20% reduction of full dose every 3 
weeks or per product labeling at the discretion of the site investigator.   
 Dose delays of >6 weeks will result in permanent discontinuation of docetaxel.  
 Subjects who permanently discontinue docetaxel due to toxicity but who have not 
progressed may remain on single-agent pembrolizumab until progression or intolerable 
toxicity. 
 
Dose Level 
Dose Modification 
Full Dose Docetaxel 
60-75 mg/m2 
Docetaxel Dose Level –1 
20% reduction of full dose 
Docetaxel Dose Level –2 
40% reduction of full dose 
Note:  A maximum of two dose reductions per subject are allowed. If > 2 dose reductions 
are required, docetaxel will be permanently discontinued.  
 
Docetaxel dose reductions should be per drug label guidelines or as follows, at the discretion of 
the site investigator: 
 
 Hematologic adjustments: 
Subjects with neutropenic fever or grade 4 neutropenia lasting > 7 days or grade 4 
thrombocytopenia or thrombocytopenic bleeding should be retreated after recovery to 
Grade≤1 or patient baseline with a one level dose reduction. 
 
 Peripheral neuropathy adjustments: 
If subject experiences a grade 2 toxicity, the subsequent retreatment after recovery to ≤ 
Grade 1 should be with a one level dose reduction. 
 


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Subjects who have grade 3 or higher peripheral neuropathy should be permanently 
discontinued from docetaxel. 
 
 Hypersensitivity reaction adjustments: 
No dose reductions will be made for any hypersensitivity reactions. If the subject experiences 
a hypersensitivity reaction, treatment should be given as indicated below: 
o Grade 1 symptoms (eg., mild flushing, rash, pruritis)—complete infusion. Supervise at 
bedside. No treatment required. 
o Grade 2 symptoms (e.g., moderate rash, flushing, mild dyspnea, chest discomfort)—
Interrupt infusion. Give intravenous diphenhydramine 25 mg and intravenous 
dexamethasone 10 mg. Resume infusion after recovery of symptoms at a slower rate, 
then increase incrementally to the initial planned rate. Depending on the intensity of the 
reaction observed, additional oral or IV premedication with an antihistamine should also 
be given for the next cycle of treatment and the rate of infusion should be decreased 
initially and then increased back to the planned rate. Report as an AE. 
o Grade 3 symptoms (e.g., hypotension requiring pressor therapy, angioedema, respiratory 
distress requiring bronchodilation therapy, generalized urticaria)—Stop infusion. Give 
intravenous diphenhydramine and dexamethasone as above. Add epinephrine or 
bronchodilators if indicated. If wheezing is present, which is not responsive to 
administration of 0.35 cc of nebulized salbutamol solution (or equivalent), epinephrine is 
recommended.  The patient will be permanently removed from docetaxel. Report as an 
AE. 
o Grade 4 symptoms - Anaphylaxis—Permanently remove from docetaxel. Report as an 
AE. 
 
 Hepatic adjustments: 
Patients who develop abnormal liver function tests for any reason while on the study will 
have the following docetaxel dose reductions: 
 
Abnormal Liver Function Dose Modifications for Docetaxel 
Bilirubin 
Alkaline 
Phosphatase 
SGOT (AST) 
Action 
≥1.5X ULN 
or > 5 X ULN 
or > 5 X ULN 
Wait up to 6 weeks. If 
recovered*, reduce docetaxel 
dose by –1 dose level.  If not, 
permanently d/c docetaxel.  
< 1.5X ULN 
and < 5 X ULN 
and 2.5-5 X ULN 
Reduce docetaxel dose by –1 
dose level. 
*Bilirubin < 1.5X ULN and alkaline phosphatase < 5 X ULN and SGOT (AST) < 5 X 
ULN. 
ULN= upper limit of normal for institution 
 
 Fluid retention adjustments: 


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If symptomatic, subjects developing fluid retention may be treated with diuretics at the 
investigator’s discretion.   
If grade 3, docetaxel should be held until resolution to < grade 1, then reinstituted after 
recovery, if medically appropriate, with a one level dose reduction. 
 Stomatitis adjustments: 
If grade 3 or 4 stomatitis occurs, retreatment after recovery to grade 1 or less with a one level 
dose reduction. 
 
 Other non-hematologic toxicities: 
If toxicities > 3, docetaxel should be held until resolution to grade 1 or less, then reinstituted, 
if medically appropriate, after recovery, with a one level dose reduction. 
 
Patients requiring a > 6 week delay in docetaxel due to non-hematologic toxicity will be 
removed from docetaxel treatment. 
6.2.2.3 Pemetrexed 
 Pemetrexed should be given at an initial dose of 500mg/m2 IV every 3 weeks. 
Pemetrexed should be discontinued if subjects develop grade 3 or 4 toxicity after two 
dose reductions or immediately if grade 3 or 4 neurotoxicity develops.  
 Dose delays of >6 weeks will result in permanent discontinuation of pemetrexed. 
 Subjects who permanently discontinue pemetrexed due to toxicity but who have not 
progressed may remain on single-agent pembrolizumab until progression or intolerable 
toxicity. 
 
If a dose reduction for pemetrexed is required for hematologic toxicity, reductions should be per 
product labeling or as follows at the discretion of the investigator: 
 
Hematologic Toxicity 
Pemetrexed dose modification 
Nadir ANC <500/mm3 and nadir platelets 
≥50,000/mm3 
Reduce dose to 75% of previous dose 
Nadir platelets <50,000/mm3 without bleeding 
(regardless of nadir ANC) 
Reduce dose to 75% of previous dose 
Nadir platelets <50,000/mm3 with bleeding 
(regardless of ANC) 
Reduce dose to 50% of previous dose 
 
If ≥ grade 3 non-hematologic (excluding neurotoxicity) toxicity develops, pemetrexed should be 
withheld until recovery to baseline. Upon recovery, dose reductions should be per product label or 
as follows at the discretion of the investigator: 
 
Non-Hematologic Toxicity 
Pemetrexed dose modification 
Grade 3 or 4 toxicity (excluding mucositis) 
Reduce dose to 75% of previous dose 
Grade 3 or 4 diarrhea or any diarrhea requiring 
hospitalization 
Reduce dose to 75% of previous dose 
Grade 3 or 4 mucositis 
Reduce dose to 50% of previous dose 


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For neurotoxicity:  
 Grade 0-2 
Continue at 100% of previous dose 
 Grade 3 or 4 
Discontinue treatment 
6.3 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined in section 6.1, a 
subject will also be discontinued from protocol therapy and followed up per protocol under the 
circumstances outlined below. The reason for discontinuation of protocol therapy will be 
documented on the eCRF. 
 
Documented disease progression per RECIST 1.1. 
 
The treating physician thinks a change of therapy would be in the best interest of the 
subject 
 
The subject requests to discontinue protocol therapy, whether due to unacceptable 
toxicity or for other reasons 
o If a subject decides to prematurely discontinue protocol therapy (“refuses treatment”), 
the subject should be asked if he or she may still be contacted for further scheduled 
study assessments. The outcome of that discussion should be documented in both the 
medical records and in the eCRF. 
 
A female subject becomes pregnant  
6.4 
Protocol Discontinuation 
If a subject decides to withdraw from the study (and not just from protocol therapy) all efforts 
should be made to complete the final study assessments. The site study team should contact the 
subject by telephone or through a clinic visit to determine the reason for the study withdrawal. If 
the reason for withdrawal is an AE, it will be recorded on the eCRF. 


