Conditions: Non Small Cell Lung Cancer
Keywords: lung cancer PD-1 antibody immune checkpoint blockade
Allocation: RANDOMIZED | Intervention model: FACTORIAL
Enrollment: 20
Healthy volunteers: no

Brief summary:
The purpose of this research study is to test the effectiveness of three treatment arms that are designed to improve survival in patients with non-small cell lung cancer. Eligible subjects could be randomized to four (4) cycles of chemotherapy followed by immunotherapy, or immunotherapy followed by chemotherapy, or four cycles of chemotherapy plus immunotherapy.

Detailed description:
This open-label, three-arm, non-comparative randomized phase II study is designed to evaluate three different sequences of double-consolidation with the humanized monoclonal antibody targeted against cell surface receptor programmed cell death-1 (PD-1), pembrolizumab, and nab-paclitaxel in patients with advanced Non small cell lung cancer post induction chemotherapy. While the goal of each arm is to guarantee exposure to each of these two agents to patients who have not progressed post induction chemotherapy, they do so with different sequence. In ARMs A and B, consolidation is sequential, with either pembrolizumab followed by nab-paclitaxel (ARM A), or nab-paclitaxel followed by pembrolizumab (ARM B). In ARM C, consolidation is concurrent, with the two agents administered concurrently. As of July 24, ARMs B and C are closed, and no patients will be enrolled on this study. ARM A remains open to enrollment.

Arms:
arm 1: Completion of four cycles of Sequential Consolidation of Pembrolizumab 200mg every 21 days and then four cycles Nab-paclitaxel 100 mg/mg2 on day 1 and day 8 every 21 days arm 2: Completion of 4 cycles of Sequential Consolidation of Nab-paclitexel 100 mg/m2 on day 1 and day 8 every 21 days and then Pembrolizumab 200 mg every 21 arm 3: Concurrent Consolidation of Nab paclitaxel 100 mg/m2 on day 1 and day 8 plus Pembrolizumab 200 m5 on day 1 every 21 days for four cycles

Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Receive Pembrolizumab 200 mg on day 1 every 21 days for four cycles.

Receive nab-paclitaxel 100 mg/m2 on day 1 and day 8 every 21 days for four cycles.

Protocol document:
Prot_SAP_000.pdf: 
LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #4 
 
 
LCCC 1516: A Phase II Trial of Sequential Consolidation with Pembrolizumab 
followed by Nab-paclitaxel after Standard First-Line Induction Chemotherapy in 
Advanced NSCLC 
 
AMENDMENT INCORPORATES (check all that apply): 
_ Editorial, administrative changes 
X Scientific changes (IRB approval) 
X Therapy changes (IRB approval) 
X Eligibility Changes (IRB approval) 
 
Rationale for Amendment: Study design is changed from an open-label three arm, non-
comparative randomized phase II study to an open-label single arm phase II study due to 
accrual rate lower than initially anticipated. All enrolled patients will receive 4 cycles of 
pembrolizumab monotherapy followed by 4 cycles of nab-paclitaxel monotherapy, 
according to the time and events schedule for Arm A of the original study design.  
 
Amendment Summary 
 
Scientific changes 
1. Updated total accrual goal to 35 subjects in Section 1.1. 
2. Removed the option for subjects to co-enroll in LCCC1108, a tissue 
procurement protocol, in section 1.8. 
3. Removed the Section 4.2 “Randomization” due to change in the study design 
to a single arm. 
4. Updated Section 4.9, Study Withdrawal, to be consistent with the latest LCCC 
protocol template. 
5. Updated Section 7.3.3 on SAE reporting to be consistent with the UNC IRB 
policy. 
 
Therapy changes 
1. 
Updated study schema to reflect changes in the study design to a single arm 
study of pembrolizumab followed by nab-paclitaxel in Section 4.1. 
2. 
Updated section 5.1 to include more detail on pembrolizumab preparation and 
handling. 
 
 
Eligibility changes 
 
1. Updated Section 3.1.5 by adding necitumumab as a recently approved agent 
used as a standard of care. 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
2. Updated Section 3.1.8 in Inclusion Criteria by removing the statement 
“exceptions to these criteria may be allowed at the discretion of the UNC PI 
for toxicities that are not expected to be exacerbated by pembrolizumab or 
nab-paclitaxel” to be consistent with the latest UNC IRB policy.  
3. Updated section 9.5.2 to state that eligibility single subject exceptions are not 
permitted for Lineberger Comprehensive Cancer Center Investigator Initiated 
Trials. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED 23 MAY 2018 INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC 1516: A Randomized, Non-comparative Three Arm Phase II Trial of Sequential 
Consolidation with Pembrolizumab followed by Nab-paclitaxel, Sequential Consolidation 
with Nab-paclitaxel followed by Pembrolizumab and Concurrent Consolidation with 
Nab-paclitaxel and Pembrolizumab after Standard First-Line Induction Chemotherapy in 
Advanced NSCLC 
 
AMENDMENT INCORPORATES (check all that apply): 
X  Editorial, administrative changes 
      Scientific changes (IRB approval) 
X_ Therapy changes (IRB approval) 
_ Eligibility Changes (IRB approval) 
 
The protocol is revised to include adverse event management language provided in a 
Dear Investigator Letter issued on 10 February 2017 by Merck and Co., Inc. regarding 
cases of Stevens-Johnson syndrome, Toxic Epidermal Necrolysis and Immune-mediated 
myocarditis with pembrolizumab. 
 
Editorial 
1. Corrected footnotes in Time and Events tables to state that a pregnancy test must 
be completed within 72 hours of Day 1 of study treatment (footnote #10 in 
sections 6.1 and 6.2 and footnote #9 in section 6.3). 
 
Scientific 
2. Section 4.5.4 was revised to include supportive care guidelines for Steven’s 
Johnson Syndrome, Toxic Epidermal Necrolysis and Immune-mediated 
myocarditis that was provided in the Dear Investigator letter. 
3. Added SJS, TEN and myocarditis to adverse events associated with 
pembrolizumab in section 5.1.6 
 
 
 
 
 
 
 
THE ATTACHED VERSION DATED 19 APRIL 2017 INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 
 
 
 
 
PROTOCOL AMENDMENT #3 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
PROTOCOL AMENDMENT #2 
 
 
LCCC 1516: A Randomized, Non-comparative Three Arm Phase II Trial of Sequential 
Consolidation with Pembrolizumab followed by Nab-paclitaxel, Sequential Consolidation 
with Nab-paclitaxel followed by Pembrolizumab and Concurrent Consolidation with 
Nab-paclitaxel and Pembrolizumab after Standard First-Line Induction Chemotherapy in 
Advanced NSCLC 
 
AMENDMENT INCORPORATES (check all that apply): 
     Editorial, administrative changes 
X  Scientific changes (IRB approval) 
__ Therapy changes (IRB approval) 
X_ Eligibility Changes (IRB approval) 
 
Amendment Summary 
1. Modified 3.2.8 criterion to exclude subjects with a history of non-infectious 
pneumonitis that required steroids because pneumonitis is an identified risk of 
pembrolizumab therapy. Subjects with current non-infectious pneumonitis are also 
excluded from study participation. 
2. Checks for respiratory signs/symptoms + respiratory history were added to 
Evaluations and Assessments in section 6.0 of the protocol. These changes are now 
noted in Time and Events tables 6.1, 6.2, 6.3 and accompanying footnotes added to 
account for these assessments.  Ongoing patients are to be evaluated for active 
pneumonitis. Patients with a history of pneumonitis should be re-consented for this 
trial to consider if they should continue pembrolizumab or discontinue treatment 
based on the risk of fatal pneumonitis reported in recent safety findings. 
In addition, assessments of respiratory signs/symptoms are now included in sections 
6.4, 6.5.1, 6.5.2, 6.6.4, 6.6.5, 6.7.1, 6.7.3, and 6.8 of the protocol. 
3. Noted that the optional biopsy only applies to patients enrolled at UNC in sections 
6.5.3 and 6.11.2 
4. Corrected the study schema to remove language about the preconsent in section 4.1. 
5. Updated the following sections of the protocol to align with the most recent dose 
modification and guidelines recommended for Merck protocols: Inclusion criteria 
3.1.11 and 3.1.12; Added section 5.1.8 – Contraception which provides details on 
acceptable methods of birth control for WOCBP and males on the study; also updated 
sections 4.5.3, 4.5.4, 4.6.1, 4.6.2, 5.1.11, 7.1.1, 7.1.4, and 7.3.3. Section 7.1.5 was 
deleted. 
6. Updated 6.13.2 to ensure irRC data is analyzed based on unidimensional 
measurements (sum of the longest diameters) 
 
 
THE ATTACHED VERSION DATED September 8,  2016 INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
PROTOCOL AMENDMENT #1 
 
 
LCCC 1516: A Randomized, Non-comparative Three Arm Phase II Trial of Sequential 
Consolidation with Pembrolizumab followed by Nab-paclitaxel, Sequential Consolidation 
with Nab-paclitaxel followed by Pembrolizumab and Concurrent Consolidation with 
Nab-paclitaxel and Pembrolizumab after Standard First-Line Induction Chemotherapy in 
Advanced NSCLC 
 
AMENDMENT INCORPORATES (check all that apply): 
X  Editorial, administrative changes 
X  Scientific changes (IRB approval) 
___ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
Amendment Summary 
3. 
Clarified in Section 1.8 that subjects at UNC in LCCC1516 trial will be given the 
option to co-enroll in LCCC1108, a tissue procurement protocol. 
4. 
Removed reference to CRA and replaced with Study Coordinator in Section 4.2 
Randomization 
5. 
Noted that Abraxane will be provided by Celgene corporation at no cost to the 
patient in Section 5.2.1 
6. 
Noted that blood/serum samples will be collected for biocorrelative studies in the 
Time and Events tables in Sections 6.1, 6.2. 6.3 and relevant footnotes clarified 
to state that 5mLs of blood will be collected into SST tube for serum collection 
7. 
Revised study assessment visits to reflect blood/serum samples to be collected in 
Study Assessment Sections 6.6.1, 6.5.1, 6.5.4, 6.6.1, 6.6.4, 6.7.1, 6.8, 6.9, and 
6.11.3. We will collect 8.5 mLs of blood per ACD tube (acid citrate dextrose = 
yellow top; 3 tubes in total) + 5 mLs of blood into SST tube for serum collection 
for biocorrelative studies; additional information provided in laboratory manual).  
8. 
Removed weight as a clinical assessment on D8 of nab-paclitaxel therapy 
(Sections 6.5.6, 6.6.3 and 6.7.2) 
9. 
Clarified that quality of life assessments will be performed at the end of 
treatment in relevant footnotes in the Time and Events tables (Sections 6.1, 6.2 
and 6.3) and in Sections 6.10.1 and 6.10.2. 
10. Added information on the handling of biospecimens to section 6.11 
11. Section 7.3.3: Noted investigator will collect/report all secondary primary 
malignancies that occur in subjects on this study for a period up to 3 years 
following discontinuation of Nab-paclitaxel to Celgene Drug Safety and Risk 
Management group 
 
THE ATTACHED VERSION DATED March 21, 2016 INCORPORATES THE ABOVE 
REVISIONS 
ATTACH TO THE FRONT OF EVERY COPY OF PROTOCOL 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC 1516: A Randomized, Non-comparative Three Arm Phase II Trial of Sequential 
Consolidation with Pembrolizumab followed by Nab-paclitaxel, Sequential Consolidation 
with Nab-paclitaxel followed by Pembrolizumab and Concurrent Consolidation with 
Nab-paclitaxel and Pembrolizumab after Standard First-Line Induction Chemotherapy in 
Advanced NSCLC 
 
Principal Investigator 
Jared Weiss, MD 
Division of Hematology/Oncology 
3115 Physicians Office Bldg 
170 Manning Dr, CB# 7305 
Chapel Hill, NC 27599-7305 
Co-Investigator(s) 
Biostatistician  
 
Clinical Protocol Office (CPO) 
Lineberger Comprehensive Cancer Center 
The University of North Carolina at Chapel Hill 
450 West Drive, 3rd Floor, CB# 7295 
Chapel Hill, NC 27599-7295 
 
CPO UNC Cancer Network (UNCCN) Project Manager: 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
Funding Source:  Merck & CO., INC. 
Version:  April 19, 2017 


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC 1516: A Randomized, Non-comparative Three-Arm Phase II Trial of Sequential 
Consolidation with Pembrolizumab followed by Nab-paclitaxel, Sequential Consolidation 
with Nab-paclitaxel followed by Pembrolizumab and Concurrent Consolidation with 
Nab-paclitaxel and Pembrolizumab after Standard First-Line Induction Chemotherapy in 
Advanced NSCLC 
 
 
Principal Investigator 
Jared Weiss, MD 
Division of Hematology/Oncology 
3115 Physicians Office Bldg 
170 Manning Dr, CB# 7305 
Chapel Hill, NC 27599-7305 
    
 
 
 
 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
Principal Investigator (PI) Name:_______________________ 
 
PI Signature: ___________________ 
 
Date:  May 23, 2017 
 
 
 
 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
4
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE .................................................................7 
1.1 
Study Synopsis .....................................................................................................7 
1.2 
Duration of therapy for metastatic NSCLC .........................................................7 
1.3 
Pembrolizumab (MK-3475) .................................................................................8 
1.4 
Clinical Efficacy of Pembrolizumab in human NSCLC ....................................11 
1.5 
Nab-paclitaxel (Abraxane®) ..............................................................................13 
1.6 
Combination of Pembrolizumab plus Chemotherapy ........................................14 
1.7 
Study Rationale ..................................................................................................14 
1.8 
Correlative Studies .............................................................................................16 
2.0 
STUDY OBJECTIVES ..........................................................................................4 
2.1 
Primary Objective ................................................................................................4 
2.2 
Secondary Objectives...........................................................................................4 
2.3 
Exploratory Objectives ........................................................................................4 
2.4 
Endpoints: ............................................................................................................4 
3.0 
PATIENT ELIGIBILITY .....................................................................................4 
3.1 
Inclusion Criteria .................................................................................................4 
3.2 
Exclusion Criteria ................................................................................................6 
4.0 
TREATMENT PLAN ............................................................................................4 
4.1 
Study Schema.......................................................................................................4 
4.2 
Treatment Summary by Arm ...............................................................................4 
4.3 
Treatment Decisions Regarding Progressive Disease by ARM ..........................5 
4.4 
Details on each Drug for ARMS A-C ..................................................................5 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
5
4.5 
Concomitant Medications/ Vaccinations (allowed & prohibited) .....................17 
4.6 
Duration of Therapy ...........................................................................................18 
4.7 
Duration of Follow-Up ......................................................................................19 
4.8 
Removal of Patients from Protocol Therapy .....................................................19 
4.9 
Study Withdrawal ..............................................................................................19 
5.0 
DRUG INFORMATION .....................................................................................20 
5.1 
Pembrolizumab ..................................................................................................20 
5.2 
Nab-paclitaxel (Abraxane®; ABI-007) .............................................................27 
6.0 
EVALUATIONS AND ASSESSMENTS ...........................................................34 
6.1 
Time and Events Table ARM A: Sequential therapy: Pembrolizumab then Nab-
paclitaxel .........................................................................................................................34 
6.2 
Time and Events ARM B: Sequential therapy: Nab-paclitaxel then 
Pembrolizumab ...............................................................................................................37 
6.3 
Time and Events ARM C: Concurrent Therapy: Pembrolizumab and Nab-
paclitaxel .........................................................................................................................40 
6.4 
Pre-Study Assessments in ARMS A, B and C ...................................................43 
6.5 
During Treatment ARM A .................................................................................43 
6.6 
During Treatment ARM B .................................................................................45 
6.7 
During Treatment ARM C .................................................................................47 
6.8 
End of Treatment Assessments ARMS A, B and C (unless otherwise noted) ..48 
6.9 
Long-Term Follow-up Assessments ARMS A, B and C ...................................48 
6.10 
Quality of Life and PRO-CTCAE Assessments ................................................49 
6.11 
Correlative Studies .............................................................................................49 
6.12 
Assessment of Safety .........................................................................................51 
6.13 
Assessment of Efficacy ......................................................................................51 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
6
7.0 
ADVERSE EVENTS ...........................................................................................55 
7.1 
Definitions..........................................................................................................55 
7.2 
Documentation of non-serious AEs or SARs ....................................................58 
7.3 
SAEs or Serious SARs and Events of Clinical Interest .....................................58 
7.4 
Data and Safety Monitoring Plan .......................................................................63 
8.0 
STATISTICAL CONSIDERATIONS ...............................................................65 
8.1 
Study Design ......................................................................................................65 
8.2 
Sample Size and Accrual ...................................................................................65 
8.3 
Data Analysis Plans ...........................................................................................65 
9.0 
STUDY MANAGEMENT ...................................................................................68 
9.1 
Institutional Review Board (IRB) Approval and Consent .................................68 
9.2 
Required Documentation ...................................................................................68 
9.3 
Registration Procedures .....................................................................................69 
9.4 
Data Management and Monitoring/Auditing .....................................................69 
9.5 
Adherence to the Protocol ..................................................................................69 
9.6 
Amendments to the Protocol ..............................................................................71 
9.7 
Record Retention ...............................................................................................71 
9.8 
Obligations of Investigators ...............................................................................72 
10.0 
REFERENCES .....................................................................................................73 
11.0 
APPENDICES ......................................................................................................76 
11.1 
Appendix A Cockcroft-Gault Formula ..............................................................76 
11.2 
Appendix B Charlson Comorbidity Index Scoring System ...............................77 
11.3 
Appendix C:  ECOG Performance Status ..........................................................78 
 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
7
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
This open-label, three-arm, non-comparative randomized phase II study is 
designed to evaluate three different sequences of double-consolidation with the 
humanized monoclonal antibody targeted against cell surface receptor 
programmed cell death-1 (PD-1), pembrolizumab, and nab-paclitaxel in patients 
with advanced NSCLC post induction chemotherapy. While the goal of each arm 
is to guarantee exposure to each of these two agents to patients who have not 
progressed post induction chemotherapy, they do so with different sequence.  In 
ARMs A and B, consolidation is sequential, with either pembrolizumab followed 
by nab-paclitaxel (ARM A), or nab-paclitaxel followed by pembrolizumab (ARM 
B. In ARM C, consolidation is concurrent, with the two agents administered 
concurrently. Effective at the time of approval of this amendment, only ARM A 
will be enrolling new subjects. 
 
We plan to enroll 35 patients into the study, with a primary objective of 
estimating overall survival (OS) in each arm. Secondary objectives include 
estimating rates of response (via RECIST1.1 and Immune Related Response 
Criteria (irRC)), clinician observed and patient reported toxicity, progression-free 
survival and quality of life in each arm. 
1.2 
Duration of therapy for metastatic NSCLC 
The standard of care to treat metastatic NSCLC is a platinum-based doublet of 
chemotherapy (“induction” therapy). Two trials established the appropriate 
duration of induction therapy.  One trial randomized patients to 4 cycles of 
treatment followed by observation vs. treatment until intolerance or progressive 
disease (PD); there was no survival advantage for indefinite therapy [2].  The 
other randomized patients with no PD after 2 cycle of platinum-based doublet 
therapy to two additional cycles of therapy or to four additional cycles of therapy; 
again, there was no survival advantage for prolongation of induction therapy [3].  
These two trials established 4 cycles of platinum-based doublet therapy as the 
standard of care.   
 
Recently, a series of trials have demonstrated a survival advantage when this 
initial induction regimen is followed by “maintenance” therapy, via use of a new 
agent (“switch maintenance”) or by continuing one or more of the non-platinum 
drugs used in induction (“continuation maintenance”). These trials have 
demonstrated small survival advantages, but at the cost of denying patients a 
treatment break.  Switch maintenance has shown a larger survival advantage than 
continuation maintenance, likely reflecting the value of guaranteed exposure to 
non-cross resistant therapy [4]. One historic trial demonstrated a PFS advantage, 
with a strong trend towards an OS advantage with fixed duration switch 
maintenance (hereafter called “consolidation”) [1]. In this trial, patients in the 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
8
experimental arm received six cycles of consolidation docetaxel, while patients in 
the control arm were observed.   
 
 
At the time of PD, patients in the observation arm who received second- line 
therapy (referred to as “delayed” therapy in slide above) received docetaxel; 40% 
of the 154 patients in the observation arm did not receive second- line docetaxel 
(mostly their PFS events were death, or they were too sick from symptoms of 
progression to receive docetaxel). Amongst the 60% who were able to receive it, 
survival was identical to that in the experimental arm (the experimental arm is 
referred to as “immediate” in the slide above), suggesting that the greatest benefit 
of switch maintenance is guaranteed exposure to a non-cross-resistant agent. 
 
 
 
The current trial seeks to guarantee exposure to two non-cross resistant agents, 
with a goal of improving OS. 
1.3 
Pembrolizumab (MK-3475) 
Pembrolizumab (MK-3475) is a potent and highly selective intravenous 
humanized mAb) of the immunoglobulin (Ig) G4/kappa isotype that directly 
blocks the interaction between PD-1 and its ligands, PD-L1 and PDL-2. This 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
9
blockade enhances functional activity of the target lymphocytes to facilitate an 
antitumor immune response, leading to tumor regression and immune rejection of 
the tumor. Indications currently under investigation by the manufacturer of 
pembrolizumab include non-small cell lung cancer and glioblastoma. KeytrudaTM 
(Pembrolizumab) has recently been approved (at a dose of 2 mg/kg IV every 3 
weeks) in the United Stated for the treatment of patients with unresectable or 
metastatic melanoma and disease progression following ipilumumab and, if 
BRAF V600 mutation positive, a BRAF inhibitor. Further development of 
pembrolizumab in non-metastatic melanoma is ongoing.[5] 
1.3.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of 
neoplastic transformation has been known for decades [6].  Accumulating 
evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in 
cancer tissue and favorable prognosis in various malignancies [7-11].  In 
particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / 
FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-
term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to 
suppress immune control.  The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate 
unwanted or excessive immune responses, including autoimmune reactions.  PD-1 
(encoded by the gene PDCD1) is an immunoglobulin (Ig) superfamily member 
related to CD28 and CTLA-4 that has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [12, 
13].  The structure of murine PD-1 has been resolved [9].  PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type 
(V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 
contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).   
 
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70, all of 
which are involved in the CD3 T-cell signaling cascade [12, 14-16].  The 
mechanism by which PD-1 down modulates T-cell responses is similar to, but 
distinct from that of CTLA-4 as both molecules regulate an overlapping set of 
signaling proteins [13; 14].  PD-1 is expressed on activated lymphocytes 
including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer 
cells [17, 18].  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [19].   
 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
10
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be 
induced in a variety of cell types, including non-hematopoietic tissues as well as 
in various tumors [19-22].  Both ligands are type I transmembrane receptors 
containing both IgV- and IgC-like domains in the extracellular region and short 
cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  
PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably 
expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments.  PD-L2 is thought to control immune T-cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-
cell function in peripheral tissues [23].  Although healthy organs express little (if 
any) PD-L1, a variety of cancers are known to express abundant levels of this T-
cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma (MEL) [24].  This suggests that the PD-
1/PD-L1 pathway plays a critical role in tumor immune evasion and should be 
considered as an attractive target for therapeutic intervention. 
1.3.2 Pre-clinical Findings  
Pembrolizumab strongly enhances T-lymphocyte immune responses in 
cultured blood cells from healthy human donors, cancer patients, and primates.   
In T-cell activation assays using human donor blood cells, the EC50 
(concentration where 50% of the maximum effect is achieved) has been 
reported to be ~0.1 to 0.3 nM.  Levels of interleukin-2 (IL-2), tumor 
necrosis factor alpha (TNFα), interferon gamma (IFN ), and other cytokines 
are modulated by MK-3475.   The antibody potentiates existing immune 
responses only in the presence of antigen and does not nonspecifically activate T-
cells.[5] 
 
Using an anti-murine PD-1 analog antibody, PD-1 blockade has been shown to 
significantly inhibit tumor growth in a variety of syngeneic murine tumor 
models.   In these experiments in mice, anti-PD-1 therapy is synergistic with 
chemotherapeutic agents such as gemcitabine and 5-fluorouracil (5-FU) and 
combination therapy results in increased complete tumor regression rates in 
vivo.[5] 
 
The safety of MK-3475 was characterized in the 1-month repeat-dose toxicity 
study in cynomolgus monkeys when administered as intravenous (IV) doses of 6, 
40 or 200 mg/kg once a week (a total of five doses) and in the 6-month repeat-
dose toxicity study in the same specids when administered as IV doses of 6, 40 
or 200 mg/kg every other week (a total of 12 doses).  MK-3475 was well-
tolerated with a systemic exposure (area under the curve (AUC)) of up to 
~170,000 μg.day/mL over the course of the 1-month study, and with an AUC of 
up to approximately 67,500 μg.day/mL over the course of the 6-month study. No 
findings of toxicological significance were observed in either study and the No 
Observed Adverse Event Level (NOAEL) was ≥200 mg/kg.   In addition, no 


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CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
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 May 23, 2018 
 
 
11
findings of toxicological relevance were observed in the in vitro tissue cross-
reactivity study using human and cynomolgus monkey tissues.[5]    
1.4 
Clinical Efficacy of Pembrolizumab in human NSCLC 
Pembrolizumab is very active against human NSCLC.  For example, in a second 
line study using pembrolizumab as monotherapy, 58% of tumors had some 
reduction in size[25]: 
 
 
 
Most of these responses occurred by 10 weeks and many were durable: 
 
 
While pembrolizumab is very active, it is has very low toxicity.  Overall toxicity 
in 119 patients treated in the study just referenced with a higher dose (10mg/kg 
Q3W) than that proposed in LCCC1516 (200mg fixed dose) was as follows: 
 
Drug-Related Adverse Events with Incidence > 5%[25] 
Adverse event % 
Any grade (%) 
Grade 3-5 (%) 
Any 
58 
10 
Fatigue 
16 
<1 


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UNIVERSITY OF NORTH CAROLINA 
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Arthralgia 
8 
<1 
Decreased appetite 
8 
0 
Pruritis 
8 
0 
Diarrhea 
7 
0 
Nausea 
4 
0 
Pyrexia 
6 
0 
Rash 
5 
0 
Hypothyroidism 
3 
0 
 
In pretreated NSCLC patients, only 1/38 experienced a grade 3-5 event, 
pulmonary edema.  Therefore, in addition to being very active, pembroliuzmab is 
far less toxic than the cytotoxic agents typically used for NSCLC.  
Pembrolizumab, along with other PD1 and PDL1 inhibitors, are however, 
associated with a novel problem: pseudo-progression: 
 
[26] 
 
In the above spider plot, the green arrows represent this phenomenon, where the 
cancer appears to grow, but later shrinks.  The two dominant explanations are that 
immunotherapy takes time to work in some cancers and that immune infiltration 
causes inflammation and takes up space.  Regardless, it creates a novel problem—
a review of the spider plots of pembrolizumab, other anti-PD1 agents, and anti-
PDL1 agents, both in NSCLC and in other cancers, reveals that the majority of 
apparent progression is, in fact, real progression.  New strategies are needed to 
address this problem. 


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UNIVERSITY OF NORTH CAROLINA 
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 May 23, 2018 
 
 
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1.5 
Nab-paclitaxel (Abraxane®) 
The active cytotoxic agent in nanoalbumin bound paclitaxel (henceforth nab-
paclitaxel) is paclitaxel, an antimicrotubule agent that promotes the assembly of 
microtubules from tubulin dimers and stabilizes microtubules by preventing 
depolymerization. Nab-paclitaxel delivers the paclitaxel bound to albumin and has 
several theoretic advantages over paclitaxel [27]. First, the cremophor solvent is 
not needed.  Cremophor requires special glass or non-PVC infusion systems, 
premedication with histamine 1 and 2 blockers, causes infusion reactions and may 
contribute to peripheral neuropathy.  As albumin facilitates the administration of 
water-insoluble compounds, effective active dose-delivery of albumin bound 
drugs may be higher than when drugs are administered without albumin.  Infusion 
time with nab-paclitaxel is faster than with paclitaxel.  Binding of the active drug 
to albumin may increase tumor-specificity, perhaps due to increased endothelial 
cell binding and transcytosis of the albumin-bound drug versus cremophor-based 
paclitaxel formulations.[28]  Critically for this study, nab-paclitaxel, unlike 
paclitaxel and most other cytotoxic agents used in NSCLC, does not require 
steroid premedication. 
 
Nab-paclitaxel showed improved response rates (RR) compared to standard 
paclitaxel when combined with carboplatin for the treatment of advanced 
NSCLC.[29] Response rate to standard carboplatin and paclitaxel was 25%; with 
carboplatin and nab-paclitaxel it was 33% (p=.005); most of this difference was 
driven by subjects with squamous histology (24% vs 41% RR).  Although 
effective dose delivery was higher with nab-paclitaxel (82 mg/m2/week) 
compared to standard paclitaxel (65 mg/m2/week) the overall toxicity profile, with 
the exception of anemia and thrombocytopenia, favored nab-paclitaxel, (table 
below summarizes the most common grade 3 and 4 treatment related adverse 
events):   
    
 
 
 
Toxicity 
Nab-paclitaxel 
(n=514) 
% 
Paclitaxel  
(n=524) 
% 
p value 
Grade 
3  
Grade 4 Grade 3 Grade 4 
Sensory 
Neuropathy 
3 
0 
11 
<1 
<0.001* 
Myalgia 
<1 
0 
2 
0 
0.011* 
Arthralgia 
0 
0 
2 
0 
0.008* 
Neutropenia 
33 
14 
32 
26 
<0.001* 
Thrombocytopenia 13 
5 
7 
2 
<0.001† 
Anemia 
22 
5 
6 
<1 
0.001† 
*P<0.05 in favor of nab-paclitaxel 
†P<0.05 in favor of paclitaxel 


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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
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1.6 
Combination of Pembrolizumab plus Chemotherapy 
Several phase I/II studies are ongoing evaluating the combination of 
pembrolizumab with chemotherapy, including a Merck-sponsored study 
combining pembrolizumab with either cisplatin and pemetrexed or carboplatin 
and paclitaxel in NSCLC (NCT01840579). A second Merck-sponsored phase I/II 
trial (NCT02039674) is ongoing in unresectable or metastatic NSCLC, and 
includes a number of arms combining fixed dose pembrolizumab with paclitaxel 
(200mg/m2) and carboplatin every 3 weeks, each given on D1 of every 3 week 
cycle, with or without bevacizumab. A third multi-arm phase I/II trial in patients 
with metastatic solid tumors (NCT02331251) is ongoing. Arm 3 of this trial 
includes a fixed dose of pembrolizumab on D1combined with gemcitabine 
(1000mg/m2 D1 and D8) and nab-paclitaxel 125mg/m2 (D1&D8) every 3 weeks.   
 
Safety data is pending from these studies. However, the major toxicities of 
pembrolizumab including low grade nausea, anorexia, arthralgia, pruritis, diarrhea 
and rash should not overlap with the major toxicities of nab-paclitaxel as outlined 
above, and the mechanisms of action are distinct (meaning we expect no more 
than additive toxicity).  Therefore, no serious safety issues are anticipated as a 
result of this combination given the low likelihood of overlapping toxicities. Any 
unexpected toxicities from the chemotherapy combination trials just summarized 
and sponsored by Merck will be shared with the PI of LCCC1516 and can be used 
to supplement toxicity monitoring if needed. In this trial, toxicity will be 
monitored continuously, with sequential boundaries employed to suspend the trial 
if excessive toxicity is seen. If the study reaches a stopping boundary, it may be 
terminated by the PI, or submitted to the DSMC with a description of the 
toxicities and a rationale for why the study should be continued. 
1.7 
Study Rationale 
 Improve survival: The primary goal of the trial is to guarantee exposure to 2 
additional active agents during first line therapy. 
 Give patients a defined end to 1st line treatment: While patients value 
improvements in survival and are willing to be treated longer if they can live 
longer, many patients also want a defined end to 1st line therapy. 
 Evaluate defined-duration checkpoint inhibitory therapy: Existing studies of PD1 
and PDL1 inhibitors almost universally study therapy until intolerance or 
progression.  It is possible that similar benefits can be achieved with defined-
duration therapy. 
 Explore the optimal sequencing of multiple consolidations:  No statistical 
comparison is planned between the three initial arms, although it is possible that 
one sequence may result in a much greater difference compared to the common 
null hypothesis than the others.  If pembrolizumab and nab-paclitaxel have 
synergistic activity, survival may be optimal with immediate concurrent 
consolidation with both agents. Further, survival may be optimal with this 
approach because it guarantees immediate exposure to both agents.  On the other 
hand, toxicity (specifically ≥ Grade 2 treatment-related adverse events (AEs)) 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
15
may be lower with serial administration of the consolidation agents; if such 
improved tolerance leads to greater feasibility, survival might be improved with 
sequential administration.  Further, if the agents have any antagonism or if a 
longer duration of treatment is superior, then survival might be better with 
sequential administration.  Results from this trial will also provide estimates that 
can be used to power a future confirmatory comparative study. 
 Demonstrate potential additive or synergistic effects of chemotherapy and 
immunotherapy: While other planned studies combine chemotherapy and PD-1 
inhibition, they suffer from the need to utilize steroids to protect against nausea 
and anaphylaxis from cytotoxic agents.  Because nab-paclitaxel uniquely does not 
require steroids, it might decrease the risk of steroid-related depletion of activated 
tumor-specific T cells. 
1.7.1 Rationale for Dose Selection of Pembrolizumab  
An open-label Merck-sponsored Phase I trial (Protocol 001) evaluated 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 (Q2W) in subjects with advanced solid tumors.  All 
dose levels were well tolerated and no dose-limiting toxicities (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.  No 
maximally tolerated dose (MTD) has been identified to date. Recent data from 
other clinical studies within the pembrolizumab program have shown that a lower 
dose of pembrolizumab and a less frequent schedule may be sufficient for target 
engagement and clinical activity. 
 
Pharmacokinetic (PK) data analysis of pembrolizumab administered Q2W and 
Q3W showed slow systemic clearance, limited volume of distribution, and a long 
half-life. [5]  Pharmacodynamic (PD) data (IL-2 release assay) suggested that 
peripheral target engagement is durable (>21 days).  This early PK and PD data 
provides scientific rationale for testing a Q2W and Q3W dosing schedule.   
 
A population PK analysis of pembrolizumab has been performed using serum 
concentration time data from 476 patients. Within the resulting population PK 
model, clearance and volume parameters of pembrolizumab were found to be 
dependent on body weight. The relationship between clearance and body weight, 
with an allometric exponent of 0.59, is within the range observed for other 
antibodies and supports both body weight normalized dosing or a fixed dose 
across all body weights (Merck, written communication).   
 
The choice of the 200 mg every 3 weeks as an appropriate dose for the switch to 
fixed dosing of pembrolizumab (which is pending FDA approval, and which is 
incorporated into this study) is based on simulations performed using the 
population PK model of pembrolizumab showing that the fixed dose of 200 mg 
every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks (the current FDA approved dose), 


LCCC 1516 
 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
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2) will maintain individual patient exposures in the exposure range established in 
melanoma as associated with maximal efficacy response and 3) will maintain 
individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe (Merck, written communication).  The fixed dosing 
regimen will also reduce potential for dosing errors and reduce the complexity 
associated with weight-based dosing.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will 
also reduce complexity in the logistical chain at treatment facilities and reduce 
wastage. 
1.8 
Correlative Studies 
Exploratory objectives based
 
  
 
 
 
 
 
 
 
 
 
 
  
 
Additional details regarding correlative studies can be found in the laboratory 
manual. 
 


LCCC 1516 
 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
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2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Estimate OS after sequential consolidation with pembrolizumab followed by nab-
paclitaxel (ARM A), sequential consolidation with nab-paclitaxel followed by 
pembrolizumab (ARM B) and concurrent consolidation with nab-paclitaxel and 
pembrolizumab (ARM C) after standard first-line induction chemotherapy in 
advanced NSCLC 
 
2.2 
Secondary Objectives  
2.2.1 Estimate PFS in each ARM with pembrolizumab and nab-paclitaxel per 
RECIST1.1 and iRRC  
2.2.2 Estimate overall rates of response via RECIST1.1 and iRRC within each ARM  
2.2.3 Estimate rates of response via RECIST1.1 and iRRC (the latter if applicable) after 
each component of therapy in ARMS A and B   
2.2.4 Characterize the toxicity profile of each ARM, both provider-defined and patient 
reported 
2.2.5 Describe quality of life over the course of therapy 
 
2.3 
Exploratory Objectives 
2.4 
Endpoints:  
2.4.1 Primary Endpoint 
OS is defined as the time from D1 of treatment to death from any cause 


LCCC 1516 
 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
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2.4.2 Secondary Endpoints 
 PFS will be defined as the time from D1 of treatment until death or 
progression. 
 Rates of response will be reported in several ways in this study: 
o Via RECIST1.1  
o Via Adapted-iRR (see section 6.13.2 for details) 
 Clinician assessed toxicity will be classified and graded according to the 
National Cancer Institute’s Common Terminology Criteria for Adverse 
Events (CTCAE, version 4.0) 
 Patient assessed toxicity will be classified based on the Patient-Reported 
Outcome version of the CTCAE (PRO-CTCAE) 
 QOL will be evaluated via the FACT-Lung 






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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
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3.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria will not be able to 
participate in this study: 
3.2.1 Patients with EGFR mutations expected to be sensitive to EGFR inhibitors and 
patients with EML4/ALK translocations are excluded, unless all available FDA-
approved targeted therapy options have been utilized.  For example, a patient with 
exon 19 EGFR mutation who has never been treated with an EGFR inhibitor 
would be excluded.  Patients with other sensitizing mutations that become 
actionable with FDA-approved targeted therapies during the course of this trial 
(e.g., crizotinib for MET deletion 14) will also be expected to have utilized all 
available FDA-approved targeted therapy options prior to eligibility.  
Note: In contrast to the above, a patient with an EGFR mutation who has been 
treated with a first-generation and third generation TKIs and then with four 
cycles of carboplatin plus pemetrexed would be eligible.   
3.2.2 Is currently participating in or has participated in a study of an investigational 
agent or using an investigational device within 4 weeks of the first dose of 
treatment. 
3.2.3 Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to the first dose 
of trial treatment. 
3.2.4 Has had prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 2 weeks prior to study Day 1. Note:  If subject received major 
surgery, they must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting therapy.   
3.2.5 Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who 
has not recovered (i.e., ≤ Grade 1 or at baseline and other than alopecia) from 
adverse events due to agents administered more than 4 weeks earlier. Exceptions 
to these criteria may be allowed at the discretion of the UNC PI for toxicities that 
are not expected to be exacerbated by pembrolizumab or nab-paclitaxel. 
3.2.6 Has a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, or in situ cervical cancer that has undergone potentially 
curative therapy.   
3.2.7 Has an active automimmune disease requiring systemic treatment within the past 
3 months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents; 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 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
7
stable on hormone replacement or Sjorgen’s syndrome will not be excluded from 
the study. 
3.2.8 Has a history of non-infectious pneumonitis that required steroids or evidence of 
interstitial lung disease or current active, non-infectious pneumonitis. 
3.2.9 Has an active infection requiring systemic therapy. 
3.2.10 Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 
subject’s participation for the full duration of the trial, or is not in the best interest 
of the subject to participate, in the opinion of the treating investigator.   
3.2.11 Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial 
3.2.12 Had inadequate home environment or social support to safely complete the trial 
procedures. 
3.2.13 Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
3.2.14 Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody 
(including ipilimumab or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways) 
3.2.15 Known hypersensitivity to protein bound paclitaxel 
3.2.16 Has received prior therapy with any taxane chemotherapy 
3.2.17 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
3.2.18 Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected). 
3.2.19 Has received a live vaccine within 30 days prior to the first dose of trial treatment   
 
 


LCCC 1516 
 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
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4.0 
TREATMENT PLAN 
4.1 
Study Schema 
 
*D1 of treatment on LCCC1516 must be 21-42 days from the last day of induction, 
consistent with timing of standard care maintenance.  
**See section 4.3 of the protocol. 
 