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7. 
STUDY CALENDAR & EVALUATIONS 
Cycle = 21 days
Screening 
Cycle 11,2 
Cycle 2+2 
Every other 
cycle2,3
Safety follow 
up
Long-term 
Follow up5
-28 days 
Day 
1
Day 
8
Day 
1 
Day 
8
Day 1 
30 days2,4 
post last dose
Every 3 months 
(±14 days)
REQUIRED ASSESSMENTS 
 
Informed Consent/ HIPAA auth. 
X
 
Medical history including smoking history6
X
 
Diagnosis and Staging6 
X
 
Physical exam 
X
X
X 
X
Vital signs, ECOG Performance status7
X
X
X 
X
AEs, ECIs & concomitant medications
X
X
X 
X
X
LABORATORY ASSESSMENTS 
 
Complete Blood Cell Count with diff (CBC)
X
X1
X11
X 
X11
X
Comprehensive Metabolic Profile (CMP)8
X
X1
X 
X
Thyroid Function (TSH, T4, free T3) 
X
 
X
PT, INR, aPTT 
X
 
Pregnancy test (serum or urine) WOCBP
-7d9
-72h9
 
DISEASE ASSESSMENT10 
 
CT of chest10 
X
 
X10
X5
CT or MRI of abdomen and pelvis, if applicable10
X
 
X10
X5
MRI Brain10 
X
 
Bone/PET Scan10 
X
 
X10
TREATMENT EXPOSURE 
 
Pembrolizumab 
X
X 
Partner chemotherapy drug11 
X
X11
X 
X11
CORRELATIVE STUDIES (SPECIMEN COLLECTION)
 
Archival tumor tissue12 
X
 
Optional tumor biopsy13 
X13
 
X13
Whole Blood samples14 
X
 
BANKING SAMPLES (SPECIMEN COLLECTION)
 
Whole Blood15 
X
 
Unstained Slides from Tumor Block16 (if available)
X
 
Serum and Plasma17 
X
 
X
FOLLOW-UP 
 
Survival status, subsequent therapy 
 
X


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Key to Footnotes  
1If screening (baseline) labs were performed within 7 days of D1 of treatment, these do not need to be repeated.   
2A window of 3 days will be applied to all treatment study visits; for safety follow-up visit and tumor imaging, a 7-day window will apply. 
3Tumor imaging and thyroid function to continue every other cycle until progression, starting with cycle 3. 
4A safety follow-up visit will occur 30 days (±7 days) after the last dose of treatment. ECIs and SAEs will be collected for 90 days after the end of 
treatment. See Sections 11.2.4 and 11.2.5. 
5Subjects without documented disease progression will be followed for every 3 months for 1 year from end of treatment or until death. Once 
disease progression is documented, subjects will be followed every 3 months for 1 year from the time of documented progression or death.  
6 Medical History to include demographics, prior treatments, radiation and surgical history, smoking history, and trial awareness question. 
Diagnosis and staging to include pathology report and Tumor Node Metastasis (TNM) staging. 
7Vital signs to include blood pressure, weight, and height (screening only) and ECOG performance status 
8CMP with liver function tests (LFTs) to include sodium, potassium, chloride, creatinine, blood urea nitrogen, AST, ALT, total bilirubin, alkaline 
phosphatase. 
9For women of childbearing potential (WOCBP): urine or serum βhCG, within 7 days prior to study registration and within 72 hours prior to 
receiving the first dose of study medication. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required. 
10Tumor response assessment will be performed every odd numbered cycle starting with cycle 3; tumor imaging to be done at treatment 
discontinuation at discretion of investigator. Subjects with ongoing response or stable disease after 1 year on study drug may reduce tumor 
response frequency to every 3 or 4 cycles (9 or 12 wks) at the discretion of the treating physician. Chest CT should include the upper abdomen 
including the adrenals and liver. Baseline (and subsequent) CT or MRI of abdomen and pelvis is required only for subjects with known 
abdominal or pelvic metastasis. MRI of brain should be performed at screening as per Section 3.2.2. Baseline bone scan will be obtained at 
discretion of investigator. PET-CT scans may be used for initial staging or follow-up imaging in place of standard CT scans at the discretion of the 
treating physician. 
11Partner chemotherapy drug, chosen at discretion of investigator, will be either docetaxel, gemcitabine or pemetrexed [for non-squamous only]. If 
gemcitabine is chosen, dosing will be on D1 and D8 of each cycle. 
12Fixed paraffin-embedded blocks/slides will be requested from tissue obtained prior to initial treatment with PD-1 inhibitor. 
13Optional biopsies will be requested at time of progression on PD-1 or PD-L1 inhibitor (study entry) and at time of progression on combination of 
pembrolizumab and chemotherapy (safety follow up visit) 
14Blood samples will be collected to support biomarker research.  See Clinical Laboratory Manual (CLM) for additional details. 
15Submission of whole blood for banking is to be collected at Pre-Treatment Cycle 1 Day 1. See CLM for collection, processing, labeling and 
shipping instructions. 
16Submission of unstained slides for banking from an archived FFPE tumor block (if available). See CLM for collection, labeling, and shipping 
instructions. 
17Submission of serum and plasma for banking are to be collected at Pre-Treatment Cycle 1 Day 1 and at the 30-Day Safety Follow up visit. See 
CLM for collection, labeling, processing, and shipping instructions. 


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A window of ±3 days will be applied to all treatment study visits; a window of ±7 days will be 
applied to all safety follow-up visits and tumor imaging. 
7.1 
Screening Evaluations 
7.1.1 Within 28 days prior to registration for protocol therapy 
 Informed consent, HIPAA authorization 
 Medical history to include demographics, prior treatments, radiation and surgical 
history, and trial awareness question. 
 Smoking history to include: amount, frequency, start and stop dates of cigarette, cigar 
and pipe usage.  
 Diagnosis and staging to include pathology report and Tumor Node Metastasis (TNM) 
staging 
 Physical exam 
 Vital signs (blood pressure, weight, and height [screening only] and ECOG 
performance status) 
 AEs, ECIs & concomitant medications 
 Complete blood cell count with differential 
 Comprehensive metabolic profile (sodium, potassium, chloride, creatinine, blood urea 
nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline 
phosphatase) 
 Thyroid function (TSH, T4, free T3) 
 [-7 days] Pregnancy test (serum or urine) for women of childbearing potential 
(WOCBP) 
 
Baseline Disease Evaluation 
Tumor response assessment will consist of evaluation by CT scans of chest and MR or CT 
of abdomen and pelvis. Subject imaging modality should remain the same throughout the 
study. PET-CT scans may be used for initial staging or follow-up imaging in place of 
standard CT scans at the discretion of the treating physician. 
 CT chest: should include the upper abdomen including the adrenals and liver 
 CT or MRI of abdomen and pelvis: required only for subjects with known abdominal 
or pelvic metastasis 
 MRI of brain, if indicated. See Section 3.2.2. 
 Bone/ PET scan: at discretion of investigator. 
 
Optional Tumor Biopsy (See CLM for additional details) 
 Optional biopsy is requested at the time of progression on PD-1 or PD-L1 inhibitor 
(study entry) 
 
 


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7.2 
On Treatment Evaluations 
7.2.1 Cycle 1 Day 1 
Note: Cycle 1 Day 1 lab testing need not be repeated if completed within 7 days of starting 
protocol therapy. 
 Physical exam 
 Vital signs and ECOG performance status 
 AEs, ECIs & concomitant medications 
 Complete blood cell count with differential 
 Comprehensive metabolic profile  
 [-72 hours prior to first dose] Pregnancy test (serum or urine) for women of 
childbearing potential 
 Pembrolizumab plus chemo (physician’s choice) 
 Correlative samples: (See CLM for additional details) 
o Unstained slides from archived tissue 
o Pre-dose blood samples will be collected to support biomarker research 
 Banking samples.  
o Whole blood 
o Unstained slides from archived tissue 
o Serum and plasma 
7.2.2 Cycle 1 Day 8 (if applicable) 
 Complete blood cell count with differential 
 Gemcitabine administration  
7.2.3 Cycle 2+ Day 1 
 Physical exam 
 Vital signs and ECOG performance status 
 AEs, ECIs & concomitant medications 
 Complete blood cell count with differential 
 Comprehensive metabolic profile  
 Pembrolizumab plus chemo (physician’s choice) 
7.2.4 Cycle 2+ Day 8 (if applicable) 
 Complete blood cell count with differential 
 Gemcitabine administration  
7.2.5 Day 1 of Every Other Cycle starting with Cycle 3 
 Thyroid function (TSH, T4, free T3) 
 CT chest 
 CT or MRI of abdomen and pelvis 
 Bone/ PET scan: at discretion of investigator 
 