 
4.2 
Treatment Summary by Arm 
D1 of treatment on LCCC1516 must be at least 21 and not more than 42 days 
from the last day of induction, consistent with timing of standard of care 
maintenance (see inclusion criteria 3.1.5). 
 
Patients will receive 4 x 3-week cycles of pembrolizumab monotherapy.  Once 
this monotherapy is complete, or at the time of progressive disease (PD), 
whichever occurs first, patients will then receive 4 x 3-week cycles of nab-
paclitaxel monotherapy. Patients who have been randomized to ARM B will 
receive the same regimen but in reverse, with nab-paclitaxel monotherapy 
followed by pembrolizumab. Both ARMS A and B will receive a total of 24 
weeks of therapy. Patients randomized to ARM C will receive concomitant nab-
paclitaxel plus pembrolizumab for 4x 3 week cycles for a total of 12 weeks of 
therapy.   


LCCC 1516 
 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
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4.3 
Treatment Decisions Regarding Progressive Disease by ARM 
At each imaging time-point throughout the study (see Section 6.0) both 
RECIST1.1 and adapted irRC will be applied. However, use of these criteria to 
make treatment decisions based on presence or absence of PD will vary by ARM 
as outlined below.  
4.3.1 ARM A 
During the first consolidation with pembrolizumab monotherapy progression will 
be assessed via an adapted irRC (see section 6.13.2) after cycle 4. All patients will 
be scanned prior to cycle 3 (after cycle 2), however in patients without symptoms 
of progression, this data will be used principally for spider-plots and hypothesis 
generation.   If symptoms of progression are evident and accompanied by a rapid 
decline in ECOG PS, or that in the opinion of the investigator otherwise 
endangers the patient, it will be acceptable to discontinue pembrolizumab and 
immediately initiate nab-paclitaxel. During the second consolidation with nab-
paclitaxel monotherapy, PD will be based on RECIST1.1 (see section 6.13.1). If 
progression is noted during the second consolidation, the patient will discontinue 
protocol mandated therapy, and be followed-up per protocol. 
4.3.2 ARM B 
During the first consolidation with nab-paclitaxel monotherapy, progression will 
be based on RECIST1.1 (see section 6.13.1). If there is evidence of progression 
prior to completion of 4 cycles of Consolidation One, the patient will discontinue 
Consolidation One early and begin Consolidation Two. During the second 
consolidation with pembrolizumab monotherapy, treatment decisions will be 
based on adapted irRC (see section 6.13.2). All patients will be scanned prior to 
cycle 3 of pembrolizumab (after cycle 2), however in patients without symptoms 
of progression, this data will be used principally for spider-plots and hypothesis 
generation.   If symptoms of progression are evident and accompanied by a rapid 
decline in ECOG PS, or that in the opinion of the investigator otherwise 
endangers the patient, it will be acceptable to discontinue protocol mandated 
therapy, and follow up patient per protocol.   
4.3.3 ARM C 
During treatment, PD will be based on RECIST1.1 (see section 6.13.1). In the 
case of PD, the patient will discontinue protocol mandated therapy, and be 
followed-up per protocol. 
4.4 
Details on each Drug for ARMS A-C 
In addition to the information provided below, also refer to Section 5, to the 
respective prescribing information for each agent 
(http://www.accessdata.fda.gov/scripts/cder/drugsatfda/, and to the Investigator’s 
Brochure for pembrolizumab [5]. 


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UNIVERSITY OF NORTH CAROLINA 
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4.4.1 Pembrolizumab Dosing Administration for Pembrolizumab Cycles 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion on D1 of 
each cycle it is scheduled for (see Schema).  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. This 
manual is provided as a document separate from the protocol. 
 
NOTE: Subjects should be assessed for possible Events of Clinical Interest (ECI: 
see the document provided separate from this protocol) prior to each dose. Lab 
results should be evaluated and subjects should be asked for signs and symptoms 
suggestive of an immune-related event.  Subjects who develop an ECI thought to 
be immune-related should have additional testing to rule out other etiologic 
causes.  If lab results or symptoms indicate a possible immune-related ECI, then 
additional testing should be performed to rule out other etiologic causes. If no 
other cause is found, then it is assumed to be immune-related. 
4.4.2 Management of Pembrolizumab Infusion Reactions 
Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.  Refer to 
the table below for infusion reaction treatment guidelines associated with 
administration of pembrolizumab. 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the investigator. If symptoms 
resolve within one hour of 
stopping drug infusion, the 
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). 


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UNIVERSITY OF NORTH CAROLINA 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
infusion may be restarted at 
50% of the original infusion 
rate (e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will 
be held until symptoms resolve 
and the subject should be 
premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued 
from further trial treatment 
administration. 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: IV fluids, 
Antihistamines, NSAIDS 
Acetaminophen, Narcotics, 
Oxygen, Pressors, 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the investigator. 
Hospitalization may be 
indicated. 
Subject is permanently 
discontinued from further 
trial treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration. 
4.4.3 Other Dose Modifications for Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab 
exposure may represent an immunologic etiology.  These adverse events may 
occur shortly after the first dose or several months after the last dose of treatment. 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-
threatening AEs as per Table below.  See section 4.4.4 for supportive care 
guidelines, including use of corticosteroids. 
 
Dosing interruptions are permitted in the case of medical / surgical events or 
logistical reasons not related to study therapy (e.g., elective surgery, unrelated 
medical events, patient vacation, and/or holidays). Subjects should be placed back 
on study therapy within 3 weeks of the scheduled interruption, unless otherwise 


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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
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discussed with the Sponsor. The reason for interruption should be documented in 
the patient's study record. 
 
If a dose of pembrolizumab is delayed, then the subsequent dose should be 
administered 3 weeks later.  Discontinuation of pembrolizumab for toxicity does 
not mandate discontinuation of nab-paclitaxel (in concurrent arm (ARM C, 
subjects may continue on nab-paclitaxel alone; in the pembrolizumab first 
sequential arm (ARM A), subjects may proceed to nab-paclitaxel immediately or 
once toxicity is sufficiently resolved). 
 
 
Hematological Toxicity Dose Delays or Discontinuation for Pembrolizumab 
Toxicity 
Hold Treatment 
For Grade 
Timing for 
Restarting 
Pembrolizumab* 
Discontinue Subject** 
Autoimmune 
hemolytic anemia, 
aplastic anemia, 
disseminated 
intravascular 
coagulation, 
Hemolytic Uremic 
Syndrome (HUS-
Idiopathic or 
immune), 
Thrombocytopenia 
Purpura (ITP), 
Thrombotic 
Thrombocytopenic 
Purpura (TTP) or 
Any Grade 4 anemia 
regardless of 
underlying 
mechanism 
2-3 
 
Toxicity resolves to 
Grade 0-1. 
Toxicity does not resolve 
within 12 weeks of last dose 
or inability to reduce 
corticosteroid to 10 mg or less 
of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently 
discontinue** 
Permanently discontinue** 
**Whenever pembrolizumab is permanently discontinued, patient should still r be followed-up per protocol. 
 
 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
 
9
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
old pembrolizumab for new onset Type 1 
diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of 
beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
2b 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; Refer to Error! Reference 
source not found. – Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
10 
4.4.4 Rescue Medications & Supportive Care for Pembrolizumab Cycles 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed 
necessary by the treating investigator.  Suggested supportive care measures for the 
management of adverse events 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 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. 
Refer to Section 4.4.3 for dose modification.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.  
 
Hematologic (see table in Section 4.4.3) 
All attempts should be made to rule out other causes such as metastases, sepsis 
and/or infection. Relevant diagnostic studies such as peripheral blood smear, 
reticulocyte count, LDH, haptoglobin, bone marrow biopsy or Coomb’s test, etc., 
should be considered to confirm the diagnosis.  
 
For Grade 2 events: 
 Hold pembrolizumab 
 Prednisone 1-2 mg/kg daily may be indicated 
 Consider Hematology consultation 
 Permanently discontinue for inability to reduce corticosteroid dose to 10 
mg or less of prednisone or equivalent per day within 12 weeks. 
 
Grade 3 events: 
 Hematology consultation 
 Hold pembrolizumab  
 Discontinuation should be considered at discretion of investigator 
 Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or 
equivalent) as appropriate 
 Permanently discontinue for inability to reduce corticosteroid dose to 10 
mg or less of prednisone or equivalent per day within 12 weeks. 
 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
11 
Grade 4 events: 
 Hematology consultation 
 Discontinue pembrolizumab 
 Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or 
equivalent) as appropriate 
 
Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) 
and of bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience 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.  For 
Grade 2 or higher diarrhea, consider GI consultation and endoscopy to 
confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids 
followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 
Type 1 diabetes mellitus (TIDM) (if new onset, including diabetic 
ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis 
(ketonuria) or metabolic acidosis (DKA) 
 
 
For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for TIDM and for Grade 3-4 
hyperglycemia associated with metabolic acidosis or ketonuria. 
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
 
 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
12 
Hypophysitis:  
o For Grade 2 events, treat with corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV 
corticosteroids followed by oral corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment; monitor patients for 
changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs and 
symptoms of thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 
 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
 
  
 
Renal Failure or Nephritis: 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
13 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
Steven’s Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) 
o For signs and symptoms of SJS or TEN, withhold pembrolizumab and 
refer the patient for specialized care for assessment and treatment 
o If SJS or TEN is confirmed, permanently discontinue pembrolizumab 
 
Immune-mediated myocarditis management 
o For suspected immune-mediated myocarditis, ensure adequate evaluation 
to exclude other etiologies and administer corticosteroids as appropriate 
 
Infusion Reaction 
See section 4.4.2  
 
4.4.5 Nab-paclitaxel Premedication 
Patients do not require premedication prior to nab-paclitaxel administration, as 
hypersensitivity reactions are rare.  
 
Administration of solvent-based taxanes (Taxol and Taxotere) requires 
premedication with corticosteroids and histamine receptor blocking agents to 
prevent the occurrence of hypersensitivity reactions.  The solubilizing agents 
Cremophor® EL and Tween® 80 have long been implicated in adverse events 
including hypersensitivity reactions due to their detergent-like nature and known 
ability to induce histamine release. [30]  However, the hypersensitizing role of the 
taxane molecules themselves cannot be ruled out.   
 
In the unlikely event of a mild hypersensitivity reaction, premedication may be 
administered using the premedication regimen the institution typically uses for 
solvent based paclitaxel. 
 
In the event of a severe hypersensitivity reaction, discontinue nab-paclitaxel (see 
section 4.4.8). 
4.4.6 Nab-paclitaxel Dosing Administration for Pembrolizumab Cycles 
Nab-paclitaxel 100mg/m2 will be infused over 30 minutes when prescribed by 
arm (see schema or time and events table).  Actual body weight will be used for 
the dose calculation.  It is not a requirement to use in-line filters during the 
administration of nab-paclitaxel.  In any event, filters of pore-size less than 15 
micrometers must not be used.  If patient body weight changes by >10%, 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
14 
recalculate the body surface area and dose of nab-paclitaxel.  Note:  Dose changes 
will apply for the next cycle; doses will not be changed mid- cycle. Following 
administration, the intravenous line should be flushed with Sodium Chloride 0.9% 
solution for injection to ensure administration of the complete dose, according to 
local practices. 
4.4.7 Supportive Care Guidelines for Nab-Paclitaxel 
Subjects should receive full supportive care during the study, including 
transfusion of blood and blood products, and treatment with antibiotics, 
antiemetics, and analgesics, as appropriate. 
 
Anti-emetic Medications 
The recommended regimen will include ondansetron 16 mg by oral, or 8 mg by 
IV route, or an alternative 5HT-3 antagonist.  Aprepitant and dexamethasone use 
are not recommended as nab-paclitaxel is not sufficiently emetogenic as to require 
aprepitant and without Cremophor, dexamethasone is not required to prevent 
infusion reactions.  While not recommended, aprepitant is not prohibited--
clinicians may adjust the antiemetic regimen as needed for individual patients. 
Dexamethasone is not allowed in any study arm. 
 
Hematopoietic Growth Factors 
Use of erythropoiesis- stimulating agents (ESAs) will not be allowed on this study 
in the concurrent arm.  In ARMs A and B, they will be allowed only during nab-
paclitaxel monotherapy.  If the clinician elects to utilize ESAs, they must be used 
within FDA-approved guidelines. The use of peg-filgrastim is not allowed in this 
study.   
 
When filgrastim is used, administer filgrastim 5 mcg/kg/day (rounded to the 
nearest vial size per investigator/institution’s standard of care).  The number of 
days of filgrastim is up to the discretion of the treating MD; however, it is 
recommended that the patient must start at least 24 hours after the dose of nab-
paclitaxel and be held at least 48 hours prior to the next dose.  The dose of 
filgrastim can be adjusted based on the investigator’s discretion.  
4.4.8 Toxicities and Dosing Delays/Dose Modifications for Nab-Paclitaxel 
See section Error! Reference source not found. for more detailed information 
on nab-paclitaxel.  Also refer to the Full Prescribing Information for nab-
paclitaxel for complete safety information:  
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. If more than 2 dose 
reductions of nab-paclitaxel are required, nab-paclitaxel is to be discontinued.  
Once a patient’s dose has been reduced, the dose reduction will be permanent.  
Dose re-escalation will not be permitted.  Discontinuation of nab-paclitaxel for 
toxicity does not mandate discontinuation of pembrolizumab (in concurrent arm 
(ARM C); patients may continue on pembrolizumab alone; in nab-paclitaxel first 
sequential arm (ARM B), the patient may proceed to pembrolizumab immediately 
or once toxicity is sufficiently resolved). 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
15 
 
For AEs that require dose reductions of nab-paclitaxel, please refer to the dose 
levels below: 
 
Dose Level 
Nab-paclitaxel dose (mg/m2) 
0 (starting dose) 
100 
-1 
75 
-2 
50 
-3 
0 
 
 
 
Hypersensitivity Reactions 
Hypersensitivity reactions to nab-paclitaxel rarely occur.  If they do occur, minor 
symptoms such as flushing, skin reactions, dyspnea, lower back pain, 
hypotension, or tachycardia may require temporary interruption of the infusion.  
However, severe reactions, such as hypotension requiring treatment, dyspnea 
requiring bronchodilators, angioedema or generalized urticaria require immediate 
discontinuation of nab-paclitaxel administration and aggressive symptomatic 
therapy.  Patients who experience a severe hypersensitivity reaction to nab-
paclitaxel should not be re-challenged. 
 
 
 
 
 




LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
17 
transaminases < 3 x ULN 
≥Grade 3 
(>5 x ULN) 
2 dose levels 
 (when treatment 
resumes) 
Renal toxicity  
If serum Cr >2 mg/dL, 
hold treatment.  Resume 
per table once serum Cr<2 
mg/dL 
≤Grade 2 
(< 3 x ULN) 
Maintain dose 
≥Grade 3 
(>3 x ULN) 
1 dose level 
(when treatment 
resumes) 
Other non-specified2 
Hold treatment until 
toxicity resolves to ≤Grade 
1.  Resume treatment with 
dose adjusted per table.   
≥ Grade 3 
1 dose level 
(when treatment 
resumes) 
1 If G-CSF (filgrastim) is given concurrently with nab-paclitaxel, administration may begin 24 
hours after nab-paclitaxel is given and should stop at least 48 hours prior to when nab-paclitaxel 
is given the following week.  The dose is 5mcg/kg/day rounded to the nearest vial size per 
investigator/institution’s standard of care.  See section Note: peg-filgrastim is not permitted 
during the study.  Note that filgrastim may only be used during single-agent nab-paclitaxel 
therapy; it is not to be used concurrently with pembrolizumab. 
2Excludes alopecia and non-refractory nausea/vomiting 
 
4.5 
Concomitant Medications/ Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are 
not allowed during the ongoing trial.  If there is a clinical indication for one of 
these or other medications or vaccinations specifically prohibited during the trial, 
discontinuation from trial therapy or vaccination may be required.  The 
investigator should discuss any questions regarding this with the Merck Clinical 
team.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  No drug interactions studies 
have been conducted with nab-paclitaxel, a drug metabolized by CYP2C8 and 
CYP3A4.  Caution should be used when administering nab-paclitaxel with 
medications known to inhibit or induce either CYP2C8 or CYP3A4.   
4.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare 
may be administered at the discretion of the investigator in keeping with the 
community standards of medical care.  All concomitant medication will be 
recorded on the case report form (CRF) 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. 
4.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the 
Screening and Treatment Phase  
 
 Anti-cancer systemic chemotherapy or biological therapy  


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
18 
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab  
 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, 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. 
 Systemic glucocorticoids for any purpose other than to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology.  The use 
of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor. 
 Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain 
may be allowed at the investigator’s discretion.   
 Hematopoietic Growth Factors: Use of erythropoiesis- stimulating agents 
(ESAs) will not be allowed on this study in the concurrent arm (ARM C). In 
the sequential arms (ARMs A and B), they will be allowed only during nab-
paclitaxel monotherapy. If the clinician elects to utilize ESAs, they must be 
used within FDA-approved guidelines. The use of peg-filgrastim is not 
allowed in this study. Filgrastim administration is allowed with single-agent 
nab-paclitaxel but not with pembrolizumab (see section 4.4.8). 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the 
trial.  Subjects may receive other medications that the investigator deems to be 
medically necessary 
4.6 
Duration of Therapy 
In the absence of treatment delays due to AEs, treatment may continue until the 
end of study-defined treatment or until: 
 Inter-current illness that prevents further administration of treatment 
 Unacceptable toxicity  
 Pregnancy 
 Patient decides to withdraw from study treatment, OR 
 General or specific changes in the patient’s condition render the 
patient unacceptable for further treatment in the judgment of the 
investigator. 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
19 
4.7 
Duration of Follow-Up 
After two years of follow-up as described in the time and events table, subsequent 
follow-up will be per standard of care and the study will follow only for 
progression and for survival for up to 3 additional years, for a total of 5 years of 
follow-up after study completion. 
4.8 
Removal of Patients from Protocol Therapy 
Patients will be removed from protocol therapy and the PI notified when any of 
the criteria listed in section 4.6 apply.  The reason for discontinuation of protocol 
therapy will be documented on the electronic case report form (eCRF).   
 
In case a patient decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the patient should be asked if she or he 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. 
4.9 
Study Withdrawal 
Patients will be removed from protocol therapy and the PI notified when any of 
the criteria listed in section 4.7 apply.  The reason for discontinuation of protocol 
therapy will be documented on the eCRF.   
 
If a patient decides to withdraw from the study (and not just from protocol 
therapy) an effort should be made to complete and report study assessments as 
thoroughly as possible.  At the time of withdrawal, the investigator should attempt 
to establish as completely as possible the reason for the study withdrawal.  
 
The patient should be asked if they are willing to allow for the abstraction 
of relevant information from their medical record in order to meet the long 
term follow up (e.g., survival) objectives outlined in the protocol.   
 
A complete final evaluation at the time of the patient’s study withdrawal 
should be obtained with an explanation of why the patient is withdrawing 
from the study.   
 
If the patient is noncompliant and does not return for an end of study 
follow up assessment, this should be documented in the eCRF.  
 
If the reason for removal of a patient from the study is an adverse event, 
the principal specific event will be recorded on the eCRF.  
 
Excessive patient withdrawals from protocol therapy or from the study can render 
the study un-interpretable; therefore, unnecessary withdrawal of patients should 
be avoided. 
 
 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
20 
5.0 
DRUG INFORMATION 
 
5.1 
Pembrolizumab 
Product description: 
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 
kappa immunoglobulin with an approximate molecular weight of 149 kDa. 
 
Mechanism of action: 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T 
cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 
ligands occurs in some tumors. Signaling through this pathway can contribute to 
inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a 
monoclonal antibody that binds to the PD-1 receptor and blocks its interaction 
with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the 
immune response, including antitumor immune response. In syngeneic mouse 
tumor models, blocking PD-1 activity resulted in decreased tumor growth. 
 
Supplier/How Supplied: 
Pembrolizumab will be provided at no cost to the study patient by Merck, the 
manufacturer of the drug. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements. 
 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor 
and/or designee are not blinded to treatment. Drug identity (name, strength) is 
included in the label text; random code/disclosure envelopes or lists are not 
provided. 
 
Pembrolizumab is supplied as single-use 100 mg vials containing a sterile, non-
pyrogenic, clear to opalescent aqueous solution (25 mg/mL), or as single-use 50 
mg vials containing lyophilized powder in a single-dose vial for reconstitution). 
Pembrolizumab solution for infusion is formulated in 10mM histidine buffer, pH 
5.2-5.8, containing 7% sucrose and 0.02% polysorbate 80, supplied in Type I 
glass vials with a cap color of red, salmon, or blue.  
 
Preparation: 
Pembrolizumab solution for infusion must be diluted prior to administration per 
institutional guidelines. Allow the required number of vials to equilibrate to room 
temperature. Do not shake the vials. Do not use if opaque or extraneous 
particulate matter other than translucent to white proteinaceous particles is 
observed. Do not use if discolored. To prepare the infusion solution add the dose 
volume of pembrolizumab to an infusion bag containing 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP. Gently invert the bag 10-15 times 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
21 
to mix the solution. The final concentration must be between 1 mg/mL to 10 
mg/mL.  
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC 
(polyolefin), EVA, or PE lined polyolefin  
 
Storage and Handling: 
Store pembrolizumab under refrigeration at 2°C to 8°C (36°F to 46°F) in the 
original carton to protect from light. Do not freeze. Do not shake. 
 
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. 
 
Stability: 
Administer prepared solutions immediately after preparation. If not administered 
immediately, prepared solutions may be stored refrigerated for up to 24 hours. 
Pembrolizumab solutions may be stored at room temperature for a cumulative 
time of up to 6 hours. This includes room temperature storage of liquid drug 
product solution in vials, room temperature storage of infusion solution in the IV 
bag, and the duration of infusion.  
 
Dose and route of administration: 
The recommended dose of pembrolizumab is 200 mg administered as an IV 
infusion over approximately 30 minutes (range: 25 - 40 minutes) every 3 weeks 
until disease progression or unacceptable toxicity. Pembrolizumab should be 
administered using an infusion set containing a low-protein binding 0.2 to 5 μm 
in-line filter made of polyethersulfone or polysulfone. Infusion rate should not 
exceed 6.7 mL/min. A central line is not required; however if a subject has a 
central venous catheter in place, it is recommended that it be used for the infusion. 
Do not co-administer other drugs through the same infusion line. Following the 
infusion, flush the IV line with normal saline. 
 
Return and Retention 
The investigator is responsible for keeping accurate records of the clinical 
supplies received from Merck or designee, the amount dispensed to and returned 
by the subjects and the amount remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per UNC IDS drug destruction 
policy. It is the Investigator’s responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
22 
according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
 
Possible side effects: refer to management guidelines in sections Error! 
Reference source not found., Error! Reference source not found. and Error! 
Reference source not found.. 
 
Immune-Mediated Pneumonitis 
Pneumonitis occurred in ~2% of melanoma patients treated in clinical trials of 
pembrolizumab. Fatal cases have occurred. The median time-to-onset was 4.3 
months (range: 2 days to 19.3 months). Monitor patients for signs and symptoms 
of pneumonitis.  
 
Immune-Mediated Colitis 
Colitis (including microscopic colitis) occurred in ~2% of patients with melanoma 
treated in clinical trials of pembrolizumab. The median time-to-onset was 3.4 
months (range 10 days to 9.7 months).  Monitor patients for signs and symptoms 
of colitis.  
 
Immune-Mediated Hepatitis  
Hepatitis (including autoimmune hepatitis) occurred in 0.5% of melanoma 
patients treated in clinical trials of pembrolizumab. The time-to-onset was 26 days 
(range: 8 days to 21.4 months). Monitor patients for signs and symptoms of 
hepatitis.  
 
Immune-Mediated Hypophysitis  
Hypophysitis occurred in 0.8% of melanoma patients treated in clinical trials of 
pembrolizumab. The time-to-onset was 3.3 months (range 1 day to 7.2 months). 
Monitor patients for signs and symptoms of hypophysitis.  
 
Thyroid disorders 
Thyroid disorders can occur at any time during treatment. Monitor patient for 
changes in thyroid function (at the beginning of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs and 
symptoms of thyroid disorders. 
 
Immune-Mediated Hyperthyroidism 
Hyperthyroidism occurred in 3.3% of patients receiving pembrolizumab in 
clinical trials. The median time-to-onset was 1.4 months (range: 1 day to 21.9 
months). Monitor patients for signs and symptoms of hypothyroidism. 
 
Immune-Mediated Nephritis and Renal Dysfunction  
Nephritis occurred in (0.4%) patients of melanoma patients treated in clinical 
trials of pembrolizumab.  The median time-to-onset of autoimmune nephritis was 
5.1 months (ranges: 12 days to 12.8 months).  Monitor patients for signs and 
symptoms of nephritis and renal dysfunction. 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
23 
 
Other Immune-Mediated Adverse Reactions 
Other clinically important immune-mediated AEs can occur. The following 
clinically significant, immune-mediated AEs occurred in less than 1% of patients 
treated with pembrolizumab, including exfoliative dermatitis, uveitis, arthritis, 
myositis, Guillain-Barré syndrome, vasculitis, myasthenia gravis, pancreatitis, 
hemolytic anemia, partial seizures arising in a patient with inflammatory foci in 
brain parenchyma. 
 
Infusion-related Reactions 
Infusion-related reactions have been reported in 0.1% of patients receiving 
pembrolizumab in clinical trials.  Monitor patients for signs and symptoms of 
infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, 
rash, hypotension, hypoxemia, and fever. 
 
Steven’s Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) 
The risk of SJS and TEN is reported at approximately 0.4 – 7 cases per million 
patient years in the general adult population. Independent risk factors include 
certain medications such as anticonvulsants, sulfonamides, aminopenicillins, 
allopurinol, and NSAIDs. Non-medication triggers include infection, contrast 
media, and vaccinations. Malignancy is associated with an increased mortality 
rate in patients with SJS and TEN. 
 
Myocarditis 
A total of 6 cases of myocarditis have been reported in patients treated with 
pembrolizumab in clinical trials in an expanded access program. There was one 
fatal case reported in a clinical trial 60.  Immune-mediated myocarditis should be 
suspected if other causes of myocarditis, such as infection or prior radiation 
therapy have been excluded. Risk factors include certain medications and 
treatment modalities such as radiation, anthracycline, alkylating agents and most 
recently checkpoint inhibitors. 
 
Embryofetal Toxicity 
Based on its mechanism of action, pembrolizumab may cause fetal harm when 
administered to a pregnant woman. Animal models link the PD-1/PDL-1 
signaling pathway with maintenance of pregnancy through induction of maternal 
immune tolerance to fetal tissue.  
 
Handling and Disposal: Please see policy on hazardous drugs:  
http://intranet.unchealthcare.org/intranet/hospitaldepartments/safetynet/policies/ha
zardousdrugs.pdf 
 
Local requirements for disposal of hazardous drugs should be followed at each 
participating clinical site. See section Error! Reference source not found. for 
details. 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
24 
 
Precautions: 
Pre-existing hypocalcemia must be corrected prior to initiating therapy with 
denosumab. See section Error! Reference source not found. for details. 
 
For additional information, please refer to the full prescribing information on 
pembrolizumab is available at: 
https://www.merck.com/product/usa/pi circulars/k/keytruda/keytruda pi.pdf 
5.1.1 Contraindications 
There are no reported contraindications associated with the use of 
pembrolizumab. 
 
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.   
5.1.2 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.   
 
For this trial, male subjects will be considered to be of non-reproductive potential 
if they have azoospermia (whether due to having had a vasectomy or due to an 
underlying medical condition).   
 
Female subjects will be considered of non-reproductive potential if they are 
either:  
(1) postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle 
stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a post-menopausal state in women not using hormonal contraception 
or hormonal replacement therapy. In the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient.);  
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to 
screening;  
OR 
(3) has a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and 
for 120 days after the last dose of study drug by complying with one of the 
following:   
(1) practice abstinence† from heterosexual activity;  


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
25 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual 
activity.   
 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• intrauterine device (IUD) 
• vasectomy of a female subject’s male partner  
• contraceptive rod implanted into the skin 
 
Combination method (requires use of two of the following): 
• diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)   
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, 
or subcutaneous contraceptive injection. 
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and 
ERCs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, 
post-ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception.  
 
‡If a contraceptive method listed above is restricted by local 
regulations/guidelines, then it does not qualify as an acceptable method of 
contraception for subjects participating at sites in this country/region. 
 
Subjects should be informed that taking the study medication may involve 
unknown risks to the fetus (unborn baby) if pregnancy were to occur during the 
study.  In order to participate in the study subjects of childbearing potential must 
adhere to the contraception requirement (described above) from the day of study 
medication initiation (or 14 days prior to the initiation of study medication for 
oral contraception) throughout the study period up to 120 days after the last dose 
of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject 
should not be entered into the study. 
5.1.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with 
pembrolizumab, the subject will immediately be removed from the study.  The 
site will contact the subject at least monthly and document the subject’s status 
until the pregnancy has been completed or terminated.  The outcome of the 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
26 
pregnancy will be reported to the Sponsor and to Merck without delay and within 
24 hours to the Sponsor and within 2 working days to Merck if the outcome is a 
serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
 
The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor.   If a male subject impregnates his female partner the study personnel at 
the site must be informed immediately and reported to the Sponsor and Merck as 
described above.  
 
See section 7.3.3 for detailed information on reporting of suspected pregnancies, 
pregnancies, and outcome of any pregnancy to the UNCCN Project Manager, 
Merck, and Celgene.  
 
Male Subjects 
Male patients treated with nab-paclitaxel are advised not to father a child during 
and up to 6 months after treatment. 
5.1.4 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. 
5.1.5 Overdose of Pembrolizumab 
For purposes of this trial, an overdose of pembrolizumab will be defined as any 
dose of 1,000 mg or greater (≥5 times the indicated dose).  No specific 
information is available on the treatment of overdose of pembrolizumab. 
Appropriate supportive treatment should be provided if clinically indicated. In the 
event of overdose, the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck 
product, the adverse event(s) is reported as a serious adverse event, 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 
overdose is reported as a non-serious Event of Clinical Interest (ECI), using the 
terminology “accidental or intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 
24 hours to the UNCCN Project Manager who will report the event within 2 
working days hours to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220) (see section 7.3.3). 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
27 
5.2 
Nab-paclitaxel (Abraxane®; ABI-007) 
Nab-paclitaxel is a protein-bound form of paclitaxel indicated in the United States 
for the treatment of breast cancer after failure of combination chemotherapy for 
metastatic disease or relapse within 6 months of adjuvant chemotherapy.  Prior 
therapy should have included an anthracycline unless clinically contraindicated.  
It is also indicated for locally advanced or metastatic NSCLC as first-line 
treatment in combination with carboplatin in patients who are not candidates for 
curative surgery or radiation therapy.  See: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ 
for additional information, and the nab-paclitaxel investigator’s brochure for 
complete information.   
5.2.1 Packaging, Labeling, Storage and Supply of nab-paclitaxel  
Nab-paclitaxel (Abraxane®) will be supplied by Celgene Corporation, in single-
use vials at no cost to the patient.  Each single-use 50 mL vial will contain 
paclitaxel (100 mg) and human albumin (HA; approximately 900 mg).  
Commercial drug will be supplied.  Each milliliter (mL) of reconstituted 
suspension contains 5 mg paclitaxel.  Un-reconstituted nab-paclitaxel 
(Abraxane®) should be stored at controlled room temperature (20 to 25C or 68 
to 77F) in its original carton to protect from bright light. Unopened vials are 
stable until the date indicated on the package when stored between 20°C to 25°C 
(68°F to 77°F), in the original package.  Neither freezing nor refrigeration 
adversely affects the stability of the product. 
 
Reconstituted nab-paclitaxel (Abraxane®) should be used immediately.  If not 
used immediately, the vial of reconstituted nab-paclitaxel (Abraxane®) must be 
placed in its carton in a refrigerator at 2 to 8C (36 to 46F) for a maximum of 8 
hours.  If not used immediately, each vial of reconstituted suspension should be 
replaced in the original carton to protect it from bright light.  Discard any unused 
portion.  Both forms should be stored in an area free of environmental extremes 
and must be accessible only to study personnel.  
 
Temperature records for nab-paclitaxel (Abraxane®) must be kept for verification 
of proper study drug storage. 
 
If storing reconstituted nab-paclitaxel (Abraxane®), some settling may occur. 
Ensure complete re-suspension by mild agitation prior to use. 
 
The suspension for infusion prepared as recommended in an infusion bag should 
be used immediately, but may be stored at ambient temperature (approximately 
25°C) and lighting conditions for up to 4 hours.   
5.2.2 Reconstitution of nab-paclitaxel 
Nab-paclitaxel will be reconstituted by appropriate study personnel and 
administered to the patient in the study site setting at weekly intervals.  The 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
28 
investigator will calculate the body surface area (BSA) of the patient in order to 
determine the total amount of nab-paclitaxel to be administered. 
 
Reconstitution and use of nab-paclitaxel: 
1. Calculate the patient’s body surface area at the beginning of the study and 
if the weight changes by >10%.  
2. Calculate the total dose (in mg) to be administered by:  
Total Dose (mg) = BSA x (study dose mg/m2) 
3. Calculate the total number of vials required by: 
Total Number of Vials =  
Total Dose (mg) 
 
 
 
 
100 mg/vial 
 
Round up the number of vials to be reconstituted to the next higher whole 
number when a fractional number of vials is obtained by the above 
formula (e.g., if the total number of vials = 4.05 or 4.5, then 5 vials would 
be reconstituted).  
4. Using sterile technique, prepare the vials for reconstitution. 
5. Swab the rubber stoppers with alcohol. 
6. Reconstitute each nab-paclitaxel (Abraxane®) vial by injecting 20 mL of 
0.9% Sodium Chloride Injection, USP or equivalent into each vial over a 
period of not less than 1 minute (Note: change the syringes after 
reconstituting every 3 vials).  
 Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, 
over a minimum of 1 minute, using the sterile syringe directing 
the solution flow onto the inside wall of the vial. 
 DO NOT INJECT the 0.9% Sodium Chloride Injection, USP 
solution directly onto the lyophilized cake as this will result in 
foaming. 
 Once the injection is complete, allow the vial to sit for a minimum 
of 5 minutes to ensure proper wetting of the lyophilized 
cake/powder.   
 Gently swirl and/or invert the vial slowly for at least 2 minutes 
until complete dissolution of any cake/powder occurs.  Avoid 
generation of foam. Rapid agitation or shaking will result in 
foaming. 
 If foaming or clumping occurs, stand solution for at least 15 
minutes until foam subsides. 
 Each mL of reconstituted product will contain 5 mg of paclitaxel. 
7. Calculate the exact total dosing volume of 5 mg/mL suspension required 
for the patient:  Dosing volume (mL) = total dose (mg)/5 (mg/mL) 
8. The reconstituted sample should be milky and homogeneous without 
visible particulates.  If particulates or settling are visible, the vial should 
be gently inverted again to ensure complete resuspension, prior to use. 
Discard the reconstituted suspension if precipitates are observed.  


LCCC 1516 
 
CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
29 
9. Once the exact volume of reconstituted Abraxane® has been withdrawn 
from the vials, discard any excess solution left over in accordance with 
standard operating procedures. 
10. Further dilution is not necessary. Inject the calculated dosing volume of 
reconstituted Abraxane® suspension into an empty sterile, standard PVC 
IV bag using an injection port.  Inject perpendicularly into the center of 
the injection port to avoid dislodging plastic material into the IV bag. 
11. Administer the calculated dosing volume of reconstituted Abraxane® 
suspension by IV infusion over 30 minutes.  The use of in-line filters is 
not recommended because the reconstituted solution may clog the filter. 
12. Following administration, the intravenous line should be flushed with 
Sodium Chloride 0.9% solution for injection to ensure administration of 
the complete dose, according to local practices. 
5.2.3 Dose and Schedule of nab-paclitaxel 
See Schema. 
5.2.4 Administration 
Nab-paclitaxel will be infused intravenously over 30 minutes. Actual body weight 
will be used for the calculation.   
 