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7.3 
Safety Follow-up Evaluations 
A safety follow-up visit should occur when subjects permanently stop study treatment for 
whatever reason (toxicity, progression, or at discretion of site investigator) and should be 
performed 30 days (±7 days) after the last dose of treatment. Subjects who have an ongoing ≥ 
grade 2 or serious AE (SAE) at this visit will continue to be followed until the AE resolves to ≤ 
Grade 1 or baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment 
starts, whichever is earlier.  
 Physical exam 
 Vital signs and ECOG performance status 
 AEs, ECIs & concomitant medications 
 Complete blood cell count with differential 
 Comprehensive metabolic profile  
 
Optional Tumor Biopsy (See CLM for additional details) 
 Optional biopsy is requested at the time of progression on combination of pembrolizumab 
and chemotherapy (safety follow up visit) 
7.4 
Long Term Follow-up Evaluations 
All subjects will be followed until documented disease progression.  Subjects who discontinue 
treatment for any reason without documented disease progression will be followed for disease 
progression every 3 months for 1 year from end of treatment or until death, whichever occurs 
first.  
 AEs, ECIs & concomitant medications 
 CT chest 
 CT or MRI of abdomen and pelvis 
 
Once disease progression is documented, subjects will enter a survival follow up period every 3 
months for 1 year from the time of documented progression or death, whichever occurs first.  
Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. 
 
8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
Please refer to the CLM for all sample collection, processing, labeling, and shipping instructions. 
8.1 
Tissue for assessment of PD-L1 status 
8.1.1 Archival  
 Prior to initial treatment with PD-1 inhibitor 
8.1.2 Optional Biopsies 
 At time of progression on PD-1 or PD-L1 inhibitor (study entry) 
 At time of progression on combination of pembrolizumab and chemotherapy (safety 
follow up visit) 


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8.2 
Tissue for genetic analysis 
 NeoTYPE Lung Tumor Profile Genetic Analysis will also be performed: Sequencing of 
select exons of AKT1, BRAF, EGFR, ERBB2, ERBB4, FGFR1, FGFR2, FGFR3, KIT, 
KRAS, MET, NOTCH1, NRAS, PDGFRA, PIK3CA, PTEN, SMAD4, SMO, SRC, 
TP53, as well as ALK FISH, HER2 FISH, MET FISH, PTEN FISH, RET FISH, ROS1 
FISH. 
8.3 
Blood for Somatic Baseline DNA 
 Peripheral blood will be drawn for somatic baseline DNA by Neogenomics in accordance 
with the NeoTYPE Lung Tumor Profile (tissue test). 
8.4 
Blood for proteomic analysis and lipidomic profiling 
 Pre-treatment blood samples will be used to explore the association of proteomic and 
lipidomic tests at baseline with ORR, PFS, and clinical benefit rate. Refer to the CLM for 
collection, processing, labeling and shipping instructions. 
8.5 
Confidentiality of Biospecimens 
Samples that are collected will be identified by a subject’s study number assigned at the time of 
registration to the trial. Any material issued to collaborating researchers will be anonymized and 
only identified by the subject’s study number. 
8.6 
Samples for future studies 
Subject consent will be obtained for additional samples collected for future Big Ten CRC 
studies. HCRN, as Administrative Headquarters for the Big Ten CRC, will manage the banked 
samples. Samples will be banked indefinitely in the HCRN Biorepository.  
 
This includes: 
 Whole blood: Whole blood will be collected prior to treatment on Cycle 1 Day 1.  
 Pre- and Post-treatment plasma: Whole blood for plasma will be collected prior to treatment 
on Cycle 1 Day 1 and at Safety Follow Up visit.  
 Pre- and Post-treatment serum: Whole blood for serum will be collected prior to treatment on 
Cycle 1 Day 1 and at Safety Follow Up visit. 
 Unstained slides: Unstained slides will be obtained from the subject’s archived formalin fixed 
paraffin embedded tumor sample.  
 
9. 
CRITERIA FOR DISEASE EVALUATION 
9.1 
Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with 
calipers by clinical exam.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 


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9.1.1 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
9.2 
Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
9.3 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
9.4 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
9.5 
Evaluation of Target Lesions 
NOTE: In addition to the information below, also see section 4.3.2 in the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 
1.1 (Eur J Cancer 45;2009:228-247) for special notes on the assessment of target lesions.  
 


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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 the diameters of target 
lesions, taking as reference the baseline sum diameters 
Progressive 
Disease (PD) 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also considered 
progressions).
Stable Disease 
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study
9.6 
Evaluation of Non-target Lesions 
Complete 
Response (CR) 
Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis) 
 
Note:  If tumor markers are initially above the upper normal 
limit, they must normalize for a subject to be considered in 
complete clinical response.
Non-CR/ Non-
PD 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits 
Progressive 
Disease (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It 
must be representative of overall disease status change, not a 
single lesion increase.
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor investigator. 
9.7 
Evaluation of Best Overall Response 
Target Lesions 
Non-Target Lesions 
New Lesions
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/ or not all 
evaluated 
No 
PR 


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SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Non-evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
9.8 
Definitions for Response Evaluation – RECIST 1.1 
9.8.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
9.8.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for response 
are first met. 
9.8.3 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since treatment started). 
9.8.4 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response until 
the first date that recurrent disease is objectively documented. 
9.8.5 Objective Response Rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded since the start of 
treatment). 


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9.8.6 Disease Control Rate: 
The disease control rate is the proportion of all subjects with stable disease (SD) for 8 weeks, or 
partial response (PR), or complete response (CR) according to RECIST 1.1, from the start of 
treatment until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the start of treatment). 
9.8.7 Time to Progression: 
A measurement from the date of treatment start until the criteria for disease progression is met as 
defined by RECIST 1.1. Subjects who have not progressed or have died due to any cause will be 
right-censored at the date of the last disease evaluation or date of death. 
9.8.8 Progression Free Survival 
A measurement from the date of treatment start until the criteria for disease progression is met as 
defined by RECIST 1.1 or death occurs. Subjects who have not progressed will be right-censored 
at the date of the last disease evaluation. 
9.8.9 Overall Survival 
Overall survival is defined by the date of treatment start to date of death from any cause. 
 
9.9 
Immune- Related RECIST Criteria 
Please refer to the full publication for complete details on immune-related RECIST criteria: 
Bohnsack O. et al. Adaptation of the immune-related response criteria: irRECIST. ESMO 2014 
Abstract 4958. http://www.irrecist.com/ 
9.9.1 Measurable lesion definitions and target lesion selection 
Follow the definitions from RECIST 1.1.  
 
Measurable lesions must be accurately measured in at least one dimension with a minimum size 
of: 
 10 mm in the longest diameter by CT or MRI scan (or no less than double the slice 
thickness) for non-nodal lesions and ≥15 mm in short axis for nodal lesions 
 10 mm caliper measurement by clinical exam 
 20 mm by chest X-ray 
 
9.9.2 Baseline: Non-measurable lesion definitions 
Follow the definitions from RECIST 1.1. 
 
Non-target lesions will include:  
 Measurable lesions not selected as target lesions 
 All sites of non-measurable disease, such as neoplastic masses that are too small to 
measure because their longest uninterrupted diameter is < 10 mm (or < two times the 
axial slice thickness), ie. the longest perpendicular diameter is ≥10 and < 15 mm. 
 Other types of lesions that are confidently felt to represent neoplastic tissue, but are 
difficult to measure in a reproducible manner. These include bone metastases, 
leptomeningeal metastases, malignant ascites, pleural or pericardial effusions, ascites, 