NOTE: It is not a requirement to use filter needles in the preparation of, or in-line 
filters during the administration of nab-paclitaxel. In any event, filters of pore-size 
less than 15 micrometers must not be used. 
5.2.5 Receipt and Return of nab-paclitaxel 
Upon receipt of the study drug supplies from Celgene Corporation  
Celgene Corporation 
86 Morris Avenue 
Summit, NJ  07901 
 
The investigator or designee will conduct an inventory and sign both copies of the 
study drug receipt form and forward one copy to the address indicated on the 
form. One copy of the receipt and the packing slip must be retained in the 
investigational drug services (IDS) records. 
 
No supplies will be shipped to any site until regulatory approval has been 
obtained.  Investigational sites will be supplied with Abraxane® upon 
identification and screening of a potential trial subject. Upon identification of a 
potential subject, sites must fax a completed Drug Request Form to Celgene 
Corporation.  Allow at least 5 working days for drug shipment.  There are no 
shipments on Fridays or holidays. For re-supply of drug, please complete and fax 
the Drug Request Form to Celgene Corporation at 908-673-2779. 
 
If the investigational site does not have a policy, procedure or SOP detailing the 
process to follow for study drug destruction, the study drug must then be returned 


LCCC 1516 
 
CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
30 
to Celgene using the Drug Return Form provided in the package containing the 
study drug. The following information must be recorded on the site’s pharmacy 
drug accountability log: quantity of vials to be returned, expiration date and lot 
number. A copy of the Drug Return Form and the study drug should be returned 
to Celgene Clinical Supplies Dept. using the mailing address on the packaging 
slip that came with the original study drug order. A copy of the Drug Return Form 
should be retained at the clinical site. In the event of study completion or 
termination, a copy of all pharmacy records (drug dispensing log, drug 
accountability log and any destruction memos) must be mailed to Celgene 
Medical Operations. 
 
If the investigational site has a policy, procedure or SOP detailing the process to 
follow for study drug destruction, the pharmacist or designee can choose to 
destroy the study drug on site. The following information must be recorded on the 
site’s pharmacy drug accountability log: quantity of vials destroyed, expiration 
date and lot number. The pharmacist must document that the study drug was 
destroyed in accordance with their institution’s drug destruction policy or SOP. A 
drug destruction memo and the site’s drug destruction SOP/policy should be sent 
to Celgene Medical Operations Dept. A copy of the drug destruction memo 
should be retained at the clinical site. In the event of study completion or 
termination, a copy of all pharmacy records (drug dispensing log, drug 
accountability log and any destruction memos) must be mailed to Celgene 
Medical Operations. 
5.2.6 Clinical Safety Summary 
See prescribing information for information on nab-paclitaxel when used 
according to its FDA indication in the treatment of metastatic breast cancer and 
dosed every 3 weeks or when used in NSCLC dosed days 1, 8 and 15 of every 21 
day cycle in combination with carboplatin on day 1: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda  
 
When used in combination with carboplatin in NSCLC, the most common 
reactions (≥10%) included anemia (98%), neutropenia (85%), thrombocytopenia 
(68%), alopecia (56%), peripheral neuropathy (48%), nausea (27%), fatigue 
(25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea 
(15%), vomiting (12%), dyspnea (12%), peripheral edema (10%), arthralgia 
(13%), rash (10%), and myalgia (10%). 
 
When administered weekly as a single agent at 100mg/m2 in 65 patients with 
locally advanced breast cancer for 12 doses, no grade 4 nab-paclitaxel adverse 
events were reported.  The most common (% of patients) nab-paclitaxel-related 
adverse events included neutropenia (grade 2: 6%, grade 3: 3%), febrile 
neutropenia (grade 3: 2%), fatigue (grade 2: 26%, grade 3:6%) neuropathy (grade 
2: 11%, grade 3: 5%), nausea (grade 2: 10%), vomiting (grade 2: 8% , grade 3: 
2%), and diarrhea (grade 2: 9%, grade 3: 5%). Dose reductions or omissions were 
required in 14 (2%) of doses [31].   


LCCC 1516 
 
CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
31 
 
The following adverse events are associated with nab-paclitaxel when studied in 
metastatic breast cancer: 
 
Hematologic:  Myelosuppression, primarily neutropenia, is dose dependent and 
reversible, but dose limiting.  Thrombocytopenia is uncommon, while anemia 
occurred in 33% (severe in <1%) of patients in the randomized trial.     
 
Infections:  Infectious episodes were reported in 24% of patients in the 
randomized phase III trial in metastatic breast cancer.   
 
Hypersensitivity: Hypersensitivity reactions (Grade 1 or 2) occurred on the day of 
nab-paclitaxel administration in the randomized phase III trial in metastatic breast 
cancer and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and 
arrhythmias (all <1%).   
 
Cardiovascular:  Hypotension occurred in 5% and bradycardia (during the 
infusion) in <1% of patients in the randomized Phase III trial.  Severe 
cardiovascular events possibly related to nab-paclitaxel occurred in approximately 
3%, and included cardiac ischemia/infarction, chest pain, cardiac arrest, 
supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, 
pulmonary emboli, and hypertension.  Strokes and TIAs have been reported. 
 
ECG abnormalities: occurred in 35% of patients who had a normal ECG at 
baseline in the randomized Phase III trial in metastatic breast cancer. 
 
Respiratory:  Following treatment with nab-paclitaxel, dyspnea (12%), cough 
(7%) and pneumothorax (<1%) were reported in the randomized Phase III trial in 
metastatic breast cancer.   
 
Neurologic: Sensory neuropathy occurs frequently with nab-paclitaxel (71% in 
the randomized clinical trial, 10% severe).  It is dose-dependent, and increases 
with cumulative dose.   
 
Vision:  Ocular/visual disturbances occurred in 13%; 1% were severe and 
included keratitis and blurred vision.   
 
Arthralgia/Myalgia:  Symptoms occurred in 44% of patients in the randomized 
clinical trial (8% of patients experienced severe symptoms). 
 
Hepatic:  Exposure and toxicity of paclitaxel can be increased with hepatic 
impairment.  Grade 3 or 4 elevations in GGT occurred in 14% of patients in the 
randomized Phase III trial. 
 
Renal:  Elevated serum creatinine occurred in 11% (1% severe) of patients in the 
randomized Phase III trial. 


LCCC 1516 
 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
32 
 
General Toxicity Information 
 
Drug Interactions: No drug interactions studies have been conducted with nab-
paclitaxel, a drug metabolized by CYP2C8 and CYP3A4.  Caution should be used 
when administering nab-paclitaxel with medications known to inhibit or induce 
either CYP2C8 or CYP3A4.   
 
Injection site reactions: These reactions occur infrequently with nab-paclitaxel 
and were mild in the randomized clinical trial.  
 
Use in patients with hepatic impairment: The starting dose of nab-paclitaxel 
should be reduced for patients with moderate and severe hepatic impairment.   
 
Use in pregnancy: Nab-paclitaxel is pregnancy category D.   Men should also be 
advised not to father a child while receiving treatment with nab-paclitaxel.   
 
Albumin: Nab-paclitaxel contains human albumin, and thus carries an extremely 
remote risk for transmission of viral diseases, and Creutzfeldt-Jakob Disease.   
 
Other potential risks associated with nab-paclitaxel include mucositis, 
bilirubin/liver enzyme elevations, edema, alopecia, asthenia, nail changes, 
dehydration and pyrexia.  
 
See the nab-paclitaxel prescribing information and investigator’s brochure for 
additional information on post-marketing toxicities reported with nab-paclitaxel.   
5.2.7 Overdose of Nab-paclitaxel 
Overdose, as defined for this protocol section 5.2.7, refers to nab-paclitaxel 
dosing only.   
 
On a per dose basis, an overdose is defined as the following amount over the 
protocol-specified dose of nab-paclitaxel assigned to a given patient, regardless of 
any associated adverse events or sequelae. 
 
PO 
any amount over the protocol-specified dose 
 
IV 
10% over the protocol-specified dose  
 
 
SC 
10% over the protocol-specified dose 
 
On a schedule or frequency basis, an overdose is defined as anything more 
frequent than the protocol required schedule or frequency.   
 
On an infusion rate basis, an overdose is defined as any rate faster than the 
protocol-specified rate.  For nab-paclitaxel, an infusion completed in less than 25 


LCCC 1516 
 
CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
33 
minutes may increase Cmax by approximately 20%, therefore a nab-paclitaxel 
infusion completed in less than 25 minutes will meet the infusion rate criterion for 
an overdose. 
 
Complete data about drug administration, including any overdose, regardless of 
whether the overdose was accidental or intentional, should be reported on the 
eCRF and to Celgene Global Drug Safety and Risk Management (FAX 908-673-
9115; see section 7.3.3). 


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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
34 
6.0 
EVALUATIONS AND ASSESSMENTS  
6.1 
Time and Events Table ARM A: Sequential therapy: Pembrolizumab then Nab-paclitaxel 
 
 
Consolidation One: 
Pembrolizumab 
3 weeks post D1 of cycle 4, begin Consolidation Two4   
Consolidation Two: Nab-
paclitaxel 
 
 
Procedure 
Screenin
g1 
D1 of 3 week cycle ( x4)3 
Within every 3 week cycle 
(x4)3 
End of Treatment5 
Follow-
up6 
C12 
C2 
C3 
C4 
D1 
D8 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History7 
X 
X 
X 
X 
X 
X 
 
X 
 
Physical Exam (PE) 
X 
X 
X 
X 
X 
X 
 
X 
X6 
Charleson Co-morbidity 
Index 
X 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
 
X 
 
CBC w/differential  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistries8 
X 
X 
X 
X 
X 
X 
 
X 
X 
Liver function tests9 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pregnancy Testing10 
X10 
 
 
 
 
 
 
 
 
Coagulation, urinalysis11 
X11 
 
 
X11 
 
X11, 12 
 
 
 
Thyroid panel13 
X13 
 
 
X13 
 
X12, 13 
 
 
 
Uric Acid 
X 
X 
X 
X 
X 
X12 
 
 
 
Tumor Imaging14 
X 
 
 
X 
 
X 14 
 
X 
X6 
Toxicity assessment 
 
X 
X 
X 
X 
X 
X15 
X 
 
Respiratory 
signs/symptoms16 
X 
X 
X 
X 
X 
 
 
 
 
Pembrolizumab 
 
X 
X 
X 
X 
 
 
 
 
Nab-paclitaxel 
 
 
 
 
 
X 
X 
 
 
Concomitant Med Rev  
X 
X 
X 
X 
X 
X 
 
 
 
Survival assessment 
 
 
 
 
 
 
 
 
X 
PRO-CTCAE17 
 
X 
 
X 
 
X17 
 
X 
X17 
Quality of Life17 
 
X 
 
X 
 
X17  
 
X 
X17 
Blood/Serum samples 
 
X1
8 
X18 
X18 
X87 
X18 
 
X18 
X18 
Archival Tissue 
X19 
 
 
 
 
 
 
 
 
Research Biopsies4 
 
 
 
 
 
 
 
 
 


LCCC 1516 
 
CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
35 
Key to Time and Events Table Footnotes 
 
1Unless otherwise noted, screening evaluations to take place within 2 weeks of day 1 of study treatment.  
Archival tissue must be made available. 
 
2Laboratory evaluations on day 1 of cycle 1 need be repeated only if >7 days have elapsed between 
screening laboratory tests and day 1.  
 
3A window of +/- 3 days will apply to each cycle.    
   
4Patients may begin nab-paclitaxel earlier if they experience progression during initial consolidation with 
pembrolizumab. NOTE: post-pembrolizumab, an optional tumor biopsy will be requested in up to 12 
patients in ARM A only.  See section 6.11.2 and the laboratory manual for additional details. 
 
5The end of treatment visit should only occur when patients permanently stop study treatment and should 
be performed 30 days (+/-7 days) after the last dose of treatment. All adverse events and concomitant 
medications should be followed up until the 30-day End of Treatment (EOT) visit. Patients who have an 
ongoing ≥grade 2 or serious AE (SAE) at the EOT will continue to be followed until the event is resolved 
or deemed irreversible by the investigator. Repeat tumor imaging at this visit required. 
 
6Long-term follow-up visits will take place per standard of care every 2 (preferred) to 3 months (depending 
on insurance coverage) for 24 months and will include radiographic tumor evaluation.   After 24 months, 
patient will be followed-up per standard of care (SOC), with documentation in the eCRF limited to 
progression and survival noted at their SOC MD visits for up to 5 years. 
 
7 Complete history at baseline only (including smoking history), thereafter focused history on 
symptoms/toxicity; PE to include height at baseline only; medical history at baseline should include 
information on molecular status of tumor if known.  See section 6.4 for additional information. 
 
8 Serum chemistries and electrolytes to include sodium, potassium, chloride, bicarbonate, BUN, serum 
creatinine, glucose, calcium, magnesium, albumin 
 
9Liver function tests (LFTs) include total bilirubin, alkaline phosphatase, AST, ALT  
 
10Serum or urineβ-HCG to be done within 72 hours of day 1 of treatment in women of childbearing 
potential; if a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required. 
 
11Coagulation includes PT/INR and PTT; urinalysis (UA) includes blood, glucose, protein, specific gravity, 
and microscopic exam if abnormal results are noted 
 
12C1D1 of nab-paclitaxel therapy only, however, if clinically indicated, (including if they are previously 
abnormal), testing, should be repeated C3D1 
 
13Thyroid panel includes TSH, T3 and free T4.  If consistent with institutional standard of care, it is 
acceptable to obtain TSH alone and only obtain T3 and free T4 if clinically useful. 
 
14CT scan of chest (if PET/CT scan done, use of CT portion of imaging for tumor evaluation acceptable as 
long as it is of diagnostic quality); screening radiologic evaluation may take place within 4 weeks of 
treatment initiation and modality should remain consistent throughout the trial (note that initial imaging 
with PET/CT and subsequent comparison of CT to the CT portion of the original is allowed, as long as the 
CT component of the original PET/CT is of diagnostic quality).  MRI of brain should be performed at 
screening only to evaluate for the presence of brain metastases (which will exclude study participation). If 
patient in unable to tolerate MRI or has contraindication to MRI a head CT scan with and without contrast 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
36 
is acceptable. During consolidation two, repeat imaging on D1 of cycles 1 and 3.  Imaging may be done up 
to 7 days prior to day of treatment. 
 
15Cycle 1 D8 of consolidation two will also serve as the 30 day post end of pembrolizumab safety check. 
Serious adverse events (SAEs) or any grade of Events of Clinical Interest (see sections Error! Reference 
source not found. and 7.3 and the ECI Guidance Document that is provided as a document separate from 
this protocol) that occur within 90 days post pembrolizumab must be recorded. Toxicity assessment is not 
required on D8 of C2-4. 
 
16Perform baseline assessment and check for history of pneumonitis, monitor for respiratory 
signs/symptoms while patients are on pembrolizumab and manage toxicity for pneumonitis as outlined in 
section Error! Reference source not found.. 
a) If applicable: ongoing patients are to be evaluated for active pneumonitis. Patients with a 
history of pneumonitis should be re-consented for this trial to consider if they should 
discontinue pembrolizumab or continue treatment based on the risk of fatal pneumonitis 
related to pembrolizumab therapy. 
 
17See section 6.10 for assessment tools; PRO-CTCAE and quality of life to be obtained on odd –numbered 
cycles only (1, 3) of both consolidations), end of treatment, and at first follow-up visit only 
 
18See section 6.11 and laboratory manual for additional information on correlatives; on D1 of each cycle  of 
each consolidation regimen (including consolidation two), at the end of treatment visit, and at the second 
follow-up visit, collect 8.5 mLs of blood  into each of 3 ACD (acid citrate dextrose = yellow top) tubes + 5 
mLs of blood into SST tube for serum collection (See section 6.5.1). 
 
19Archival tissue, if available, may be obtained at any point during conduct of the study. 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
37 
6.2 
Time and Events ARM B: Sequential therapy: Nab-paclitaxel then Pembrolizumab 
 
 
Consolidation One:  
Nab-paclitaxel 
3 weeks post D1 of cycle 4, begin Consolidation Two4 
Consolidation Two: 
Pembrolizumab 
 
 
Procedure 
Screening
1 
Within every 3 week cycle (x4)3 
D1 of 3 week cycle ( x4)3 
End of Treatment5 
Follow-
up6 
D12 
D8 
C1 
C2 
C3 
C4 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History7 
X 
X 
 
X 
X 
X 
X 
X 
 
Physical Exam (PE) 
X 
X 
 
X 
X 
X 
X 
X 
X6 
Charleson Co-morbidity 
Index 
X 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
X 
X 
X 
X 
X 
 
CBC w/differential  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistries8 
X 
X 
 
X 
X 
X 
X 
X 
X 
Liver function tests9 
X 
X 
 
X 
X 
X 
X 
X 
X 
Pregnancy Testing10 
X10 
 
 
 
 
 
 
 
 
Coagulation, urinalysis11 
X11 
 
 
X11 
 
X11 
 
 
 
Thyroid panel12 
X12 
 
 
X12 
 
X12 
 
X12 
 
Uric Acid 
X 
 
 
X 
X 
X 
X 
 
 
Tumor Imaging13 
X 
X18 
 
X 
 
X 
 
X 
X6 
Toxicity assessment 
 
X 
 
X 
X 
X 
X 
X5 
X14 
Respiratory 
signs/symptoms19 
X 
 
 
X 
X 
X 
X 
X 
 
Pembrolizumab 
 
 
 
X 
X 
X 
X 
 
 
Nab-paclitaxel 
 
X 
X 
 
 
 
 
 
 
Concomitant Med Rev  
X 
X 
 
X 
X 
X 
X 
 
 
Survival assessment 
 
 
 
 
 
 
 
 
X 
PRO-CTCAE15 
 
X15 
 
X 
 
X 
 
X 
X15 
Quality of Life15 
 
X15 
 
X15 
 
X15 
 
X15 
X15 
Blood/Serum samples 
 
X16 
 
X16 
X1
6 
X16 
X1
6 
X16 
X16 
Archival Tissue 
X17 
 
 
 
 
 
 
 
 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
38 
Key to Time and Events Table Footnotes 
 
1Unless otherwise noted, screening evaluations to take place within 2 weeks of day 1 of study treatment.  
Archival tissue must be made available to confirm eligibility 
 
2Laboratory evaluations on day 1 of cycle 1 need be repeated only if >7 days have elapsed between 
screening laboratory tests and day 1.  
 
3A window of +/- 3 days will apply to each cycle.    
   
4Patients may begin pembrolizumab earlier if they experience progression during initial consolidation with 
nab-paclitaxel. 
 
5The end of treatment visit should only occur when patients permanently stop study treatment and should 
be performed 30 days (+/-7 days) after the last dose of treatment. All adverse events and concomitant 
medications should be followed up until the 30-day End of Treatment (EOT) visit. Patients who have an 
ongoing ≥grade 2 or serious AE (SAE) at the EOT will continue to be followed until the event is resolved 
or deemed irreversible by the investigator. Repeat tumor imaging at this visit required. 
 
6Long-term follow-up visits will take place per standard of care every 2 (preferred) to 3 months (depending 
on insurance coverage) for 24 months and will include radiographic tumor evaluation. After 24 months, 
patient will be followed-up per standard of care (SOC), with documentation in the eCRF limited to 
progression and survival noted at their SOC MD visits for up to 5 years.   
 