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inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, ill-defined 
abdominal masses, skin lesions, etc. 
9.9.3 Baseline: Target and Non-Target Lymph Node Lesion Definitions 
Follow the definitions from RECIST 1.1. 
9.9.4 Baseline: Bone Lesions 
Follow the definitions from RECIST 1.1.  
 Regardless of the imaging modality blastic bone lesions will not be selected as target 
lesions. Lytic or mixed lytic-blastic lesions with a measurable soft tissue component ≥10 
mm can be selected as target lesions. 
9.9.5 Baseline: Brain Lesions 
 Brain lesions detected on brain scans can be considered as both target or non-target 
lesions. 
9.9.6 Baseline: Cystic and necrotic lesions as target lesions 
 Lesions that are partially cystic or necrotic can be selected as target lesions. The longest 
diameter of such a lesion will be added to the Total Measured Tumor Burden (TMTB) of 
all target lesions at baseline. If other lesions with a non-liquid/non-necrotic component 
are present, those should be preferred. 
9.9.7 Baseline: Lesions with prior local treatment 
 During target lesion selection the radiologist will consider information on the anatomical 
sites of previous intervention (e.g. previous irradiation, RF-ablation, TACE, surgery, 
etc.). Lesions undergoing prior intervention will not be selected as target lesions unless 
there has been a demonstration of progress in the lesion. 
9.9.8 Baseline: No Disease at Baseline 
 If a patient has no measurable and no non-measurable disease at baseline the radiologist 
will assign ‘No Disease’ (irND) as the overall tumor assessment for any available follow-
up timepoints unless new measurable lesions are identified and contribute to the TMTB. 
9.9.9 Follow-up: Recording of Target and New Measurable Lesion Measurements 
 The longest diameters of non-nodal target and new non-nodal measurable lesions, and 
short axes of nodal target and new nodal measurable lesions will be recorded. Together 
they determine the Total Measured Tumor Burden (TMTB) at follow-up. 
9.9.10 Follow-up: Definition of Measurable New Lesions:  
 In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, 
per timepoint), new lesions must meet criteria as defined for baseline target lesion 
selection and meet the same minimum size requirements of 10 mm in long diameter and 
minimum 15 mm in short axis for new measurable lymph nodes. New measurable lesions 
shall be prioritized according to size, and the largest lesions shall be selected as new 
measured lesions. 


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9.9.11 Follow-up: Non-Target Lesion Assessment 
 The RECIST 1.1 definitions for the assessment of non-target lesions apply. The response 
of non-target lesions primarily contributes to the overall response assessments of irCR 
and irNon-CR/Non-PD (irNN). Non-target lesions do not affect irPR and irSD 
assessments. Only a massive and unequivocal worsening of non-target lesions alone, 
even without progress in the TMTB is indicative of irPD. 
9.9.12 Follow-up: New Non-Measurable Lesions Definition and Assessment:  
 All new lesions not selected as new measurable lesions are considered new non-
measurable lesions and are followed qualitatively. Only a massive and unequivocal 
progression of new non-measurable lesions leads to an overall assessment of irPD for the 
timepoint. Persisting new non-measurable lesions prevent irCR. 
9.9.13 irRC Overall Tumor Assessments 
 Complete response (irCR) is defined by the complete disappearance of all lesions. Lymph 
nodes must decrease to < 10 mm in short axis. Confirmation of response is not 
mandatory. 
 Partial response (irPR) is defined by the decrease of ≥ 30% in TMTB relative to baseline, 
non-target lesions are irNN, and no unequivocal progression of new non-measurable 
lesions.  
 Stable disease (irSD) is when the measurements do not meet criteria for irCR or irPR, in 
absence of progressive disease (irPD). 
 irNN is when no target disease was identified at baseline and at follow-up the patient fails 
to meet criteria for irCR or irPD. 
 irPD is defined by a minimum 20% increase and minimum 5 mm absolute increase in 
TMTB compared to nadir, or irPD for non-target or new non-measurable lesions. 
Confirmation of progression is recommended minimum 4 weeks after the first irPD 
assessment. 
 
10. 
DRUG INFORMATION 
10.1 
Pembrolizumab 
Please refer to the current version of the Investigator’s Brochure (IB) for additional information 
regarding this drug 
10.1.1 Supplier/How Supplied 
Merck will supply pembrolizumab at no charge to subjects participating in this clinical trial.  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
10.1.2 Preparation  
Please refer to the Pharmacy Manual for a comprehensive description of pembrolizumab 
preparation. 


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Merck will supply pembrolizumab directly to sites at no cost to subjects in this clinical trial.  
 
The product after reconstitution with sterile water for injection and the liquid drug product is a 
clear to opalescent solution, which may contain extraneous and proteinaceous particulates. The 
reconstituted product and liquid product is intended for IV administration. The reconstituted drug 
product solution and liquid drug product can be further diluted with normal saline in IV containers 
made of polyvinyl chloride (PVC) or non-PVC material. Reconstituted vials should be 
immediately used to prepare the infusion solution in the IV bag and the infusion solution should 
be immediately administered. If not used immediately, vials and/or IV bags may be stored at 2-8 
°C for up to a cumulative time of 20 hours. If refrigerated, the vials and/or IV bags should be 
allowed to equilibrate to room temperature prior to subsequent use. Pembrolizumab solutions may 
be stored at room temperature for a cumulative time of up to 4 hours. This includes room 
temperature storage of reconstituted drug product solution and liquid drug product in vials, room 
temperature storage of infusion solution in the IV bag and the duration of infusion. 
10.1.3 Storage and Stability 
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. 
10.1.4 Dispensing 
Pembrolizumab must be dispensed only from official study sites and to eligible subjects under 
the supervision of the site investigator. Pembrolizumab should be stored in a secure area 
according to local regulations.  It is the responsibility of the site investigator to ensure that study 
drug is only dispensed to subjects.   
10.1.5 Adverse Events 
Please refer to the current version of the Investigator’s Brochure for a complete list of AEs. 
 
Pembrolizumab is generally well tolerated and demonstrates a favorable safety profile in 
comparison to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on this 
mechanism of action, immune mediated adverse events are of primary concern. Important 
identified risks for pembrolizumab monotherapy are primarily of an immune mediate nature, 
and included the following in the last IB (edition 16): pneumonitis, colitis, hepatitis, nephritis, 
endocrinopathies that include hypophysitis (including hypopituitarism and secondary adrenal 
insufficiency), thyroid disorder (hypothyroidism, hyperthyroidism and thyroiditis), Type I 
diabetes mellitis, uveitis, myositis, Guillain-Barré syndrome, pancreatitis, myocarditis, 
myasthenic syndrome, encephalitis, sarcoidosis, severe skin reactions including Stevens-
Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal outcome; and 
“solid organ transplant rejection following pembrolizumab treatment in donor organ recipients” 
(risk applicable to post-marketing setting only, as such patients are currently excluded from 
Merck clinical trials with pembrolizumab).  


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Immune-mediated adverse reactions (ARs), including severe and fatal cases, have occurred in 
patients receiving pembrolizumab. Immune-mediated ARs can occur after discontinuation of 
treatment. Immune-mediated ARs affecting more than one body system can occur 
simultaneously. In clinical studies, most immune-mediated ARs were reversible and managed 
with interruptions of pembrolizumab, administration of corticosteroids, and/or supportive care. 
 
The safety profile for pembrolizumab also includes 2 important potential risks – i.e. increased 
risk of severe complications (such as early severe graft versus host disease and veno-occlusive 
disease) of allogeneic transplant in patients with hematologic malignancies who have previously 
been treated with PD-1 inhibitors; and GVHD after pembrolizumab administration in patients 
with a history of allogeneic HSCT. 
 
Since the last IB (Edition 16), 1 new identified risk in the specific population of RCC patients 
who receive the combination of pembrolizumab plus axitinib, has been added to the safety 
profile for pembrolizumab. An increase in hepatic events (ie, increased incidences of Grades 3 
and 4 elevated ALT and AST) was observed in RCC patients who received the combination of 
pembrolizumab plus axitinib. Details are provided in section 5.4.2.2 of the IB. The Grade 3 or 4 
ALT and AST elevations can be managed with prompt interruption or discontinuation of both 
study treatments, close liver enzyme and function monitoring, and with or without concomitant 
steroid treatment. 
 
In addition to 1 new identified risk in the RCC population receiving the combination of 
pembrolizumab plus axitinib, based upon additional information received from the clinical 
study and postmarketing environments after release of IB Edition 16, the following changes 
have been made to the safety information for pembrolizumab:  
 Information regarding exacerbation of myasthenia gravis was added to product labeling 
to further characterize the existing risk of myasthenic syndrome; 
 Information regarding primary adrenal insufficiency was added to product labeling to 
further characterize the existing risk of immune-mediated endocrinopathies; 
 A new adverse drug reaction of Vogt-Koyanagi-Harada syndrome was identified based 
primarily on postmarketing experience. Note: Vogt-Koyanagi-Harada syndrome may 
include a constellation of signs/symptoms which are already listed in product labeling, 
namely, the existing AE of special interest/risk of ‘uveitis’. However, considering the 
clinical significance of timely recognition and treatment of the condition, and that the 
term was identified primarily based on postmarketing experience, Merck decided to add 
the distinct preferred term of Vogt-Koyanagi-Harada syndrome to the company core 
data sheet Postmarketing Experience section. 
 A new ADR of hemophagocytic lymphohistiocytosis was identified based primarily on 
postmarketing experience. 
 
Further details around frequency, reporting, and management of immune-related AEs (irAEs) 
can be found in the current version of the Investigator’s Brochure. In addition to the previously 
noted identified risks, infusion-related reactions are a risk but are not considered immune 
mediated; these are also further described in the current IB. 
 


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10.2 
Docetaxel 
NOTE: Please refer to the current package insert for complete prescribing and toxicity 
information. Institutional guidelines may be used for preparation and administration of this 
medication. 
10.2.1 Supplier/How Supplied  
Docetaxel is commercially available in single-dose vials containing 20 mg (0.5 ml) or 80 mg (2.0 
ml) docetaxel (anhydrous). 
10.2.2 Preparation  
Just prior to use, allow the docetaxel vial to reach room temperature for 5 minutes. Add the entire 
contents of the ethanol diluent vial and mix by gently rotating the vial for 15 seconds. Allow to 
stand for 5 minutes at room temperature, and check that the solution is homogeneous and clear 
(persistent foam is normal). The resulting solution contains 10 mg/mL of docetaxel. Please note 
that the solution contains 15% overfill. Dosing amounts should be based in the concentration per 
extractable volume, not the total volume of the vial. The desired dose is diluted in D5W or NS. 
The volume of the infusion should be adjusted in order to have a final docetaxel concentration of 
between 0.3 mg/mL and 0.9 mg/mL. Non-PVC-containing intravenous infusion bags and 
administration sets should be used to avoid patient exposure to the plasticizer DEHP. 
10.2.3 Storage and Stability  
Docetaxel is stored at 4oC protected from light. The solvent vials may be stored at room temperature 
or at 4oC. The premix solution is stable for 8 hours at room temperature (15o- 25oC) or refrigerated (at 
2o- 8oC). The final dilution is also stable for 8 hours. (Please note that the company is no longer 
recommending that the final product be placed in PVC bags). 
10.2.4 Incompatibilities  
Intravenous bags and administration sets containing DEHP (di-[2-ethylexyl] phthalate). No further 
information is available.  
10.2.5 Side Effects  
1. Cardiac: arrhythmias, pericardial effusions, palpitations.  
2. Hematologic: dose-related neutropenia, leukopenia, thrombocytopenia, anemia, hypoglycemia, 
hypernatemia.  
3. Gastrointestinal: nausea and vomiting, diarrhea, oral mucositis, pancreatitis, esophagitis.  
4. Neurologic: reversible dysthesias or paresthesias, peripheral neuropathy, mild or moderate lethargy 
or somnolence, headache, seizures.  
5. Hypersensitivity: hypersensitivity (local or general skin rash, flushing, pruritus, drug-fever, chills 
and rigors, low back pain), severe anaphylactoid reactions (flushing with hypo- or hypertension, 
with or without dyspnea).  
6. Dermatologic: alopecia, desquamation following localized pruriginous maculopapular eruption, 
skin erythema with edema, extravasation reaction (erythema, swelling, tenderness, pustules), 
reversible peripheral phlebitis, nail changes.  
7. Hepatic: increased transaminase, alkaline phosphatase, bilirubin; hepatic failure; hepatic drug 
reaction.  
8. Pulmonary: dyspnea with restrictive pulmonary syndrome, pleural effusions.  


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9. Other: asthenia, dysgeusia, anorexia, conjunctivitis, arthralgia, muscle aches, myopathy, 
peripheral edema, fluid retention syndrome, ascites, flu-like symptoms, fever. 
 
10.3 
Pemetrexed Disodium Heptahydrate (Alimta)  
NOTE: Please refer to the current package insert for complete prescribing and toxicity 
information. Institutional guidelines may be used for preparation and administration of this 
medication. 
10.3.1 Supplier/How Supplied  
Pemetrexed is commercially available.  
 
Pemetrexed is supplied as a sterile lyophilized powder for intravenous infusion available in 
single-dose vials. The product is a white to either light yellow or green-yellow lyophilized solid. 
Pemetrexed is supplied in 100mg and 500 mg vials. Each 500-mg vial of pemetrexed contains 
pemetrexed disodium equivalent to 500 mg pemetrexed and 500 mg of mannitol. Each 100-mg 
vial of pemetrexed disodium contains equivalent to 100mg pemetrexed and 106mg of mannitol. 
Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.  
10.3.2 Preparation 
1. Use aseptic technique during the reconstitution and further dilution of pemetrexed for 
intravenous infusion administration.  
2. Calculate the dose and the number of pemetrexed vials needed. Each vial contains 500 mg 
or 100mg of Pemetrexed. The vial contains an excess of Pemetrexed to facilitate delivery of 
label amount.  
3. Reconstitute 500-mg vials with 20 mL of 0.9% Sodium Chloride Injection (preservative 
free) to give a solution containing 25 mg/mL Pemetrexed. Gently swirl each vial until the 
powder is completely dissolved, reconstitute 100mg vials with 4.2 ml of 0.9% Sodium 
Chloride injection (preservative free) to give a Solution containing 4.3 mg/ml pemetrexed. 
The resulting solution is clear and ranges in color from colorless to yellow or green-yellow 
without adversely affecting product quality. The pH of the reconstituted pemetrexed 
solution is between 6.6 and 7.8. FURTHER DILUTION IS REQUIRED.  
4. Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration. If particulate matter is observed, do not administer.  
5. The appropriate volume of reconstituted Pemetrexed solution should be further diluted to 
100 mL with 0.9% Sodium Chloride Injection (preservative free) and administered as an 
intravenous infusion over 10 minutes. 
6. Chemical and physical stability of reconstituted and infusion solutions of pemetrexed were 
demonstrated for up to 24 hours following initial reconstitution, when stored at refrigerated 
or ambient room temperature [see USP Controlled Room Temperature] and lighting. When 
prepared as directed, reconstitution and infusion solutions of pemetrexed contain no 
antimicrobial preservatives. Discard any unused portion. Reconstitution and further dilution 
prior to intravenous infusion is only recommended with 0.9% Sodium Chloride Injection 
(preservative free). Pemetrexed is physically incompatible with diluents containing calcium, 
including Lactated Ringer’s Injection, USP and Ringer’s Injection, USP and therefore these 