7 Complete history at baseline only (including smoking history), thereafter focused history on 
symptoms/toxicity; PE to include height at baseline only; medical history at baseline should include 
information on molecular status of tumor if known.  See section 6.4 for additional information. 
 
8 Serum chemistries and electrolytes to include sodium, potassium, chloride, bicarbonate, BUN, serum 
creatinine, glucose, calcium, magnesium, albumin 
 
9Liver function tests (LFTs) include total bilirubin, alkaline phosphatase, AST, ALT  
 
10Serum or urine β-HCG to be done within 72 hours of day 1 of treatment in women of childbearing 
potential. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required. 
 
11Coagulation includes PT/INR and PTT; urinalysis (UA) includes blood, glucose, protein, specific gravity, 
and microscopic exam if abnormal results are noted 
 
12Thyroid panel includes TSH, T3 and free T4.  If consistent with institutional standard of care, it is 
acceptable to obtain TSH alone and only obtain T3 and free T4 if clinically useful. 
 
13CT scan of chest (if PET/CT scan done, use of CT portion of imaging for tumor evaluation acceptable as 
long as the CT is of diagnostic quality); screening radiologic evaluation may take place within 4 weeks of 
treatment initiation and modality should remain consistent throughout the trial (note that initial imaging 
with PET/CT and subsequent comparison of CT to the CT portion of the original is allowed as long as the 
CT component of the original PET/CT is of diagnostic quality).  MRI of brain should be performed at 
screening only to evaluate for the presence of brain metastases (which will exclude study participation). If 
patient in unable to tolerate MRI or has contraindication to MRI a head CT scan with and without contrast 
is acceptable. During consolidation one, repeat imaging on D1 of cycle 3 only. Imaging may be done up to 
7 days prior to day of treatment. 
 
14Serious adverse events (SAEs) or any grade of Events of Clinical Interest (see sectionsError! Reference 
source not found. and 7.3 and the ECI Guidance Document that is provided as a document separate from 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
39 
this protocol) occur within 90 days of the end of pembrolizumab (or prior to start of new anti-cancer 
therapy) must be recorded.  NOTE: This 90 day follow-up for safety does not necessarily require an on-site 
visit. 
 
15See section 6.10 for tools.  PRO-CTCAE and quality of life to be obtained on odd –numbered cycles only 
(1, 3 of both consolidations), end of treatment, and at first-follow-up visit only 
 
16See section See section 6.11 and laboratory manual for additional information on correlatives; on D1 of 
cycle 1 of each consolidation regimen (including consolidation two), at the end of treatment visit, and at the 
second follow-up visit, collect 8.5 mLs of blood into each of 3 ACD (acid citrate dextrose = yellow top) 
tubes + 5 mLs of blood into SST tube for serum collection for biocorrelative studies. 
 
17Archival tissue, if available, may be obtained at any point during conduct of the study 
 
18Prior to cycle 3 only. 
 
19Perform baseline assessment and check for history of pneumonitis, monitor for respiratory 
signs/symptoms while patients are on pembrolizumab and manage toxicity for pneumonitis as outlined in 
section Error! Reference source not found.. 
a) If applicable: ongoing patients are to be evaluated for active pneumonitis. Patients with a 
history of pneumonitis should be re-consented for this trial to consider if they should 
discontinue pembrolizumab or continue treatment based on the risk of fatal pneumonitis 
related to pembrolizumab therapy. 
 
 
 
 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
40 
6.3 
Time and Events ARM C: Concurrent Therapy: Pembrolizumab and Nab-paclitaxel 
Procedure 
Screening1 
C1D1 2,3 
C1D8
3 
C2D13 
C2D83 
C3D13 
C3D83 
C4D13 
C4D83 
End of 
Treatment4 
Follow-
up5 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History6 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Physical Exam (PE) 
X 
X 
 
X 
 
X 
 
X 
 
X 
X5 
Charleson Co-morbidity 
Index 
X 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
CBC w/differential  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistries7 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Liver function tests8 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Pregnancy Testing9 
X9 
 
 
 
 
 
 
 
 
 
 
Coagulation, urinalysis10 
X10 
 
 
 
 
X10 
 
 
 
 
 
Thyroid panel11 
X11 
 
 
 
 
X11 
 
 
 
X11 
 
Uric Acid 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Tumor Imaging12 
X 
 
 
 
 
X 
 
 
 
X 
X5 
Toxicity assessment 
 
X 
 
X 
 
X 
 
X 
 
X4 
X13 
Respiratory 
signs/symptoms14 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Pembrolizumab 
 
X 
 
X 
 
X 
 
X 
 
 
 
Nab-paclitaxel 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Med Rev  
X 
X 
 
X 
 
X 
 
X 
 
 
 
Survival assessment 
 
 
 
 
 
 
 
 
 
 
X 
PRO-CTCAE15 
 
X 
 
 
 
X 
 
 
 
X 
X18 
Quality of Life15 
 
X 
 
 
 
X 
 
 
 
X 
X18 
Blood/Serum samples16 
 
X 
 
X 
 
X 
 
X 
 
X 
X16 
Archival Tissue 
X17 
 
 
 
 
 
 
 
 
 
 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
41 
Key to Time and Events Table Footnotes 
 
1Unless otherwise noted, screening evaluations to take place within 2 weeks of day 1 of study treatment.  
Archival tissue must be made available to confirm eligibility 
 
2Laboratory evaluations on day 1 of cycle 1 need be repeated only if >7 days have elapsed between 
screening laboratory tests and day 1.  
 
3A window of +/- 3 days will apply to each cycle.    
   
4The end of treatment visit should only occur when patients permanently stop study treatment and should 
be performed 30 days (+/-7 days) after the last dose of treatment.  All adverse events and concomitant 
medications should be followed up until the 30-day End of Treatment (EOT) visit. Patients who have an 
ongoing ≥grade 2 or serious AE (SAE) at the EOT will continue to be followed until the event is resolved 
or deemed irreversible by the investigator. Repeat tumor imaging at this visit required. 
 
5Long-term follow-up visits will take place per standard of care every 2 (preferred) to 3 months (depending 
on insurance coverage) for 24 months and will include radiographic tumor evaluation.  After 24 months, 
patient will be followed-up per standard of care (SOC), with documentation in the eCRF limited to 
progression and survival noted at their SOC MD visits for up to 5 years. 
 
6 Complete history at baseline only (including smoking history), thereafter focused history on 
symptoms/toxicity; PE to include height at baseline only; medical history at baseline should include 
information on molecular status of tumor if known.  See section 6.4 for additional information. 
 
7 Serum chemistries and electrolytes to include sodium, potassium, chloride, bicarbonate, BUN, serum 
creatinine, glucose, calcium, magnesium, albumin 
 
8Liver function tests (LFTs) include total bilirubin, alkaline phosphatase, AST, ALT  
 
9Serum or urine β-HCG to be done within 72 hours of day 1 of treatment in women of childbearing 
potential; If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required. 
 
10Coagulation includes PT/INR and PTT; urinalysis (UA) includes blood, glucose, protein, specific gravity, 
and microscopic exam if abnormal results are noted 
 
11Thyroid panel includes TSH, T3 and free T4.  If consistent with institutional standard of care, it is 
acceptable to obtain TSH alone and only obtain T3 and free T4 if clinically useful. 
 
12CT scan of chest (if PET/CT scan done, use of CT portion of imaging for tumor evaluation acceptable as 
long as the CT is of diagnostic quality); screening radiologic evaluation may take place within 4 weeks of 
treatment initiation and modality should remain consistent throughout the trial (note that initial imaging 
with PET/CT and subsequent comparison of CT to the CT portion of the original is allowed as long as the 
CT component of the original PET/CT is of diagnostic quality).  MRI of brain should be performed at 
screening only to evaluate for the presence of brain metastases (which will exclude study participation). If 
patient in unable to tolerate MRI or has contraindication to MRI a head CT scan with and without contrast 
is acceptable. Imaging may be done up to 7 days prior to day of treatment if scheduled for a day treatment 
is due. 
 
13Serious adverse events (SAEs) or any grade of Events of Clinical Interest (see sections Error! Reference 
source not found. and 7.3 and the ECI Guidance Document that is provided as a document separate from 
this protocol) occur within 90 days of the end of pembrolizumab (or prior to start of new anti-cancer 
therapy) must be recorded.  NOTE: This 90 day follow-up for safety does not necessarily require an on-site 
visit. 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
42 
 
14Perform baseline assessment and check for history of pneumonitis, monitor for respiratory 
signs/symptoms while patients are on pembrolizumab and manage toxicity for pneumonitis as outlined in 
section Error! Reference source not found.. 
a) If applicable: ongoing patients are to be evaluated for active pneumonitis. Patients with a 
history of pneumonitis should be re-consented for this trial to consider if they should 
discontinue pembrolizumab or continue treatment based on the risk of fatal pneumonitis 
related to pembrolizumab therapy. 
 
15See section 6.10 for tools; PRO-CTCAE and quality of life to be obtained on odd –numbered cycles only 
(1, 3), end of treatment and at first two follow-up visits only 
 
16See section 6.11 for additional information on correlatives; on D1 of cycle 1, at the end of treatment visit, 
and at the second follow-up visit, collect 8.5 mLs of blood  into each of 3 ACD (acid citrate dextrose = 
yellow top) tubes tubes + 5 mLs of blood into SST tube for serum collection for biocorrelative studies.  
 
17Archival tissue, if available, may be obtained at any point during conduct of the study 
 
 
 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
43 
6.4 
Pre-Study Assessments in ARMS A, B and C 
Clinical evaluation:  complete medical history, physical examination to include 
height and weight, ECOG performance status (see Appendix C), and Charleston 
Comorbidity index (see Appendix B) 
Laboratory studies:   
 Pregnancy Test: A urine or serum pregnancy test (β-HCG) is 
required for all women of childbearing potential at screening within 
72 hours prior to the first dose of treatment under this protocol.  If a 
urine test is done and it is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required. 
 CBC with differential  
 Serum Chemistries: sodium, potassium, chloride, bicarbonate, 
BUN, serum creatinine (calculate creatinine clearance via Cockcroft-
Gault, see Appendix A), glucose, calcium, magnesium, albumin 
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT) 
 Uric Acid 
 Urinalysis: blood, glucose, protein, specific gravity, and microscopic 
exam if abnormal results are noted 
 Coagulation Panel: PT/INR and PTT 
 Thyroid Panel: TSH, T3 and free T4.  If consistent with institutional 
standard of care, it is acceptable to obtain TSH alone and only obtain 
T3 and free T4 if clinically useful 
Check respiratory history (signs/symptoms) 
Concomitant medications review: 
Tumor imaging: CT scan of the chest or PET-CT that covers the chest within 4 
weeks prior to treatment; MRI of the brain (if patient unable to tolerate MRI or 
has contraindication to MRI, a head CT scan with or without contrast is 
acceptable). 
Archival tissue: request access to archival tissue to support correlative studies 
(see section 6.11.1) 
Molecular status: To the extent known, molecular status will be reported.  If 
additional information on molecular status is learned subsequent to screening, it 
may be entered at a later time. When available, de-identified (to subject number) 
molecular pathology reports should be submitted as source documents 
6.5 
During Treatment ARM A 
6.5.1 Treatment Assessments: D1 of each Cycle of Consolidation One 
(Pembrolizumab); NOTE: See section 6.10 for schedule of QOL and PRO-
CTCAE assessments 
Clinical evaluation:  Focused history on symptoms/toxicity, physical examination 
to include weight, and ECOG performance status 
Laboratory studies:   
 CBC with differential  


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
44 
 Serum Chemistries: sodium, potassium, chloride, bicarbonate, 
BUN, serum creatinine (calculate creatinine clearance via Cockcroft-
Gault, see section 11.1 Appendix A), glucose, calcium, magnesium, 
albumin 
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT) 
 Uric Acid 
Check Respiratory signs/ Symptoms 
Concomitant Medications: Review any changes 
Toxicity: Assessed according to the NCI CTCAE v4.0  
Blood draws for Correlative Studies : collect 8.5 mLs of blood into each of 3 
ACD (acid citrate dextrose = yellow top) tubes + 5 mLs of blood into SST tube 
for serum collection for biocorrelative; additional information provided in 
laboratory manual.  
6.5.2 Treatment Assessments: D1 of Cycle 3 of Consolidation One 
(Pembrolizumab) 
Laboratory studies:   
 Urinalysis: blood, glucose, protein, specific gravity, and microscopic 
exam if abnormal results are noted 
 Coagulation Panel: PT/INR and PTT 
 Thyroid Panel: TSH, T3 and free T4.  If consistent with institutional 
standard of care, it is acceptable to obtain TSH alone and only obtain 
T3 and free T4 if clinically useful 
Check Respiratory signs/ Symptoms 
Tumor imaging: Remain consistent with baseline imaging; Brain MRI does NOT 
need to be repeated unless clinically indicated. 
Blood draws for Correlative Studies: collect 8.5 mLs of blood into each of 3 ACD 
(acid citrate dextrose = yellow top) tubes + 5 mLs of blood into SST tube for 
serum collection for biocorrelative; additional information provided in laboratory 
manual.  
 
6.5.3 Prior to Beginning of Consolidation Two  
Optional tumor biopsy (Applies only to subjects enrolled at UNC): to be 
performed in up to 12 patients in ARM A only. See section 6.11.2 and laboratory 
manual for additional details. 
6.5.4 Treatment Assessments: D1 of each Cycle of Consolidation Two (Nab-
paclitaxel); NOTE: See section 6.10 for schedule of QOL and PRO-CTCAE 
assessments 
Clinical evaluation:  Focused history on symptoms/toxicity, physical examination 
to include weight, and ECOG performance status 
Laboratory studies:   
 CBC with differential  


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
45 
 Serum Chemistries: sodium, potassium, chloride, bicarbonate, 
BUN, serum creatinine (calculate creatinine clearance via Cockcroft-
Gault, see Appendix A), glucose, calcium, magnesium, albumin 
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT) 
 Uric Acid:  (Cycle 1 only unless clinically indicated, if so repeat 
Cycle 3) 
 Urinalysis: blood, glucose, protein, specific gravity, and microscopic 
exam if abnormal results are noted; (Cycle 1 only unless clinically 
indicated, if so repeat Cycle 3) 
 Coagulation Panel: PT/INR and PTT; (Cycle 1 only unless 
clinically indicated, if so repeat Cycle 3) 
 Thyroid Panel: TSH, T3 and free T4.  If consistent with institutional 
standard of care, it is acceptable to obtain TSH alone and only obtain 
T3 and free T4 if clinically useful; (Cycle 1 only unless clinically 
indicated, if so repeat Cycle 3) 
Concomitant Medication: Review any changes 
Toxicity: Assessed according to the NCI CTCAE v4.0  
Blood draws for Correlative Studies: collect 8.5 mLs of blood (to fill line of 
10mL as each tube starts with 2mL acid citrate dextrose) into each of 3 ACD 
(acid citrate dextrose = yellow top) tubes + 5mLs of blood into SST tube for 
serum collection for biocorrelative studies. 
6.5.5 Treatment Assessments: D1 of Cycles 1 and 3 of Consolidation Two (Nab-
paclitaxel) 
Tumor imaging: Remain consistent with baseline imaging; Brain MRI does NOT 
need to be repeated unless clinically indicated. 
6.5.6 Treatment Assessments: D8 of each Cycle of Consolidation Two (Nab-
paclitaxel) 
Laboratory studies:   
 CBC with differential 
Toxicity (Cycle 1 D8 only; not needed Cycles 2-4): Assessed according to the 
NCI CTCAE v4.0; NOTE: Serious adverse events (SAEs) or any grade of Events 
of Clinical Interest (see section 7.3 and the ECI Guidance Document that is 
provided as a document separate from this protocol) that occur within 90 days 
post pembrolizumab must be recorded, this should correspond to approximately 
Cycle 1 D8 of Consolidation Two. 
6.6 
During Treatment ARM B 
6.6.1 Treatment Assessments: D1 of each Cycle of Consolidation One (Nab-
paclitaxel): NOTE: See section 6.10 for schedule of QOL and PRO-CTCAE 
assessments 
Clinical evaluation:  Focused history on symptoms/toxicity, physical examination 
to include weight, and ECOG performance status 


LCCC 1516 
 
CONFIDENTIAL 
PI: Jared Weiss, MD 
 
UNIVERSITY OF NORTH CAROLINA 
Amendment 4 
 
 May 23, 2018 
 
46 
Laboratory studies:   
 CBC with differential  
 Serum Chemistries: sodium, potassium, chloride, bicarbonate, 
BUN, serum creatinine (calculate creatinine clearance via Cockcroft-
Gault, see Appendix A), glucose, calcium, magnesium, albumin 
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT) 
Concomitant Medications: Review any changes 
Toxicity: Assessed according to the NCI CTCAE v4.0 
Blood draws for Correlative Studies: collect 8.5 mLs of blood into each of 3 ACD 
(acid citrate dextrose = yellow top) tubes + 5mLs of blood into SST tube for 
serum collection for biocorrelative studies. 
 
6.6.2 Treatment Assessments: D1 of Cycle 3 of Consolidation One (Nab-paclitaxel) 
Tumor imaging: Remain consistent with baseline imaging; Brain MRI does NOT 
need to be repeated unless clinically indicated. 
6.6.3 Treatment Assessments: D8 of each Cycle of Consolidation One (Nab-
paclitaxel) 
 Laboratory studies:   
 CBC with differential 
6.6.4 Treatment Assessments: D1 of each Cycle of Consolidation Two 
(Pembrolizumab); NOTE: See section 6.10 for schedule of QOL and PRO-
CTCAE assessments 
Clinical evaluation:  Focused history on symptoms/toxicity, physical examination 
to include weight, and ECOG performance status  
Laboratory studies:   
 CBC with differential  
 Serum Chemistries: sodium, potassium, chloride, bicarbonate, 
BUN, serum creatinine (calculate creatinine clearance via Cockcroft-
Gault, see Appendix A), glucose, calcium, magnesium, albumin 
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT) 
 Uric Acid 
Check Respiratory signs/ Symptoms 
Concomitant Medications: Review and changes 
Toxicity: Assessed according to the NCI CTCAE v4.0  
Blood draws for Correlative Studies: collect 8.5 mLs of blood into each of 3 ACD 
(acid citrate dextrose = yellow top) tubes + 5mLs of blood into SST tube for 
serum collection for biocorrelative studies. 
 