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should not be used. Co-administration of pemetrexed with other drugs and diluents has not 
been studied, and therefore is not recommended. 
10.3.3 Storage and Stability 
Pemetrexed for injection, should be stored at 25°C (77°F); excursions permitted to 15-30°C (59-
86°F). Chemical and physical stability of reconstituted and infusion solutions of pemetrexed were 
demonstrated for up to 24 hours following initial reconstitution, when stored refrigerated, 2-8°C 
(36-46°F), or at 25°C (77°F), excursions permitted to 15-30°C (59-86°F). When prepared as 
directed, reconstituted and infusion solutions of Pemetrexed contain no antimicrobial 
preservatives. Discard unused portion. Pemetrexed is not light sensitive. 
10.3.4 Incompatibilities and Potential Drug Interactions  
Ibuprofen — Daily ibuprofen doses of 400 mg QID reduce pemetrexed’s clearance by about 20% 
(and increase AUC by 20%) in patients with normal renal function. The effect of greater doses of 
ibuprofen on pemetrexed PK is unknown. Pemetrexed is primarily eliminated unchanged renally 
as a result of glomerular filtration and tubular secretion. Concomitant administration of 
nephrotoxic drugs could result in delayed clearance of pemetrexed. Concomitant administration 
of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed 
clearance of pemetrexed. Although ibuprofen (400 mg QID) can be administered with pemetrexed 
in patients with normal renal function (creatinine clearance (80 mL/min), caution should be used 
when administering ibuprofen concurrently with pemetrexed to patients with mild to moderate 
renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate 
renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 
2 days before, the day of, and 2 days following administration of pemetrexed. In the absence of 
data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives, all 
patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 
days following pemetrexed administration. If concomitant administration of an NSAID is 
necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, 
and gastrointestinal toxicity.  
10.3.5 Side Effects  
1. Renal: creatinine elevation (10%)  
2. Neurologic: neuropathy-sensory (9%), taste disturbance (8%)  
3. Hematologic: anemia (33%), neutropenia (29%), leucopenia (18%), thrombocytopenia (10%)  
4. Gastrointestinal: nausea (56%), vomiting (40%), anorexia (27%), constipation (21%), 
stomatitis/pharyngitis (14%), diarrhea (12%), dyspepsia/heartburn (5%)  
5. Dermatology/skin: alopecia (12%), rash/desquamation (7%)  
6. Other: fatigue, febrile neutropenia, infection, pyrexia, dehydration, increased AST, increased 
ALT, creatinine clearance decrease, renal failure, conjunctivitis, arrhythmia, chest pain, 
increased GGT, motor neuropathy 
 
10.4 
Gemcitabine 
NOTE: Please refer to the current package insert for complete prescribing and toxicity 
information. Institutional guidelines may be used for preparation and administration of this 
medication. 


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10.4.1 Supplier/How Supplied 
Gemcitabine is commercially available in 200 mg and 1 gm vials. 
10.4.2 Preparation 
Reconstitute the 200 mg vial with 5ml and the 1 gm vial with 25 ml preservative free normal 
saline to make a solution containing 38 mg/ml. Shake to dissolve. 
10.4.3 Storage and Stability 
Unreconstituted drug vials are stored at controlled room temperature. Reconstituted solution 
should be stored at controlled room temperature and used within 24 hours. Solutions of 
gemcitabine should not be refrigerated; crystallization may occur. The unused portion should be 
discarded. 
10.4.4 Side Effects 
1. Hematologic: Neutropenia, anemia, thrombocytopenia, and leukopenia are reported. 
2. Dermatologic: A rash is seen in about 25% of patients and is associated with pruritus in 
about 10% of patients. The rash is usually mild, not dose-limiting, and responds to local 
therapy. Desquamation, vesiculation, and ulceration have been reported rarely. Alopecia is 
usually minimal. Injection-site reactions. 
3. Gastrointestinal: Nausea and vomiting are reported in about two-thirds of patients and 
requires therapy in about 20% of patients. It is rarely dose-limiting, and is easily 
manageable with standard antiemetics. Diarrhea, constipation, mucositis. 
4. Hepatic: Abnormalities of hepatic transaminase enzymes occur in two-thirds of patients, but 
they are usually mild, nonprogressive, and rarely necessitate stopping treatment. However, 
gemcitabine should be used with caution in patients with impaired hepatic function. 
5. Pulmonary: In clinical trials, dsypnea, unrelated to underlying disease, has been reported in 
association with Gemzar therapy. Dyspnea was occasionally accompanied by 
bronchospasm. Pulmonary toxicity has been reported with the use of Gemzar. [Parenchymal 
toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult 
respiratory distress syndrome (ARDS) has been reported rarely following one or more doses 
of Gemzar administered to patients with various malignancies. Some patients experienced 
the onset of pulmonary symptoms up to 2 weeks after the last Gemzar dose. Respiratory 
failure and death occurred very rarely in some patients despite discontinuation of therapy.] 
The etiology of these effects is unknown. If such effects develop, Gemzar should be 
discontinued. Early use of supportive care measures may help ameliorate these conditions. 
6. Neurologic: Somnolence, insomnia, paresthesia, pain. 
7. Cardiovascular: A few cases of hypotension were reported. Some cases of myocardial 
infarction, congestive heart failure, and arrhythmias have been reported. Peripheral edema is 
reported in about 30% of patients. Some cases of facial edema have also been reported. 
Edema is usually mild to moderate, rarely dose-limiting, sometimes painful, and reversible 
after stopping gemcitabine treatment. 
8. Other: Flu-like symptoms are reported for about 20% of patients. This includes fever, 
headache, back pain, chills, myalgia, asthenia, and anorexia. Malaise and sweating are 
reported. 
 


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11. 
ADVERSE EVENTS 
11.1 
Definitions 
11.1.1 Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
 Unintended or unfavorable sign or symptom 
 A disease temporally associated with participation in the protocol 
 An intercurrent illness or injury that impairs the well-being of the subject 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an 
AE (e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
11.1.2 Serious Adverse Event (SAE) 
An SAE is an adverse event that: 
 Results in death.  
NOTE: Death due to disease progression should not be reported as a SAE, unless it is 
attributable by the site investigator to the study drug(s) 
 Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization.  
NOTE: Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional therapy, 
resection of primary tumor, or elective surgery, will not be considered serious adverse 
events. 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 


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11.1.3 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, package insert, or when it is not included in the 
informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.   
11.1.4 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
Unrelated 
The Adverse Event is not related to the drug(s)  
Unlikely 
The Adverse Event is doubtfully related to the drug(s)  
Possible 
The Adverse Event may be related to the drug(s)  
Probable 
The Adverse Event is likely related to the drug(s)  
Definite 
The Adverse Event is clearly related to the drug(s)  
11.2 
Reporting 
11.2.1 Adverse Events 
 AEs will be recorded from time of registration until 30 days after discontinuation of study 
drug(s). 
 AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
 All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within OnCore. 
 All AEs considered related to study drug(s) will be followed until resolution to ≤ Grade 1 
or baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment 
starts, whichever occurs first. 
11.2.2 Definition and Reporting of a Pembrolizumab Overdose:  
For purposes of this trial, an overdose will be defined as any dose exceeding the 
prescribed dose for pembrolizumab by 20% over the prescribed dose. No specific 
information is available on the treatment of overdose of pembrolizumab. In the event of 
overdose, subject should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.  
 
 If an AE (s) is associated with (“results from”) the overdose of a Merck product, the 
AE(s) is reported as a SAE, even if no other seriousness criteria are met. 
 If a dose of Merck’s product meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the 


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overdose is reported as a non-serious ECI, using the terminology “accidental or 
intentional overdose without adverse effect.” 
 
All reports of overdose with and without an AE must be reported within 1 working day 
to Big Ten CRC Administrative Headquarters (AHQ). Big Ten CRC AHQ will report 
the event within 1 working day to Merck Global Safety (Attn: Worldwide Product 
Safety; FAX 215-993-1220). 
11.2.3 Reporting of Pregnancy and Lactation: 
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject’s female 
partner that occurs during the trial or within 120 days of completing the trial, or 30 days 
following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier. All subjects and female partners of male subjects who become 
pregnant 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 
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 1 working day to Big Ten CRC AHQ on the 
Pregnancy Report Form (See Documents/Info tab of the EDC). Big Ten CRC AHQ will 
report the event within 1 working day to Merck Global Safety (Attn: Worldwide Product 
Safety; FAX 215-993-1220). 
11.2.4 Definition and Reporting of Events of ECI: 
Selected non-serious and SAEs are also known as ECI and must be recorded as such on 
the Adverse Event case report forms/worksheets and reported to Big Ten CRC AHQ 
within 1 working day of the event. 
ECI for this trial include: 
1. An overdose of Merck product, as defined above, 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 3 × the upper limit 
of normal, and an elevated total bilirubin lab value that is greater than or equal to 2 
× the upper limit of normal, and, at the same time, an alkaline phosphatase lab value 
that is less than 2 × the upper limit of normal, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.* 
*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.  
 
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an 
immune-related event. Subjects who develop an ECI thought to be immune-related 
should have additional testing to rule out other etiologic causes. If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be 


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performed to rule out other etiologic causes. If no other cause is found, then it is 
assumed to be immune-related.  
 