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6.6.5 Treatment Assessments: D1 of Cycles 1 and 3 of Consolidation Two 
(Pembrolizumab) 
Laboratory studies:   
 Urinalysis: blood, glucose, protein, specific gravity, and microscopic 
exam if abnormal results are noted 
 Coagulation Panel: PT/INR and PTT 
 Thyroid Panel: TSH, T3 and free T4.  If consistent with institutional 
standard of care, it is acceptable to obtain TSH alone and only obtain 
T3 and free T4 if clinically useful 
Check Respiratory signs/ Symptoms 
Tumor imaging: Remain consistent with baseline imaging; Brain MRI does NOT 
need to be repeated unless clinically indicated. 
6.7 
During Treatment ARM C 
6.7.1 Treatment Assessments: D1 of each Cycle of Concurrent Consolidation 
(Pembrolizumab plus Nab-paclitaxel): NOTE: See section 6.10  for schedule 
of QOL and PRO-CTCAE assessments 
Clinical evaluation:  Focused history on symptoms/toxicity, physical examination 
to include weight, and ECOG performance status 
Laboratory studies:   
 CBC with differential  
 Serum Chemistries: sodium, potassium, chloride, bicarbonate, 
BUN, serum creatinine (calculate creatinine clearance via Cockcroft-
Gault, see Appendix A), glucose, calcium, magnesium, albumin 
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT) 
 Uric Acid:   
Check Respiratory signs/ Symptoms 
Concomitant Medications: Review any changes 
Toxicity: Assessed according to the NCI CTCAE v4.0 
Blood draws for Correlative Studies: collect 8.5 mLs of blood into each of 3 ACD 
(acid citrate dextrose = yellow top) tubes + 5mLs of blood into SST tube for 
serum collection for biocorrelative studies. 
 
6.7.2 Treatment Assessments: D8 of each Cycle of Concurrent Consolidation 
(Pembrolizumab plus Nab-paclitaxel): NOTE: See section 6.10  for schedule 
of QOL and PRO-CTCAE assessments 
  
Laboratory studies:   
 CBC with differential  


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6.7.3 Treatment Assessments: D1 of Cycle 3 of Concurrent Consolidation 
(Pembrolizumab plus Nab-paclitaxel) 
Laboratory studies:   
 Urinalysis: blood, glucose, protein, specific gravity, and microscopic 
exam if abnormal results are noted 
 Coagulation Panel: PT/INR and PTT 
 Thyroid Panel: TSH, T3 and free T4.  If consistent with institutional 
standard of care, it is acceptable to obtain TSH alone and only obtain 
T3 and free T4 if clinically useful 
Check Respiratory signs/ Symptoms 
 
Tumor imaging: Remain consistent with baseline imaging; Brain MRI does NOT 
need to be repeated unless clinically indicated. 
6.8 
End of Treatment Assessments ARMS A, B and C (unless otherwise noted) 
Clinical evaluation:  Focused history on symptoms/toxicity, physical examination 
to include weight, and ECOG performance status 
Laboratory studies:   
 CBC with differential  
 Serum Chemistries: sodium, potassium, chloride, bicarbonate, 
BUN, serum creatinine (calculate creatinine clearance via Cockcroft-
Gault, see Appendix A), glucose, calcium, magnesium, albumin 
 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT) 
 Thyroid panel: (ARMS B & C) 
 Uric Acid (ARM C only) 
Check Respiratory signs/ Symptoms (ARMS B & C) 
Tumor imaging: Remain consistent with baseline imaging; Brain MRI does NOT 
need to be repeated unless clinically indicated. 
Toxicity: Assessed according to the NCI CTCAE v4.0  
Blood draws for Correlative Studies: collect 8.5 mLs of blood  into each of 3 
ACD (acid citrate dextrose = yellow top) tubes + 5mLs of blood into SST tube for 
serum collection for biocorrelative studies.  Additional information provided in 
laboratory manual 
6.9 
Long-Term Follow-up Assessments ARMS A, B and C 
Note: Long-term follow-up visits will take place per standard of care every 2 
(preferred) to 3 months (depending on insurance coverage) for 24 months and will 
include radiographic tumor evaluation.   
Clinical evaluation:  Physical Exam, ECOG performance status 
Laboratory studies:   
 CBC with differential  
 Serum Chemistries: sodium, potassium, chloride, bicarbonate, 
BUN, serum creatinine (calculate creatinine clearance via Cockcroft-
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 LFTs: These include total bilirubin (direct and indirect), alkaline 
phosphatase AST (SGOT), ALT (SGPT) 
Tumor imaging: Remain consistent with baseline imaging; Brain MRI does NOT 
need to be repeated unless clinically indicated. Long-term follow-up visits will 
take place per standard of care every 2 (preferred) to 3 months for 24 months and 
will include radiographic tumor evaluation. After 24 months, patient will be 
followed-up per standard of care (SOC), with documentation in the eCRF limited 
to progression and survival noted at their SOC MD visits for up to 5 years.   
Toxicity: Serious adverse events (SAEs) or any grade of Events of Clinical 
Interest (see section 7.3 and the ECI Guidance Document that is provided as a 
document separate from this protocol) that occur within 90 days post 
pembrolizumab must be recorded; this applies in Follow-Up to ARMs B and C 
Survival: Document survival status 
Blood draws for Correlative Studies (2nd follow-up visit only): collect 8.5 mLs of 
blood  into each of 3 ACD (acid citrate dextrose = yellow top) tubes  + 5mLs of 
blood into SST tube for serum collection for biocorrelative studies; additional 
information will provided in the study manual. 
 
6.10 
Quality of Life and PRO-CTCAE Assessments 
6.10.1 FACT-Lung: Provided as a document separate from this protocol  
To be obtained on odd –numbered cycles only (1, 3) of both consolidations in 
ARMs A and B, and in cycles 1 and 3 of ARM C, at the end of treatment visit for 
each ARM, at first follow-up visit only in ARMs A and B, and in first two follow-
up visits in ARM C.  
6.10.2 Patient Reported Outcomes version of the CTCAE:  
A subset (25-30) of items pertinent to lung cancer will be drawn from the PRO-
CTCAE system. These items will be used to evaluate the presence and/or severity 
of range of symptoms, as well as the degree to which symptom/toxicity interferes 
with usual function. This tool will be used on odd –numbered cycles only (1, 3) of 
both consolidations in ARMs A and B, and in cycles 1 and 3 of ARM C, at the 
end of treatment visit for each ARM, at first follow-up visit only in ARMs A and 
B, and in first two follow-up visits in ARM C. 
6.11 
Correlative Studies  
These are described in more detail in the laboratory manual.  
 
Handling of Biospecimens Collected for Correlative Research 
Samples will be collected and used only in accordance with the protocol. Study 
subject biological samples will not be retained or used for any research outside 
the confines set forth within this protocol and will not be retained for bio-banking. 
Study subject biological samples will be discarded/destroyed after relevant data 
are collected for this study. 


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6.11.1 Archival Tissue for ARMS A-C 
Archival tumor tissue form the patient’s original diagnostic biopsy will be 
requested and collected from all enrolled patients.  See accompanying laboratory 
manual for additional details. 
6.11.2 Research Biopsies for ARM A  
Twelve patients who demonstrate regression of disease (tumor shrinkage > 30%) 
after 3 months of pembrolizumab monotherapy and consent to optional biopsy 
(only applies to subjects enrolled at UNC) will undergo repeat biopsy for further 
analysis of biocorrelatives; see laboratory manual for additional details. 
 
Three (3) twenty-gauge core biopsies and 3 fine needle aspirates (FNA) will be 
the goal.  Ultimately, the ratio of FNA/core biopsies will be up to the discretion of 
the physician performing the procedure, with primary consideration being safety.    
Additional details regarding processing, storing and handling tissue will be 
provided in a separate laboratory manual.   
  
Biological samples collected for the study will be stored at the research 
laboratories at the Lineberger Comprehensive Cancer Center (LCCC), University 
of North Carolina at Chapel Hill, NC until the completion of the study.  With 
patient consent, any remaining tumor tissue after protocol specific studies are 
complete will be stored for future research concerning lung cancer. 
 
Risks associated with lung FNAs and biopsies include the following: 
 Likely: local discomfort and minor bleeding 
 Less likely: pneumothorax, hemothorax, intraparenchymal hemorrhage, 
hemoptysis, bronchopleural fistula, air embolism, and vascular injury 
 
Prior to the procedure, the physician performing the procedure will discuss the 
risks with each study participant and answer any questions.  Patients receiving 
therapeutic anticoagulation, with abnormal coagulation studies, or 
thrombocytopenia (defined as platelet count <50,000) will not undergo biopsy 
until and unless these resolve because of the increased risk of potential 
complications under these circumstances.  After lung biopsies, patients will be 
observed for approximately 4 hours (range 4-6 hours) after the procedure, or per 
institutional standard guidelines.  Less than the goal quantity of tissue is 
acceptable for each type of biopsy, and will be left to the clinical judgment of the 
physician performing the procedure.  
 
6.11.3 Serial Blood Samples for ARMS A-C 
On D1 of cycle 1 of each consolidation regimen (including consolidation two) for 
ARMS A and B, and on D1 of cycle 1 of ARM C, at the end of treatment visit for 
ARMS A-C, and at the second follow-up visit for ARMS A-C, collect 8.5 mLs of 
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each of 3 ACD (acid citrate dextrose = yellow top) tubes + 5 mLs of blood into 
SST tube for serum collection for biocorrelative studies.  Additional details can be 
found in the laboratory manual. 
6.12 
Assessment of Safety 
Any patient who receives treatment on this protocol will be evaluable for toxicity.  
Each patient will be assessed periodically for the development of any toxicity 
according to the Time and Events table (section 6.0).  Toxicity will be assessed 
according to the NCI CTCAE v4. Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to 
trial treatment. 
 
For subjects receiving treatment with pembrolizumab all AEs of unknown 
etiology associated with pembrolizumab exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially 
immunologic etiology (termed immune-related adverse events, or irAEs); see the 
separate ECI guidance document (provided as a document separate from this 
protocol) regarding the identification, evaluation and management of potential 
irAEs.   
 
Please refer to section 7.2  detailed information regarding the assessment and 
recording of AEs.   
6.13 
Assessment of Efficacy 
Patients who have received at least 1 dose of nab-paclitaxel or pembrolizumab 
will be evaluable for assessment of response and progression.   Patients whose 
cancer growth is documented by physical examination without imaging 
confirmation will count as progression.   
6.13.1 Assessment of Disease-Tumor Measurement Based on RECIST 1.1 
  Measurable disease will be defined as the presence of at least one measurable 
lesion that can be accurately measured in at least one dimension with the longest 
diameter a minimum size of: 
 >10mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-
measurable). 
 20 mm by chest x-ray. 
 
For malignant lymph nodes to be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5mm).  At 
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All other lesions, including small lesions (longest diameter <10mm or 
pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-
measurable lesions, will be considered non-measurable.  Lesions considered truly 
non-measurable include:leptomeningeal disease; ascites; pleural/pericardial 
effusion; inflammatory breast disease; lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed. All baseline evaluations should be performed as close as 
possible to the treatment start and never more than 4 weeks before the beginning 
of the treatment.  The same method of assessment and the same technique should 
be used to characterize each identified and reported lesion at baseline and during 
follow-up.  Imaging based evaluation should always be done rather than clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam.  Clinical lesions will only be considered measurable 
when they are superficial and ≥10 mm diameter as assessed using calipers (e.g. 
skin nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesions is recommended. 
 
Baseline Documentation of Target and Non-Target Lesions  
All measurable lesions up to a maximum of 5 lesions total (and a maximum of 
two lesions per organ) representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline.   
 
Target lesions should be selected on the basis of their size (lesions with the longer 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  
 
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, only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to 
further characterize the objective tumor response of the measurable dimension of 
the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should 
be identified as non-target lesions and should also be recorded at baseline. In 
subsequent assessments, non-index lesions will be recorded as “stable or 
decreased disease,” “absent,” or “progression.” 
 
Evaluation of Target Lesions using RECIST 1.1 Criteria 
Complete response (CR)−Disappearance of all target lesions.  Any pathological 
lymph node (LN) (whether target or non-target) must have decreased in short axis 
to <10mm. 
 


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Partial response (PR)−At least a 30% decrease in the sum of the LD of the target 
lesions taking as reference the baseline sum LD. 
 
Progressive Disease (PD)−At least a 20% increase in the sum of the LD of the 
target lesions taking as reference the smallest sum LD recorded since the 
treatment started including baseline 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 5mm.  The appearance of one or more new lesions also constitutes PD. 
 
Stable disease (SD)−Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum LD since the 
treatment started. 
 
Nonprogressive disease: Measurable disease is not required for this study.  
Patients with CR at the time of study entry or otherwise nonmeasurable disease 
will be assessed for progression.  In the event of PD, this should be noted.  In the 
absence of meeting criteria for progression, nonprogressive disease should be 
coded (NPD). 
 
Evaluation of Non-Target Lesions using RECIST 1.1 Criteria 
Complete response (CR)−Disappearance of all non-target.  All LN must be non-
pathological in size (<10mm short axis).   
 
Non-complete response (non-CR)/non-progression (non-PD)−Persistence of one 
or more non-target lesion(s) or/and 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. 
6.13.2 irRC for this study (Adapted from [32, 33]   
New measurable lesions in irRC:  
New measurable lesions will not necessarily constitute PD or preclude partial 
response (PR).  Rather, the difference between the current size of a measurable 
lesions and its size prior to meeting criteria for measurability will be added to the 
sum of tumor measurements.  
 
Definition of Response Using  irRC 
 irComplete Response (irCR): Complete disappearance of all lesions 
(whether measurable or not) and no new lesions.  Lymph nodes must 
decrease to <10mm.  It is the judgment of the investigator whether a 
nonmeasurable radiographic nodule is likely cancerous; only nodules felt 
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 irPartial Response (irPR): Decrease in tumor burden > 30%, relative to 
baseline (or, for the case of measurement of response for individual 
sequenced treatments, from the beginning of that treatment), of 30% or 
greater in the sum of the longest diameter of all index lesions plus new 
measurable lesions.  The appearance of new measurable lesions is factored 
into the overall tumor burden, but does not automatically qualify as 
progressive disease.   
 
 irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the 
absence of PD. 
 
 irProgressive Disease (irPD): At least 20% increase in tumor burden (i.e., 
taking sum of the longest diameter of all index lesions and any newly 
measurable lesions) when compared to disease burden at nadir; minimum 
5mm absolute increase in tumor burden required.  The investigator may 
assign the designation of irPD for massive and unequivocal worsening of 
non-target lesions alone. 
 
 Nonprogressive disease: Measurable disease is not required for this study.  
Patients with CR at the time of study entry or otherwise nonmeasurable 
disease will be assessed for progression.  In the event of PD, this should be 
noted.  In the absence of meeting criteria for progression, nonprogressive 
disease should be coded (NPD). 
 
Immmune-related Best Overall Response (irBOR):  
IrBOR is the best response observed during the relevant time period.  Of note, 
when total tumor burden increases and the patient is maintained on therapy, and 
tumor then shrinks (pseudo-progression) the second measurement will be utilized. 
 
Designation of pseudo-progression:  
The phenomenon of pseudo-progression is of particular interest in this trial. For 
the purpose of this trial, pseudo-progression will be defined as any > 10% 
increase in tumor burden followed by a > 10% decrease in tumor burden prior to 
change in therapy.  Such occurrences will be noted for the purpose of exploratory 
hypothesis-generating analyses. 
 


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7.0 
ADVERSE EVENTS 
7.1 
Definitions  
7.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
drug) in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the 
medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered 
AEs and should not be recorded as an AE.  Disease progression should not be 
recorded as an AE, unless it is attributable by the investigator to the study therapy. 
 
All adverse events that occur after the consent form is signed but before treatment 
must be reported by the investigator if they cause the subject to be excluded from 
the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or 
a procedure. 
 
From the time of treatment through 30 days following cessation of treatment, all 
adverse events must be reported by the investigator. Such events will be recorded 
at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.1.4. The investigator will make every attempt to follow all subjects with 
non-serious adverse events for outcome. 
 
Adverse events will not be collected for subjects during the pre-screening period 
(for determination of archival tissue status) as long as that subject has not 
undergone any protocol-specified procedure or intervention.  If the subject 
requires a blood draw, fresh tumor biopsy etc., the subject is first required to 
provide consent to the main study and AEs will be captured according to 
guidelines for standard AE reporting.  
 
 
7.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause.   Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE.  A 


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suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration 
of the following factors: temporal relationship of the AE to study drug exposure, 
known mechanism of action or side effect profile of study treatment, other recent 
or concomitant drug exposures, normal clinical course of the disease under 
investigation, and any other underlying or concurrent medical conditions.  Other 
factors to consider in considering drug as the cause of the AE: 
 Single occurrence of an uncommon event known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
 One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon 
rupture); often more than once occurrence from one or multiple studies 
would be needed before the sponsor could determine that there is 
reasonable possibility that the drug caused the event.   
 An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the drug treatment group 
than in a concurrent or historical control group. 
7.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure 
(IB) for an unapproved investigational product or package insert/summary of 
product characteristics for an approved product).  Unexpected also refers to AEs 
or SARs that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.   
7.1.4 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
 Death; 
 Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
 Requires inpatient hospitalization (>24 hours) or prolongation of 
existing hospitalization* 
 Results in congenital anomaly/birth defect; 
 Results in a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; 
 Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
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medical or surgical intervention to prevent one of the outcomes listed 
in the definition.  For reporting purposes, also consider the occurrences 
of pregnancy as an event which must be reported as an important 
medical event. 
 
*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. 
 Note: In addition to the above criteria, adverse events meeting either of 
the below criteria, although not serious per ICH definition, are 
reportable to the Merck in the same timeframe as SAEs to meet certain 
local requirements. Therefore, these events are considered serious by 
Merck for collection purposes. 
● Is a new cancer (that is not a condition of the study); 
● Is associated with an overdose. 
 
For the time period beginning when the consent form is signed until treatment, 
any serious adverse event, or follow up to a serious adverse event, including death 
due to any cause other than progression of the cancer under study that occurs to 
any subject must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to 
a serious adverse event, including death due to any cause other than progression 
of the cancer under study whether or not related to the Merck product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention 
of the investigator at any time following consent through the end of the specified 
safety follow-up period specified in the paragraph above, or at any time outside of 
the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to 
the Merck Global Safety facsimile number:  +1-215-993-1220 
 
 


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7.2 
Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from signing of the 
informed consent and continue through the 30 day follow-up period after 
treatment is discontinued.   
 
Collected information should be recorded in the eCRF for that patient.  Please 
include a description of the event, its severity or toxicity grade, onset and resolved 
dates (if applicable), and the relationship to the study drug.    Documentation 
should occur at least monthly.  
7.3 
SAEs or Serious SARs and Events of Clinical Interest 
7.3.1 Timing 
All SAEs from the time of the signing of the informed consent document until 90 
days after the last dose of study drug (or to the initiation of new anti-cancer 
treatment, whichever is earliest) will be documented and reported to Celgene and 
to Merck (see details on reporting in Section 7.3.3)  
7.3.2 Documentation and Notification 
SAEs or Serious SARs must be recorded in the SAE console within Oncore™ for 
that patient within 24 hours of learning of its occurrence.  Additionally, the 
NCCN Project Manager must also be notified via email of all SAEs within 24 
hours of learning of its occurrence.  
 
7.3.3 Reporting of SAEs, Events of Clinical Interest, Pregnancies and Overdoses 
IRB Reporting Requirements: 
UNC: 
 The UNC-IRB will be notified of all SAEs that qualify as an 
Unanticipated Problem as per the UNC IRB Policies using the IRB’s web-
based reporting system (see section 9.5.3) within 7 days of the Investigator 
becoming aware of the problem.   
 
Affiliate sites:   
 For affiliate sites using a local IRB of record, please submit adverse events 
per local IRB policy. 
Any SAEs that qualify as an Unanticipated Problem will be entered into 
Oncore and reported to the UNC IRB by the UNC Research Personnel 
using the IRB’s web-based reporting system (see section 9.5.3) within 7 
days of the Investigator becoming aware of the problem.   
 