ECIs that occur in any subject from the date of first dose through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates 
a new anticancer therapy, whichever is earlier, whether or not related to the Merck’s 
product, must be reported within 1 working day to Big Ten CRC AHQ. Big Ten CRC 
AHQ will report the event within 1 working day to Merck Global Safety (Attn: 
Worldwide Product Safety; FAX 215-993-1220). 
11.2.5 Serious Adverse Events (SAEs) 
11.2.5.1 Site Requirements for Reporting SAEs to Big Ten CRC Administrative 
Headquarters 
 SAEs will be reported from time of registration until 90 days after discontinuation of 
study drug(s).  
 SAEs will be reported on the SAE Submission Form and entered in the SAE tab in 
OnCore within 1 business day of discovery of the event.   
 SAEs include events related and unrelated to the study drug(s).  
 All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within OnCore.   
 All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 
1 or baseline and/or deemed clinically insignificant and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
 
Non-serious ECI will be reported to Big Ten CRC AHQ and will be handled in the same manner as 
SAEs.  
 
Additionally, any SAE, considered by an investigator to be related to either study drug, which is 
brought to the attention of the investigator at any time outside of the 90-day time period specified 
in the previous paragraph, also must be reported immediately to Big Ten CRC AHQ.  
 
The site will submit the completed SAE Submission Form (see Documents/Info tab of the EDC) 
to Big Ten CRC AHQ within 1 business day of discovery of the event.  The form will be sent 
electronically to Big Ten CRC AHQ at SAFETY@hoosiercancer.org.  The site investigator is 
responsible for informing the IRB and/or other local regulatory bodies as per local requirements. 
 
The original copy of the SAE Report and the email correspondence or fax confirmation sheet 
must be kept within the study file at the study site. 
 
Once the SAE has resolved (see resolution guidelines listed in 11.2.2.1), sites must submit a 
follow up SAE Submission Form within a reasonable timeframe to Big Ten CRC AHQ at 
SAFETY@hoosiercancer.org. 
 


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11.2.5.2 Big Ten CRC AHQ Requirements for Reporting SAEs to Merck 
Big Ten CRC AHQ will submit all immediately reportable events (e.g. SAEs, ECIs, overdose, 
pregnancy, etc.) received from sites to Merck within 1 business day of receipt of the SAE 
Reporting Form and to regulatory authorities (FDA) per federal guidelines.  
 
Big Ten CRC AHQ will submit all SAE reports and any other relevant safety information to: 
 
Merck Global Safety (Attn: Worldwide Product Safety) at: 
Facsimile number:  +1-215-993-1220 
 
Follow-up information will be provided to Merck as reasonably requested.   
11.2.5.3 Sponsor-Investigator Responsibilities 
Big Ten CRC AHQ will send a SAE summary to the sponsor-investigator within 1 business day 
of receipt of SAE Submission Form from a site.  The sponsor-investigator will promptly review 
the SAE summary and assess for expectedness and relatedness. 
11.2.5.4 Big Ten CRC AHQ Responsibilities for Reporting SAEs to FDA 
Big Ten CRC AHQ has been designated to manage the Investigational New Drug Application 
(IND) associated with this protocol on behalf of the sponsor-investigator.  Big Ten CRC AHQ 
will cross-reference this submission to Merck’s parent IND at the time of submission.  
Additionally, Big Ten CRC AHQ will submit a copy of these documents to Merck at the time of 
submission to FDA. 
 
Big Ten CRC AHQ will be responsible for all communication with the FDA in accordance with 
21CFR312 including but not limited to the 7 and 15 Day Reports, as well as an Annual Progress 
Report. Additionally, Big Ten CRC AHQ will submit a copy of these reports to Merck at the 
time of submission to FDA. 
11.2.5.5 IND Safety Reports Unrelated to this Trial 
Merck will provide Big Ten CRC AHQ with IND safety reports from external studies that 
involve the study drug(s) per their guidelines. Big Ten CRC AHQ will forward the safety reports 
to the sponsor-investigator who will review these reports and determine if revisions are needed to 
the protocol or consent.  Big Ten CRC AHQ will forward these reports to participating sites 
within 1 business day of receiving the sponsor-investigator’s review. Based on the sponsor-
investigator’s review, applicable changes will be made to the protocol and informed consent 
document (if required). All IND safety reports will also be made available to sites via OnCore. 
 
Upon receipt from Big Ten CRC AHQ, site investigators (or designees) are responsible for 
submitting these safety reports to their respective IRBs, as per their IRB policies. 
 
12. 
STATISTICAL METHODS 
Statistical analysis of this study will be the responsibility of Biostatistics and Data Management 
Core at Indiana University Melvin and Bren Simon Cancer Center (IUSCC). Parameter estimates 
and relevant summary statistics will be reported where appropriate. For continuous variables, 
summary statistics will include number of subjects, mean, median, standard deviation, minimum 


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and maximum. Categorical endpoints will be summarized using number of subjects, frequency, 
and percentages. Missing data will not be imputed. Data analysis will be performed in SAS. 
 
Additional exploratory analyses of the data will be conducted as deemed appropriate. Changes 
from this analysis plan will not require an amendment to the protocol unless it changes a 
significant feature of the protocol. 
12.1 
Study Design 
This is a single-arm phase II study of continuation immunotherapy with pembrolizumab 
following initial benefit (CR, PR, or SD ≥ 3 months) with a PD-1 or PD-L1 inhibitor. 
12.2 
Endpoints 
12.2.1 Definition of Primary Endpoint 
The primary endpoint is PFS assessed by RECIST 1.1 and is defined as the time from date of 
treatment start until the criteria for disease progression is met as defined by RECIST 1.1 criteria 
or death as a result of any cause.  Those alive and without disease progression at the end of 
study follow-up will be censored at date of last disease assessment.  
12.2.2 Definition of Secondary Endpoints 
Secondary endpoints are: 
 PFS assessed by irRECIST defined as the time from date of treatment start until the 
criteria for disease progression is met as defined by irRECIST criteria or death as a result 
of any cause.  Those alive and without disease progression at the end of study follow-up 
will be censored at date of last disease assessment. 
 Objective response rate (CR+PR) assessed via RECISIT 1.1 and irRECIST 
 Clinical benefit rate (CR+PR+SD≥3 months) assessed via RECISIT 1.1 and irRECIST 
 OS defined as the time from date of treatment start until death 
 Toxicity assessed by CTCAE Version 4.   
12.3 
Sample Size and Accrual 
 The historical control is a median PFS of 3 months (in the 2nd/3rd line setting).  
 Null hypothesis - Pembrolizumab plus chemo will have a median PFS of 3 months.  
 Alternative hypothesis –Pembrolizumab plus chemo will have a median PFS of 6 months  
 
When the sample size is 31, a non-parametric test of median survival with a one-sided 0.05 
significance level will have 80% power to detect the difference between a median survival of 3 
months vs 6 months assuming an accrual period of approximately 6 months (6 per month) and 
maximum follow-up of 1.5 years. To allow for replacement of patients who are not evaluable for 
efficacy (estimated to be 10%), up to 35 patients will be enrolled.  
12.4 
Analysis Datasets 
 


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Population 
Definition 
Enrolled 
This will comprise all subjects who meet the eligibility 
criteria and are registered onto the study.  
Efficacy 
This will comprise all subjects who receive at least one 
dose of trial treatment (both pembrolizumab and partner 
chemotherapy) and either undergo at least one post-
baseline assessment or die before any evaluation. 
Safety 
This will comprise all subjects that contribute data to the 
safety analysis including any patient who has received 
any treatment (including partial treatment or single agent 
therapy).   
 
12.5 
Assessment of Safety 
Safety will be assessed by the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4. Please refer to the Study Calendar for the schedule of 
toxicity assessment. 
12.6 
Assessment of Efficacy 
All subjects who have received at least one dose of treatment and have their disease re-evaluated 
will be evaluable for assessment of PFS and other efficacy outcomes. 
12.7 
Data Analysis Plans 
12.7.1 Analysis Plans for Primary Objective 
PFS by RECIST 1.1 will be estimated using Kaplan-Meier methodology in the Efficacy 
population.  Median PFS of Ho:  3 months vs Ha: 6 months by RECIST 1.1 will be tested using 
a non-parametric test. 
12.7.2 Analysis Plans for Secondary Objectives 
In the Efficacy population, median PFS by irRECIST will be estimated and tested similarly to 
the primary endpoint.  Objective response rate and clinical benefit rate will be estimated with 
two-sided 95% exact binomial confidence intervals.  OS will be estimated using Kaplan-Meier 
methodology. Toxicities will be tabulated in the Safety population. 
12.7.3 Analysis Plans for Exploratory Objectives 
In the Efficacy population, change in tumor levels of PD-L1 will be descriptively summarized 
and compared over time using paired t-tests.  Proportional hazards regression (for PFS) and 
logistic regression (for ORR and clinical benefit rate) will be used to correlate proteomic, 
lipidomic and genomic results with clinical outcomes.  
12.7.4 Subgroup Analyses 
No subgroup analyses are planned. 


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12.7.5 Other Planned Analyses 
For the Enrolled population, descriptive statistics will be used the characterize subject 
demographic and clinical characteristics, disposition, and significant protocol violations.  In the 
Safety population, concomitant medications and exposure will be described. 
12.8 
Interim Analysis/Criteria for Stopping Study 
No formal interim safety or efficacy analyses are planned. 
 
13. 
TRIAL MANAGEMENT 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted in accordance with Indiana University Melvin and Bren Simon 
Cancer Center’s (IUSCC) DSMP for High Risk Phase II Trials. 
 
Big Ten CRC AHQ facilitated oversight activities for high risk phase II trials include: 
 Review and processing of all AEs requiring expedited reporting as defined in the protocol 
 Provide trial accrual progress, safety information, and data summary reports to the 
sponsor-investigator, including a weekly update of aggregate AE data. For any 
increase in frequency of grade 3 or above adverse events (above the rate reported in 
the Investigator Brochure or package insert), the sponsor investigator will notify Big 
Ten CRC AHQ who will notify the DSMC Chair and Compliance Officer 
immediately. The notification will include the incidence of study adverse events, 
grades, and attributions, as well as investigator statements regarding comparison with 
risks per the IB/ package insert. 
 Notify participating sites of adverse events potentially requiring expedited reporting 
and subsequent DSMC recommendations for study modifications. 
 Investigators will conduct continuous review of data and patient safety.  
 Coordinate monthly (Phase II) meetings which will include representation from each 
accruing site. 
o These meetings should include review of data, the number of subjects, and 
significant toxicities as described in the protocol. Big Ten CRC AHQ should 
maintain meeting minutes and attendance for submission to the DSMC upon 
request. 
 Conduct the trial across all participating sites in accordance with the requirements set forth in 
the IUSCC DSMP. 
13.2 
IUSCC Data Safety Monitoring Committee Oversight 
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of 
subject safety, regulatory compliance, and data integrity for this trial. The DSMC will review this 
study to assess toxicity, compliance, data integrity, and accrual per the Institutional DSMP. Trials 
managed by Big Ten CRC AHQ are not routinely audited or monitored by IUSCC; however, the 
IUSCC DSMC retains the right to audit Big Ten CRC AHQ trials on a for cause basis. 
 
The IUSCC DSMC will review study data bi-annually per the IUSCC DSMP.   
 


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In preparation for the IUSCC DSMC review, Big Ten CRC AHQ will provide the IUSCC DSMC 
with the following: 
 Monthly summary reports 
 Reports of the following, if not already included in the Monthly Summary Report: 
o Adverse event summary report (including serious adverse events) 
o Study accrual patterns  
o Protocol deviations 
 Audit and/or monitoring results, if applicable 
 Data related to stopping/decision rules described in study design 
 Big Ten CRC meeting minutes/ attendance 
 
Documentation of DSMC reviews will be provided to sponsor-investigator and Big Ten CRC 
AHQ.  The IUSCC DSMC will notify the sponsor-investigator and other regulatory bodies, as 
appropriate, for issues of immediate concern.  The sponsor-investigator will work with Big Ten 
CRC AHQ to address the DSMC’s concerns as appropriate.   
 
At any time during the conduct of the trial, if it is the opinion of the sponsor investigator that the 
risks (or benefits) to the patient warrant early closure of the study, this recommendation should 
be made in writing to the DSMC Chair and Compliance Officer. Alternatively, the DSMC may 
initiate suspension or early closure of the study based on its review of the study reports. 
13.3 
IND Annual Reports 
As this trial has an IND held locally by the IU principal investigator, the IND Annual Report will 
be prepared and submitted to the Compliance Team. This report will be reviewed by the DSMC 
at the time of FDA submission. 
13.4 
Data Quality Oversight Activities 
Remote validation of OnCore data will be completed on a continual basis throughout the life 
cycle of the study.  A summary report (QC Report) of these checks together with any queries 
resulting from manual review of the eCRFs will be generated for each site and transmitted to the 
site and the site monitor. Corrections will be made by the study site personnel. 
 
Monitoring visits to the trial sites will be made periodically during the trial to ensure key aspects 
of the protocol are followed. Additional for-cause visits may occur as necessary. Source 
documents will be reviewed for verification of agreement with data entered into OnCore.  It is 
important for the site investigator and their relevant personnel to be available for a sufficient 
amount of time during the monitoring visits or audit, if applicable. The site investigator and 
institution guarantee access to source documents by Big Ten CRC AHQ or its designee. 
 
The trial site may also be subject to quality assurance audit by Merck or its designee as well as 
inspection by appropriate regulatory agencies. 
13.5 
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 sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 


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requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. The 
sponsor-investigator has delegated responsibility to Big Ten CRC AHQ for registering the trial 
and posting the results on clinicaltrials.gov. 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 study site 
contact information. 
 
14. 
DATA HANDLING AND RECORD KEEPING 
14.1 
Data Management 
Big Ten CRC AHQ will serve as the Clinical Research Organization for this trial. Data will be 
collected through the web-based clinical research platform, OnCore, a system compliant with 
Good Clinical Practices and Federal Rules and Regulations. Big Ten CRC AHQ personnel will 
coordinate and manage data for quality control assurance and integrity. All data will be collected 
and entered into OnCore by study site personnel from participating institutions.   
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in OnCore and correlative results will be 
captured in OnCore or other secure database(s). If procedures on the study calendar are 
performed for standard of care, at minimum, that data will be captured in the source document. 
Select standard of care data will also be captured in OnCore, according to study-specific 
objectives. Please see the Data and Safety Oversight Process (DSOP) guidelines for further 
details.  
 
The completed dataset is housed at Big Ten CRC AHQ and is the sole property of the sponsor-
investigator’s institution. It should not be made available in any form to third parties, except for 
authorized representatives of appropriate Health/Regulatory Authorities, without written 
permission from the sponsor-investigator and Big Ten CRC AHQ. After the initial publication, 
the complete data set will be available to all Big Ten CRC institutions. 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/Big Ten CRC AHQ, the site 
investigator agrees to keep records, including the identity of all subjects (sufficient information 
to link records; e.g., hospital records), all original signed informed consent forms, copies of all 
source documents, and detailed records of drug disposition.  All source documents are to remain 
in the subject’s file and retained by the site investigator in compliance with local and federal 
regulations. No records will be destroyed until Big Ten CRC AHQ confirms destruction is 
permitted. 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information.  All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  


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Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, Big Ten CRC AHQ, Merck, IRB, or government agencies, like 
the FDA, may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subjects’s identity will remain confidential. 
15. 
ETHICS 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB.  The site investigator must submit written approval by the IRB to Big Ten 
CRC AHQ before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements.  In addition, the IRB must approve all advertising used to 
recruit subjects for the study.  The protocol must be re-approved by the IRB as local regulations 
require.  
 
Progress reports and notifications of AEs will be provided to the IRB according to local 
regulations and guidelines. 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki. Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study.  Subjects must 
also be notified they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study.  The site investigator must store the original, signed 
informed consent form.  A copy of the signed informed consent form must be given to the 
subject. 
 


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