Pregnancies (Information for Reporting to Merck) 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or 


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lactation in a subject (spontaneously reported to them. Pregnancies and lactations 
that occur after the consent form is signed but before treatment must be reported 
by the investigator if they cause the subject to be excluded from the trial, or are 
the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.   
 
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 completing the trial, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, as a 
serious adverse event within 24 hours to the UNCCN Project Manager who will 
report the event within 2 days to Merck Global Safety (see contact information 
below).   
 
The patient is to be discontinued immediately from any protocol directed therapy. 
The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the 
UNCCN Project Manager.   All subjects and female partners of male subjects who 
become pregnant must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of death, spontaneous abortion, congenital 
anomaly, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, 
intrauterine death, miscarriage and stillbirth or other disabling or life-threatening 
complications to the mother or newborn must be reported as SAEs.  If the 
pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the UNCCN Project Manager 
who will report the event within 2 days to Merck Global Safety. 
 
Pregnancies (Information for Reporting to Celgene) 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject 
is on IP, or within 28 days of the subject’s last dose of nab-paclitaxel, are 
considered immediately reportable events.  Nab-paclitaxel is to be discontinued 
immediately. The pregnancy, suspected pregnancy, or positive pregnancy test 
must be reported to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form. The female subject may be referred to an obstetrician-
gynecologist (not necessarily one with reproductive toxicity experience) or 
another appropriate healthcare professional for further evaluation. 
 
The Investigator will follow the female subject until completion of the pregnancy, 
and must notify Celgene Drug Safety immediately about the outcome of the 
pregnancy (either normal or abnormal outcome) using the Pregnancy Follow-up 
Report Form, or approved equivalent form.  
 


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If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE.  If the 
abnormal outcome meets any of the serious criteria, it must be reported as an SAE 
to Celgene Drug Safety immediately by facsimile, or other appropriate method, 
within 24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form, or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the IP should also be 
reported to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the 
SAE Report Form, or approved equivalent form. 
 
It is the responsibility of investigators or their designees to report any pregnancy 
or suspected pregnancy to Celgene Global Drug Safety Risk Management using a 
Pregnancy Report Form within 24 hours (see contact information below). If a 
female partner of a male subject taking nab-paclitaxel becomes pregnant, the male 
subject taking nab-paclitaxel should notify the Investigator, and the pregnant 
female partner should be advised to call their healthcare provider immediately. 
Male patients treated with nab-paclitaxel are advised not to father a child during 
and up to 6 months after treatment. 
 
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported 
to the UNCCN Project Manager within 24 hours via facsimile to 919-966-4300.  
The female subject should be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 
 
 
FDA Expedited Reporting requirements: 
If an investigator deems that an event is both a serious SAR AND unexpected, it 
must also (in addition to Oncore) be recorded on the MedWatch Form 3500A as 
per 21 CFR 312.32. The MedWatch form should be faxed to the UNCCN Project 
Manager at 919-966-4300 (or emailed, with address provided at the Start up 
Meeting (SIM)) along with supporting documentation defining the event and 
causality.  The UNCCN Project Manager will send report to the manufacturers. 
The MedWatch 3500a form can be accessed at:  
 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.ht
m  
 
(Please be sure and access form 3500a, and not form 3500).   UNC, as the 
Sponsor of the study, will make the final determination regarding FDA 
submission.   
 
Once the UNC Principal Investigator determines an event is a serious SAR AND 
unexpected, the MedWatch 3500A form will be submitted to the FDA. 


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The UNCCN Project Manager will also be responsible for informing each 
Affiliate site of all serious and unexpected SARs reported to the FDA via fax as 
soon as possible.   
 
Expedited Reporting by Investigator to Celgene 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the 
expectedness of events of being related to nab-paclitaxel (ABRAXANE®) based 
on the Investigator Brochure.  In the United States, all suspected unexpected 
serious adverse reactions (SUSARs) will be reported in an expedited manner in 
accordance with 21 CFR 312.32. 
 
SAEs are defined above.  The investigator must inform Celgene in writing using a 
Celgene SAE form or MEDWATCH 3500A form of any SAE within 24 hours of 
being aware of the event.  The written report must be completed and supplied to 
the UNC Research Personnel within 24 hours (the UNC Research Personnel will 
then fax to Celgene).  The initial report must be as complete as possible, including 
an assessment of the causal relationship between the event and the investigational 
product(s).  Information not available at the time of the initial report (e.g., an end 
date for the adverse event or laboratory values received after the report) must be 
documented on a follow-up report.  A final report to document resolution of the 
SAE is required.  The Celgene tracking number and the institutional protocol 
number should be included on SAE reports (or on the fax cover letter) sent to 
Celgene.  A copy of the fax transmission confirmation of the SAE report to 
Celgene should be attached to the SAE and retained with the patient records. 
 
Any overdose of nab-paclitaxel (see Section 5.2.7) should be reported within 24 
hours to Celgene.  
 
The investigator will collect and report all secondary primary malignancies that 
occur in subjects on this study for a period up to 3 years following discontinuation 
of Nab-paclitaxel to the Celgene Drug Safety and Risk Management group. 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
 
Merck Reporting Requirements: 
Any SAE, or follow up to a SAE, including death due to any cause other than 
progression of the cancer under study that occurs to any subject from the time the 
consent is signed through 90 days following cessation of treatment, or the 


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initiation of new anti-cancer therapy, whichever is earlier, whether or not related 
to Merck product, must be reported within 24 hours to the UNCCN Project 
Manager who will report the event within 2 working days to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety 
and will be handled in the same manner as SAEs.  
 
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention 
of the investigator at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the UNCCN Project Manager 
who will report the event to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to 
the UNC Research Personnel via facsimile at 919-966-4300, or scanned and 
emailed to UNC Research Personnel (CPOMultiCenter@med.unc.edu) who 
will then fax to the Merck Global Safety facsimile number:  +1-215-993-1220. 
 
All 15-Day Reports and Annual Progress Reports must be submitted as required 
to FDA. Investigators will cross-reference these reports to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., 
Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of 
submission to FDA. 
 
Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of 
Clinical Interest (ECI) and must be reported within 24 hours to the Sponsor and 
within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220). 
 
For the time period beginning when the consent form is signed until treatment, 
any ECI, or follow up to an ECI, that occurs to any subject must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety 
if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether 
or not related to Merck product, must be reported within 24 hours to the Sponsor 
and within 24 hours to Merck Global Safety. 
 


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Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 5.1.5 Pembrolizumab 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* 
*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. 
 
 
Pregnancy and Lactation 
See above in this section for additional information. Such events must be reported 
within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220). 
 
Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck unless 
there is evidence suggesting a causal relationship between the drug and the event. 
Any such event will be submitted to the Sponsor within 24 hours and to Merck 
Global Safety within 2 working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any 
event that is disease progression of the cancer under study. 
 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and 
safety data to ensure the safety of the subjects in the trial. Any suspected endpoint 
which upon review is not progression of the cancer under study will be forwarded 
to Merck Global Safety as a SAE within 2 working days of determination that the 
event is not progression of the cancer under study 
 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be 
considered a SAE. 
7.4 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the Data and Safety Monitoring Committee 
(DSMC).  
 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician.  These meetings will include the 
investigators as well as protocol nurses, clinical research associates, regulatory 
associates, data managers, biostatisticians, and any other relevant personnel the 


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principal investigators may deem appropriate.  At these meetings, the research 
team will discuss all issues relevant to study progress, including enrollment, 
safety, regulatory, data collection, etc. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight (Office of Human Research Ethics (OHRE) 
Biomedical IRB, the Oncology Protocol Review Committee (PRC) or the North 
Carolina TraCS Institute Data and Safety Monitoring Board (DSMB).   
 
The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the 
study on a regular (quarterly to annually) basis, with the frequency of review 
based on risk and complexity as determined by the UNC Protocol Review 
Committee.  The UNC PI will be responsible for submitting the following 
information for review: 1) safety and accrual data including the number of 
patients treated; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response 
data; and 4) summaries of team meetings that have occurred since the last report.  
Findings of the DSMC review will be disseminated by memo to the UNC PI, 
PRC, and the UNC IRB and DSMB.   
 


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8.0 
STATISTICAL CONSIDERATIONS 
8.1 
Study Design 
This open-label, three-arm, non-comparative randomized phase II study is 
designed to evaluate three different sequences of double-consolidation with 
pembrolizumab and nab-paclitaxel in patients with advanced NSCLC post 
induction chemotherapy.  In ARMs A and B, consolidation is sequential, with 
either pembrolizumab followed by nab-paclitaxel (ARM A), or nab-paclitaxel 
followed by pembrolizumab (ARM B). In ARM C, consolidation is concurrent, 
with the two agents administered concurrently.   
 
The primary objective is to estimate overall survival in each arm.  Secondary 
objectives include estimating rates of response (via RECIST1.1 and Immune 
Related Response Criteria (irRC)), clinician observed and patient reported 
toxicity, and quality of life in each arm. 
8.2 
Sample Size and Accrual 
In the Fidias trial referred to earlier [1], cytotoxic consolidation therapy provided 
an overall survival advantage of 2.6 months.  While data are currently limited, we 
believe pembrolizumab, particularly in patients with tumors known to be PD-
L1(+), could yield at least an additional 2.6 months. Given the null hypothesis of 
9.7 months (using data from the Fidias trial), our alternative hypothesis is that 
double consolidation will yield a median OS of at least 15 months. Assuming 
uniform accrual, no loss to follow-up, exponentially distributed times, and a one-
side alpha of 0.1, 35 patients per arm provide 80% power to detect this level of 
improvement.  We anticipate accrual to take 18 months, with follow-up time of at 
least 12 months. This calculation was made using the SWOG Statistical Center 
online tool for one arm survival (https://stattools.crab.org/#). 
 
We will consider any of the 3 ARMS worthy of additional study if the lower end 
of the 95% confidence interval for the estimated median OS is greater than 9.7 
months, and the interval includes or exceeds 15 months. 
8.3 
Data Analysis Plans 
The primary endpoint is the estimation of OS from the first day of study 
treatment, and will be done using the Kaplan-Meier (KM) method separately for 
each arm.  The median OS will be provided along with a 95% confidence interval.  
If the intervals for any of the arms exclude the null hypothesis of 9.7 months, and 
include the alternative hypothesis of 15 months, data from those arms will be 
combined to provide an aggregate estimate.  This will be done in the absence of a 
formal test to determine equivalence given the sample size.   
 
All patients who receive at least one dose of treatment will be included in these 
estimates, with censoring used as needed (ex. if a patient drops out of the study, or 
analysis is done before all patients have had the event of interest).  The KM 






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9.0 
STUDY MANAGEMENT 
9.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
9.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North 
Carolina. 
 
 A copy of the official IRB approval letter for the protocol and 
informed consent 
 IRB membership list 
 CVs and medical licensure for the principal investigator and any sub-
investigators who will be involved in the study. 
 Form FDA 1572 appropriately filled out and signed with appropriate 
documentation (NOTE: this is required if UNC holds the IND.  
Otherwise, the Investigator’s signature documenting understanding of 
the protocol and providing commitment that this trial will be 
conducted according to all stipulations of the protocol is sufficient to 
ensure compliance) 
 CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
 Executed clinical research contract 


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9.3 
Registration Procedures 
All patients must be registered with the LCCC CPO UNCCN at the University of 
North Carolina before enrollment to study.  To register a patient call the UNCCN 
at 919-966-7359 M-F 8:30am- 5pm EST. Fax (919-966-4300) or email (address 
to be provided at SIM) registration form, signed informed consents and all source 
documents to confirm eligibility..  
9.4 
Data Management and Monitoring/Auditing 
The CPO UNCCN of the UNC LCCC will serve as the coordinating center for 
this trial. Data will be collected through a web based clinical research platform, 
OnCore®.  Other study institutions will be given a password to directly enter their 
own data onto the web site via eCRFs.  UNCCN personnel will coordinate and 
manage data for quality control assurance and integrity. 
 
All data will be collected and entered into OnCore® by Clinical Research 
Associates (CRAs) from UNC LCCC and participating institutions.  The 
investigators at each site will allow monitors to review all source documents 
supporting data entered into OnCore®.   The UNCCN Data Coordinator can be 
reached at 919-843-2742 or 1-877-668-0683. 
 
As an investigator initiated study, this trial will also be audited by the Lineberger 
Cancer Center audit committee every six or twelve months, depending on the 
participation of affiliate sites. 
9.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   
9.5.1 Emergency Modifications 
UNC and Affiliate investigators may implement a deviation from, or a change of, 
the protocol to eliminate an immediate hazard(s) to trial subjects without prior 
UNC or their respective institution’s IRB/IEC approval/favorable opinion.   
 
For Institutions Relying on UNC’s IRB: 
For any such emergency modification implemented, a UNC IRB modification 
form must be completed by UNC Research Personnel within five (5) business 
days of making the change.   
 
For Institutions Relying on Their Own IRB: 
For Affiliate investigators relying on their own institution’s IRB, as soon as 
possible after the modification has been made, the implemented deviation or 
change and the reasons for it should be submitted to: 
 
 To UNC Principal Investigator for agreement  


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 The Affiliate institution’s IRB for review and approval.  (Once 
IRB’s response is received, this should be forwarded to the 
UNCCN Regulatory Associate). 
 
 
9.5.2 Single Patient/Subject Exceptions 
Eligibility single subject exceptions are not permitted for Lineberger 
Comprehensive Cancer Center Investigator Initiated Trials under any 
circumstance. Other types of single subject exceptions may be allowed if proper 
regulatory review has been completed in accordance with for Lineberger 
Comprehensive Cancer Center’s Single Subject Exceptions Policy. 
9.5.3 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
 Is generally noted or recognized after it occurs 
 Has no substantive effect on the risks to research participants 
 Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
 Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  
 Has harmed or increased the risk of harm to one or more research 
participants. 
 Has damaged the scientific integrity of the data collected for the study. 
 Results from willful or knowing misconduct on the part of the 
investigator(s). 
 Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
For Institutions Relying on UNC’s IRB: 
Protocol Deviations: UNC or Affiliate personnel will record the deviation in 
OnCore®, and report to any sponsor or data and safety monitoring committee in 
accordance with their policies.  Deviations should be summarized and reported to 
the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.   
 


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For Institutions Relying on Their Own IRB: 
In addition to adhering to the policies regarding protocol compliance set forth by 
your institution’s IRB, the following is also required: 
 
Protocol Deviations: In the event a deviation from protocol procedures is 
identified, record the deviation in OnCore®. 
 
Protocol Violations: Any protocol violation that occurs must be reported to your 
IRB per institutional policies and reported to the UNCCN Project Manager within 
5 days. UNC-CH will determine if the violation affects the safety of the patient 
and integrity of the data.  Once your institution’s IRB response is received, please 
forward to the UNCCN Regulatory Associate. 
 
Unanticipated Problems: 
Affiliate Sites: 
Any events that meet the criteria for “Unanticipated Problems (UPs)” as defined 
by UNC’s IRB must also be reported to the UNCCN Project Manager.   The 
UNCCN Project Manager will report the event to the UNC IRB using the IRB’s 
web-based reporting system.  Examples of such UPs include a lost or stolen 
laptop computer that contains sensitive study information. 
 
UNC 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the Study Coordinator using the IRB’s web-
based reporting system.   
9.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC.  It should also 
be noted that when an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be 
required.   
 
For Institutions Relying on UNC’s IRB: 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation.   
 
For Institutions Relying on Their Own IRB: 
Investigators must submit the UNC IRB approved amendment to their 
institution’s IRB for approval.  For multi-center studies, any affiliate site must 
submit their informed consent revisions to the UNCCN Regulatory Associate 
prior to submission to their IRB.   
9.7 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 


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regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
9.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
 
 


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10.0 REFERENCES 
 
1. 
Fidias, P.M., et al., Phase III study of immediate compared with delayed docetaxel 
after front-line therapy with gemcitabine plus carboplatin in advanced non-small-
cell lung cancer. J Clin Oncol, 2009. 27(4): p. 591-8. 
2. 
Socinski, M.A., et al., Phase III trial comparing a defined duration of therapy 
versus continuous therapy followed by second-line therapy in advanced-stage 
IIIB/IV non-small-cell lung cancer. J Clin Oncol, 2002. 20(5): p. 1335-43. 
3. 
Park, J.O., et al., Phase III trial of two versus four additional cycles in patients 
who are nonprogressive after two cycles of platinum-based chemotherapy in non 
small-cell lung cancer. J Clin Oncol, 2007. 25(33): p. 5233-9. 
4. 
Soon, Y.Y., et al., Duration of chemotherapy for advanced non-small-cell lung 
cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol, 
2009. 27(20): p. 3277-83. 
5. 
Merck Sharp & Dohme, I., Pembrolizumab Investigator's Brochure. 2014. 
6. 
Disis, M.L., Immune regulation of cancer. J Clin Oncol, 2010. 28(29): p. 4531-8. 
7. 
Brown, J.A., et al., Blockade of programmed death-1 ligands on dendritic cells 
enhances T cell activation and cytokine production. J Immunol, 2003. 170(3): p. 
1257-66. 
8. 
Dong, H., et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential 
mechanism of immune evasion. Nat Med, 2002. 8(8): p. 793-800. 
9. 
Francisco, L.M., P.T. Sage, and A.H. Sharpe, The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev, 2010. 236: p. 219-42. 
10. 
Sharpe, A.H. and G.J. Freeman, The B7-CD28 superfamily. Nat Rev Immunol, 
2002. 2(2): p. 116-26. 
11. 
Thompson, R.H., et al., PD-1 is expressed by tumor-infiltrating immune cells and 
is associated with poor outcome for patients with renal cell carcinoma. Clin 
Cancer Res, 2007. 13(6): p. 1757-61. 
12. 
Talmadge, J.E., M. Donkor, and E. Scholar, Inflammatory cell infiltration of 
tumors: Jekyll or Hyde. Cancer Metastasis Rev, 2007. 26(3-4): p. 373-400. 
13. 
Usubutun, A., et al., Prognostic factors in renal cell carcinoma. J Exp Clin 
Cancer Res, 1998. 17(1): p. 77-81. 
14. 
Deschoolmeester, V., et al., Tumor infiltrating lymphocytes: an intriguing player 
in the survival of colorectal cancer patients. BMC Immunol, 2010. 11: p. 19. 
15. 
Diez, M., et al., Histopathologic prognostic score in colorectal adenocarcinomas. 
Anticancer Res, 1998. 18(1B): p. 689-94. 
16. 
Galon, J., et al., Type, density, and location of immune cells within human 
colorectal tumors predict clinical outcome. Science, 2006. 313(5795): p. 1960-4. 
17. 
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32. 
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11.0  APPENDICES 
11.1 
Appendix A Cockcroft-Gault Formula 
 
Estimated creatinine clearance (mL/min) = (140-age in years) X (weight in kg) 
 
 
 
 
 
      72 X (serum creatinine in mg/dL) 
 
For females, use 85% of calculated creatinine clearance value. 
 
 
 


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11.2 
Appendix B Charlson Comorbidity Index Scoring System 
 
 


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11.3 
Appendix C:  ECOG Performance Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair.