Clinical trial NCT02382406
Conditions: Non-Small Cell Lung Cancer
Keywords: MK-3475 Pembrolizumab Carboplatin Nab-paclitaxel
Sponsor: Nisha Mohindra, MD
Start date: 2015-06-04; Completion date: 2022-04-14
Enrollment: 46 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase I/II study for previously untreated subjects with advanced NSCLC. The study will take place in two phases. First, a cohort of twelve participants will be enrolled in phase I part and will be treated with carboplatin, nab-paclitaxel and pembrolizumab. A cohort of twelve subjects will be evaluated for safety and tolerability after 2 cycles of therapy. All subjects who receive either nab-paclitaxel or pembrolizumab will be evaluable. If 33% of subjects or less have unacceptable toxicity in the first cohort or any subsequent cohort (if necessary), the study will proceed to the Phase II part. If more than 33% have unacceptable toxicity, 12 additional subjects will be enrolled in a second cohort, if necessary. If unacceptable toxicity is seen in more than 33% in Cohort 2, the study will end due to unacceptable toxicity of this drug combination.

The phase II part of the study is a single arm study. All subjects will be treated with carboplatin, nab-paclitaxel, and pembrolizumab in 21-day cycles for up to 4 cycles.

Mandatory pre-treatment tumor biopsies will be obtained prior to initiating treatment for all subjects (only if adequate archived samples are unavailable). Mandatory tumor biopsies will be obtained in the Phase II part of the study after 4 cycles of study treatment or at the time of progression, whichever comes first.

For subjects without progression of disease after Cycle 4, pembrolizumab will continue every 3 weeks for up to 2 years or until unacceptable toxicity.

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

INVESTIGATIONAL TREATMENT:

Phase I, Cohort 1 Induction Therapy:

* Carboplatin AUC 6 IV, Day 1
* Nab-paclitaxel 100 mg/m\^2 IV, Days 1, 8, 15
* pembrolizumab 2 mg/kg IV, Day 1
* Cycle length: 21 days; number of cycles: 4

Phase I, Cohort 1 Maintenance Therapy:

For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction therapy, maintenance therapy with pembrolizumab 2\* mg/kg will continue on Day 1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or for a maximum of 2 years from Cycle 1, Day 1 (C1D1). Subjects who complete 24 months of treatment with pembrolizumab may be eligible for up to one year of additional study treatment if they progress after stopping study treatment provided they continue to meet inclusion criteria requirements.

If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional participants will be enrolled.

Phase I, Cohort 2 Induction Therapy (if necessary):

* Carboplatin AUC 6 IV, Day 1
* Nab-paclitaxel 100 mg/m\^2 IV, Days 1, 8, 15
* pembrolizumab 2 mg/kg IV, Day 1 (cycle 2-4 only)
* Cycle length: 21 days; Number of cycles: 4

Phase I, Cohort 2 Maintenance Therapy:

For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction therapy, maintenance therapy with pembrolizumab 2\* mg/kg will continue on Day 1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or for a maximum of 2 years from Cycle 2, Day 1 (C2D1). Subjects who complete 24 months of treatment with pembrolizumab may be eligible for up to one year of additional study treatment if they progress after stopping study treatment provided they continue to meet inclusion criteria requirements.

Phase II Induction Therapy:

* Carboplatin AUC 6 IV, Day 1
* Nab-paclitaxel 100 mg/m\^2 IV, Days 1, 8, 15
* pembrolizumab 200mg IV, Day 1 of each cycle
* Cycle length: 21 days; number of cycles: 4

Phase II Maintenance Therapy:

For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction therapy, maintenance therapy with pembrolizumab 200 mg will continue on Day 1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or for a maximum of 2 years from Cycle 1, Day 1 (C1D1). Subjects who complete 24 months of treatment with pembrolizumab may be eligible for up to one year of additional study treatment if they progress after stopping study treatment provided they meet the requirements.

\*As additional data from ongoing trials becomes available, the dose of pembrolizumab may be adjusted.

Arms: arm 1: Twelve subjects will be enrolled and treated with carboplatin AUC 6 IV on Day 1, nab-paclitaxel 100 mg/m\^2 IV on Day 1, Day 8, and Day 15, pembrolizumab 2\* mg/kg IV on Day 1 for 4 cycles. pembrolizumab (Phase I) treatment for Cohort 1 will continue for a maximum duration of 4 21-day cycles

Phase I, Cohort 1 Maintenance Therapy:

Participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles, maintenance therapy with MK-3475 2\* mg/kg will continue on D1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or a maximum of 2 years from C1D1.

If unacceptable toxicity is seen in Phase I Cohort 1, 12 additional participants will be enrolled in Cohort 2 and treated with carboplatin AUC 6 IV on D1, nab-paclitaxel 100 mg/m2 IV on D1, D8, and D15, MK-3475 2\*mg/kg IV on D1 starting C2. MK-3475 (Phase 1) treatment for Cohort 2 will continue for a maximum duration of 3 21-day cycles (C2-4 only). arm 2: Subjects will be treated with carboplatin AUC 6 given IV on Day 1, nab-paclitaxel 100 mg/m\^2 given IV on Day 1, Day 8, and Day 15, and pembrolizumab 200mg IV on Day 1 of each cycle. Pembrolizumab Phase II treatment will continue for a maximum duration of 4 cycles (cycle = 21 days).

Maintenance Therapy For participants who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction therapy, maintenance therapy with MK-3475 2\* mg/kg will continue on Day 1 of each 21-day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or for a maximum of 2 years from C1D1.

\*As additional data from ongoing trials becomes available, the dose of MK-3475 may be adjusted.
Interventions: intervention 1: Carboplatin intervention 2: Nab-paclitaxel intervention 3: MK-3475 (Phase I) intervention 4: MK-3475 (Phase II)
Intervention descriptions: intervention 1: Carboplatin AUC 6 IV, D1 for 4 cycles (cycle = 21 days) intervention 2: Nab-paclitaxel 100 mg/m2 IV, D1, D8, D15 for 4 cycles (cycle = 21 days) intervention 3: MK-3475 2 mg/kg IV, D1 for 4 cycles (Cohort 1) or 3 cycles (Cohort 2) (cycle = 21 days)

Maintenance MK-3475 2 mg/kg IV continues every 21 days after Cycle 4 for up to 2 years. intervention 4: MK-3475 200 mg IV Day 1 of each cycle (cycle = 21 days)

Maintenance MK-3475 2 mg/kg IV continues every 21 days after Cycle 4 for up to 2 years.

Protocol documents:
Prot_SAP_000.pdf: 
Hoosier Cancer Research Network LUN13-175                                                           Confidential 
 
Version Date: 10OCT2019 
 
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Phase I/II study of carboplatin/nab-paclitaxel and pembrolizumab for 
patients with advanced non-small cell lung cancer (NSCLC) 
 
Hoosier Cancer Research Network: LUN13-175 
 
SPONSOR INVESTIGATOR:  
Nisha A Mohindra MD 
 
Division of Hematology/Oncology 
 
Robert H. Lurie Comprehensive Cancer Center 
 
Northwestern University 
 
Feinberg School of Medicine 
 
676 N. St. Clair St, Suite 850 
 
Chicago, IL 60611 
 
Phone #: (312) 695-6180 
 
nisha.mohindra@nm.org 
 
CO-INVESTIGATORS: 
Ryan D. Gentzler, MD 
 
Therese Zumdahl, PA 
 
 
 
PARTICIPATING SITES: 
Hoosier Cancer Research Network  
 
PATHOLOGIST: 
Kirtee Raparia, MD 
Northwestern University
 
RADIOLOGIST: 
FUNDING AGENCIES: 
Eric M. Hart, MD 
Merck Sharp & Dohme Corp.
Northwestern University
Celgene Corporation 
 
 
IND#: Exempt per FDA 1.28.15 
 
Initial Protocol Version Date: 31OCT2014 
Protocol Amendment Version Date:  
16DEC2015 
27MAY2015 
28JUL2015  
15MAR2016 
20SEP2016 
07MAR2017 
27SEP2017 
10OCT2019 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Phase I/II study of carboplatin/nab-paclitaxel and pembrolizumab for patients with  
advanced non-small cell lung cancer (NSCLC) 
 
VERSION DATE: 10OCT2019 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the individual.  
I will accept the monitor’s overseeing of the study.  I will promptly submit the protocol to 
applicable ethical review board(s). 
 
 
 
 
 
 
 
 
 
____________________________________ 
________________________ 
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       Date 
 
 
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____________________________________ 
 Investigator Title 
 
 
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PLEASE COMPLETE AND EMAIL COPY TO THE HOOSIER CANCER RESEARCH NETWORK  
 
 
Instructions to the investigator:  Please SIGN and DATE this signature page.  
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date.  Scan and email 
the completed form to Hoosier Cancer Research Network and keep a copy for 
your files. 


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Synopsis 
TITLE 
Phase I/II study of carboplatin/nab-paclitaxel and 
pembrolizumab for advanced non-small cell lung cancer 
(NSCLC)
SHORT TITLE 
Phase I/II carboplatin/nab-paclitaxel and pembrolizumab in 
NSCLC
PHASE  
I/II 
OBJECTIVES 
Primary Objective: 
Phase I: To determine the recommended Phase II dose schedule 
(RP2DS) and evaluate the safety and tolerability of the 
combination of pembrolizumab with carboplatin/nab-paclitaxel 
for the first line treatment of subjects with advanced NSCLC. 
 
Phase II: To evaluate progression-free survival (PFS) and 
objective response rate for subjects receiving carboplatin/nab-
paclitaxel and pembrolizumab for the first line treatment of 
advanced NSCLC. 
 
Secondary Objectives: 
Phase I: 
1. To describe the following for subjects receiving 
carboplatin/nab-paclitaxel and pembrolizumab: 
a) Progression-free survival (PFS) 
b) Objective response  
c) Anti-tumor activity using change in tumor measurements 
d) Overall survival (OS) 
 
2. To evaluate the association of PD-L1 expression on PFS for 
subjects receiving pembrolizumab. 
 
Phase II:  
1. To evaluate the following for subjects receiving 
carboplatin/nab-paclitaxel and pembrolizumab:  
a) Overall survival (OS)  
b) Anti-tumor activity using change in tumor measurements 
c) Safety and tolerability 
 
2. To evaluate the association of PD-L1 expression on PFS for 
subjects receiving pembrolizumab.
TREATMENT 
SUMMARY 
Phase I: 
Cohort 1 
Carboplatin AUC 6 IV, Day 1 
nab-paclitaxel 100 mg/m2 IV, Days 1, 8, 15 
pembrolizumab 2 mg/kg IV, Day 1 
Cycle length: 21 days


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Number of cycles: 4 
Maintenance pembrolizumab 2 mg/kg IV continues every 21 
days after Cycle 4 for up to 2 years. 
 
Cohort 2 (if necessary) 
Carboplatin AUC 6 IV, Day 1 
nab-paclitaxel 100 mg/m2 IV, Days 1, 8, 15 
pembrolizumab 2 mg/kg IV, Day 1 (cycle 2-4 only) 
Cycle length: 21 days 
Number of cycles: 4 
Maintenance pembrolizumab 2 mg/kg IV continues every 21 
days after Cycle 4 for up to 2 years. 
 
Phase II: 
Carboplatin AUC 6 IV, Day 1 
nab-paclitaxel 100 mg/m2 IV, Days 1, 8, 15 
pembrolizumab 200 mg IV, Day 1  
Cycle length: 21 days 
Number of cycles: 4 
Maintenance pembrolizumab 200 mg IV continues every 21 days 
after Cycle 4 for up to 2 years.
ELIGIBILITY 
CRITERIA  
Inclusion Criteria 
 
1. Subjects must be ≥ 18 years of age. 
 
2. Individuals with stage IIIB or IV, unresectable non-small cell 
lung cancer (NSCLC) who have not received prior 
chemotherapy for Stage IIIB or IV disease, and who are not 
candidates for curative surgery or radiation therapy. 
 
3. ECOG performance status (PS) 0-1 
 
4. Measurable disease by RECIST v1.1 criteria 
 
5. Prior to registration, all subjects must have either adequate 
archival tissue identified or available PD-L1 testing results 
using the Dako 22C3 antibody. If the patient has not had 
prior PD-L1 testing and no acceptable archival tissue is 
available, subjects must be willing to consent to providing a 
pre-treatment biopsy for PD-L1 testing.  Regardless of PD-
L1 testing status, archival tissue will be requested for 
research testing if available. PD-L1 status is required but 
does not need to be positive to be eligible for study. 
 
6. Phase II subjects must be willing to consent to providing a 
post-treatment core biopsy for research if clinically feasible.


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7. Women are eligible to participate if they are of non-
childbearing potential or have documentation of a negative 
pregnancy test (serum or urine β-hCG) within 3 days of 
registration. Sexually active pre-menopausal women of 
childbearing potential must agree to use adequate, highly 
effective contraceptive measures, starting with the first dose 
of study drug through 120 days after the last dose of the last 
study drug. 
 
8. Male subjects should agree to use an adequate method of 
contraception starting with the first dose of study drug 
through 120 days after the last dose of the last study drug. 
 
Exclusion Criteria 
1. Individuals with the presence of symptomatic CNS 
metastases requiring radiation treatment, surgery, or ongoing 
use of corticosteroids. 
 
2. Untreated or brain metastasis causing any symptoms.  
Treated brain metastases must be stable for 4 weeks prior to 
first dose of study drug and not requiring steroids for at least 
7 days prior to study treatment. 
 
3. History of solid organ or stem cell transplant requiring 
immunosuppressive medications. 
 
4. Any prior adjuvant cytotoxic chemotherapy within the last 12 
months.  Subjects who received chemotherapy for earlier 
stage disease more than 12 months prior to study registration 
are eligible for this trial. 
 
5. 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).  
 
6. Any radiotherapy within 2 weeks prior to registration (4 
weeks for brain radiotherapy as noted above) 
 
7. 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 study drug. 
 


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8. History of other invasive malignancy that is currently active 
and/or has been treated within 12 months prior to registration 
(Notable exceptions include; basal cell carcinoma, squamous 
cell carcinoma of the skin, localized prostate cancer, in situ 
carcinomas of the cervix and breast, and superficial bladder 
cancers [non- muscle-invasive]). 
 
9. Has known history of Human Immunodeficiency Virus 
(HIV) (HIV 1/2 antibodies). 
 
10. Active autoimmune disease that has required systemic 
treatment in past 2 years (i.e. with use of disease 
modifying agents, corticosteroids or immunosuppressive 
drugs).  Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment 
 
11. Pulmonary conditions such as sarcoidosis, silicosis, 
idiopathic pulmonary fibrosis, or hypersensitivity 
pneumonitis.  
12. Has a history of pneumonitis that required steroids or current 
pneumonitis. 
 
13. Pre-existing peripheral neuropathy ≥ Grade 2 by CTCAE v4 
criteria. 
 
14. Known significant liver disease including viral, alcoholic, 
active hepatitis B or C, and/or cirrhosis. 
 
15. Abnormal liver or renal function. 
 
16. Abnormal baseline hematologic or coagulation parameters. 
 
17. Has received a live vaccine within 30 days of first dose of 
study drug. 
 
18. Known activating EGFR mutation or ALK translocation.  
Testing is not required but should be performed if 
clinically indicated; results are not required prior to 
enrollment. 
STATISTICAL 
CONSIDERATIONS 
 
Phase I: 
Analytic plan for primary objective:  
Cohort 1 
All subjects who receive treatment will be evaluated for toxicity. 
Toxicities by type and grade will be summarized overall and by 


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dose level. 
 
During the phase I portion of the study, there will be weekly 
teleconferences to review toxicities for all subjects on study.   If 
at any point more than 4 subjects experience a DLT, enrollment 
to the current cohort will end.  These ongoing assessments will 
occur throughout phase I for both cohort 1 and cohort 2 (if 
necessary).  For example, if all 5 of the first 5 subjects enrolled 
have a DLT, no more subjects will be enrolled to that Phase I 
cohort or treated.  If this occurs during cohort 2, the trial will 
end. 
 
After 12 subjects in Cohort 1 are treated, if the rates of 
unacceptable toxicity after 2 cycles of pembrolizumab, defined 
in Section 5.2.1.1 Definition of DLT, are ≤ 33% of subjects (≤ 4 
of 12), the study will advance to the Phase II with 
pembrolizumab dose at 200 mg.  If unacceptable toxicity occurs 
in > 33% of subjects (≥ 5 of 12), a second cohort of subjects will 
be enrolled.  
 
Cohort 2 (if necessary) 
Twelve subjects will be treated with delayed initiation of 
pembrolizumab 2 mg/kg.  Pembrolizumab will be omitted for 
Cycle 1 and start on Day 1 of Cycle 2.  If ≤ 33% of subjects have 
unacceptable toxicity (as defined above) at this dose level, 2 
mg/kg starting Cycle 2, Day 1 will be the RP2D and schedule 
and the study will proceed to the Phase II part of the study.  If > 
33% of subjects (≥ 5 of 12) have unacceptable toxicity at this 
level, the study will be discontinued due to unacceptable toxicity 
of this drug combination. 
 
Analytic plan for secondary objectives:   
Median PFS and median OS outcomes will be described using 
KM method and two-sided 80% confidence intervals will be 
calculated.   
 
Response will be reported as a percentage of subjects registered 
to the study. 
 
PD-L1 expression will be categorized as positive or negative 
from pre-treatment biopsies.  Positive PD-L1 expression rates are 
estimated to be 70%, based on preliminary data from 
pembrolizumab PN 001. The distribution of PFS will be 
summarized by PD-L1 expression using Kaplan-Meier method 
and PFS will be compared using one-sided logrank test.  
Nominal p-values will be reported to measure the strength of the 


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differences tested. 
 
Anti-tumor activity will be reported as a percentage change in 
the sum of the dimensions of all measurable lesions as defined 
by RECIST 1.1 criteria.  The baseline imaging before treatment 
will be compared to each subsequent imaging assessment.  The 
maximum anti-tumor activity will be reported using the 
assessment with the smallest sum of dimensions (maximum 
response). 
 
Phase II: 
Analytic plan for primary objective:  
Recruitment of 43 subjects will last approximately 12 months 
and subjects will be followed until 39 PFS events occur or a 
maximum of 2 years from enrollment of the last subject.  The 
estimated study duration is 3 years.  Two co-primary outcomes 
are chosen –PFS based on mechanism of action and RR based on 
acknowledgement of ‘traditional’ single arm studies. 
 
For the first co-primary outcome, PFS, assumptions are that the 
addition of pembrolizumab will increase PFS by 50% to 9.0 
months compared to historical control of 6.0 months.  After 
completion of the study, or when 39 or more subjects have 
experienced a PFS event, the distribution of PFS will be 
summarized using Kaplain-Meier method, and median PFS will 
be reported. A one-sided 5% type I error, 20% type II error and 
exponential distribution of PFS were assumed. Success will be 
defined as a lower 95% one sided confidence limit for the 
median (Brookmeyer, R. and Crowley, J. (1982), “A Confidence 
Interval for the Median Survival Time,” Biometrics, 38, 29-41.) 
being greater than 6 months.  
 
For the second co-primary outcome, response rate, a single stage, 
single arm design will assume a historical control response rate 
of 31% and a hypothesized study rate of 50%. This effect size 
may be detected with 80% power, a one-sided 5% type I error 
rate and 20% type II error rate. Success will be defined as the 
number of responses being greater than or equal to 19 out of 43.  
The analysis of both co-primary outcomes will use the intention-
to-treat approach from the time of registration.   
 
Analytic plan for secondary objectives:   
OS outcomes will be summarized using KM method.  Safety and 
tolerability will be reported as rates of Grade 1-5 toxicity by 
CTCAE v4 criteria for all events with a frequency of ≥ 1. Anti-
tumor activity will be reported as a percentage change in the sum 


Hoosier Cancer Research Network LUN13-175                                                           Confidential 
 
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of the dimensions of all measurable lesions as defined by 
RECIST 1.1 criteria. The baseline imaging before treatment will 
be compared to each subsequent imaging assessment.  The 
maximum anti-tumor activity will be reported using the 
assessment with the smallest sum of dimensions (maximum 
response). 
 
PD-L1 expression will be categorized as positive (≥ 1% 
expression) or negative (< 1% expression) from pre-treatment 
and post-treatment biopsies.  Positive PD-L1 expression rates 
are estimated to be 70%, based on preliminary data from 
pembrolizumab PN 001. The distribution of PFS will be 
summarized by PD-L1 expression using Kaplan-Meier 
method and PFS will be compared using one-sided logrank 
test.  
 
TOTAL  
NUMBER OF 
SUBJECTS 
Phase I: 12 to 24 
Phase II: 43 
ESTIMATED 
STUDY DURATION  
Estimated 36 months utilizing Northwestern University as 
lead institution with additional Hoosier Cancer Research 
Network sites 
 
 
 


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Table of Contents 
 
SYNOPSIS ................................................................................................................................. 3 
1. BACKGROUND AND RATIONALE ......................................................................................... 12 
2. OBJECTIVES ........................................................................................................................ 17 
3. SELECTION OF SUBJECTS .................................................................................................... 18 
4. SUBJECT REGISTRATION ..................................................................................................... 20 
5. TREATMENT PLAN .............................................................................................................. 20 
6. RESPONSE ASSESSMENT .................................................................................................... 35 
7. STUDY PARAMETERS .......................................................................................................... 40 
8. DRUG FORMULATION AND PROCUREMENT ....................................................................... 48 
9. STATISTICAL CONSIDERATIONS .......................................................................................... 53 
10. ADVERSE EVENT REQUIREMENTS ..................................................................................... 58 
11. DATA HANDLING AND RECORD KEEPING .......................................................................... 65 
12. ETHICS ............................................................................................................................. 66 
13. PATHOLOGY REQUIREMENTS ........................................................................................... 67 
14. REFERENCES ..................................................................................................................... 69 
15. APPENDICES ..................................................................................................................... 72 
 


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Carboplatin AUC 6, Day 1 
Nab-paclitaxel 100 mg/m2 Days 1, 8, 15 
MK-3475 200 mg/m2 Day 1 
Cycle length: 21 days 


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1. 
BACKGROUND AND RATIONALE 
The hypothesis of this study is that the addition of pembrolizumab, an anti-PD-1 antibody to 
carboplatin/nab-paclitaxel for the first-line treatment of patients with advanced non-small cell 
lung cancer (NSCLC) will improve the median progression-free survival (PFS) by 4 months 
(from 6 months to 10 months) when compared to historical controls of patients treated with 
carboplatin/nab-paclitaxel alone. 
 
1.1 
Non-Small Cell Lung Cancer 
Lung cancer is the most commonly diagnosed cancer worldwide and accounts for nearly 1.4 
million deaths annually [1].  In the United States, over 228,000 new cases of lung cancer are 
diagnosed each year, and it is the leading cause of cancer mortality, resulting in more deaths than 
breast, prostate, and colon cancer combined [2].  The most common type of lung cancer, 
comprising nearly 7 of 8 cases, is NSCLC.  Over 50% of patients are diagnosed with advanced 
stage disease, and only 18% of all patients with NSCLC are alive five years after diagnosis [3]. 
Platinum-based double chemotherapy has been the standard treatment for patients with good 
performance status (PS) and advanced stage (stage IIIB/IV) NSCLC.  A large cooperative group 
study compared 4 platinum doublets, cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-
docetaxel, and carboplatin-paclitaxel, and found no differences in outcomes, including overall 
survival (OS), between these regimens [4].   
 
1.2 
Maintenance Therapy 
Although some studies have shown that extending chemotherapy beyond four to six cycles of 
platinum-based doublet chemotherapy can improve outcomes in individual patients, early studies 
that continued platinum-based doublets beyond four or six cycles were largely negative due to 
minimal improvements in overall survival and additional toxicity and deterioration of quality of 
life [5].  In 2006, the Eastern Cooperative Oncology Group (ECOG) 4599 study, demonstrated 
an improved overall survival with the addition of bevacizumab, a monoclonal antibody targeting 
VEGF, to carboplatin-paclitaxel chemotherapy.  In this study, bevacizumab was continued past 
induction therapy until progression of disease or unacceptable toxicity.  With the results of this 
study and development of other better-tolerated therapies with activity in lung cancer, there has 
been renewed interest in maintenance therapy.  One of the first notable studies to show that 
maintenance chemotherapy was a viable strategy was conducted by Fidias, et al [6].  In this 
randomized, phase III study, patients who received early docetaxel after induction chemotherapy 
had a 3-month improvement in progression-free survival (PFS) and 2.6-month improvement in 
OS when compared to patients who received second-line docetaxel at the time of progression.  
The OS improvement did not reach statistical significance, but the study was not powered for 
OS.  Continuation of pemetrexed after cisplatin-pemetrexed induction has been shown to 
improve OS by nearly three months to 13.9 months from randomization in the PARAMOUNT 
trial [7].  Similarly, maintenance pemetrexed after other platinum-based doublet chemotherapy 
and maintenance therapy with erlotinib, a tyrosine kinase with anti-EGFR activity, have been 
shown to improve OS [8, 9].  Other maintenance strategies have resulted in significant 
improvement in PFS as well [9-12].  In PointBreak, a trial that randomized 939 patients to two 
commonly used chemotherapy and maintenance strategies, median overall survival from 
initiation of first line treatment was 12.6 months and 13.4 months in the two arms.  There was no 
statistically significant difference between the two arms [12] 
 


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1.3 
Nab-Paclitaxel 
Paclitaxel is an anti-microtubule agent with broad-spectrum activity against human cancers.  
Paclitaxel is dissolved in a proprietary solvent of Cremophor and ethanol in its formulation, 
known as Taxol (Bristol-Myers Squibb, New York, New York).  ABI-007 (nab-paclitaxel, 
Abraxane, Celgene) is a proprietary solvent-free, protein-stabilized formulation of paclitaxel 
comprised of paclitaxel and human albumin in a non-crystalline amorphous state.  Nab-paclitaxel 
has been developed to improve the therapeutic index of paclitaxel and reducing the toxicities 
associated with Taxol.  Nab-paclitaxel has linear pharmacokinetic (PK) characteristics and based 
on its PK properties, the dose and short infusion time, and increase in maximum concentration 
(Cmax) of free paclitaxel up to 10-fold greater than with soluble paclitaxel has been reported in 
the literature [13].  In vitro studies demonstrated that the transport of paclitaxel across the 
endothelium is enhanced through albumin receptor mediated transcytosis, and the delivery of 
paclitaxel to tumors may be enhanced by binding of the albumin-bound paclitaxel to interstitial 
albumin binding proteins, such as secreted protein acidic and rich in cysteine (SPARC) [14].  
Nab-paclitaxel conferred the ability to achieve a higher maximum tolerated dose (MTD) based 
on every 3-weeks dosing: 300 mg/m2 versus 175 mg/m2 of soluble paclitaxel.  Nab-paclitaxel can 
also be given in a shorter timeframe of 30 minutes compared to 3 hours with soluble paclitaxel.  
Nab-paclitaxel is given without steroid and anti-histamine pre-medication, which is required for 
soluble paclitaxel to prevent solvent-related hypersensitivity reactions. 
 
1.4 
Nab-paclitaxel and Lung Cancer 
Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is approved for the treatment of NSCLC 
based on the results of a Phase III study that compared nab-paclitaxel 100 mg/m2 (weekly) and 
carboplatin with soluble paclitaxel (200 mg/m2) and carboplatin [15].  This large non-inferiority 
study randomized 1,052 patients to one of the two arms.  Those receiving nab-paclitaxel had a 
higher overall response rate (ORR) (33% vs. 25%, p=0.005).  The median duration of response 
was similar in both arms; 9.6 months in the nab-paclitaxel/carboplatin arm and 9.5 months in the 
paclitaxel/carboplatin arm (p=0.551).  The nab-paclitaxel arm demonstrated equal efficacy 
compared to the control arm, with significantly less severe peripheral neuropathy, arthralgia, and 
myalgia. 
 
1.5 
Immune Checkpoints 
T-cells are responsible for cellular immunity and are activated when antigen-presenting cells 
(APC) present an antigen to the T-cell receptor (TCR) in the presence of a costimulatory 
molecule, B7.  After activation of the T-cell, cytotoxic T-lymphocyte antigen 4 (CTLA-4), a 
receptor on the T-cell is upregulated and binds to B7 on APCs, which acts as a negative regulator 
of T-cell activation.  Programmed cell death 1 receptor (PD-1), is another receptor on the T-cell 
surface that acts as a negative regulator.  Its normal role is to down-modulate excessive immune 
responses, such as autoimmune reactions. This receptor interacts its ligand (PD-L1 and PD-L2), 
which is often present on tumor or host cells, and when activated, will also downregulate antigen 
receptor signaling [16, 17].  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 [18, 19].  Binding of either PD-L1 or PD-L2 to PD-1 inhibits T-cell activation 
triggered through the T-cell receptor.  PD-L1 is expressed at low levels on various non-
hematopoietic tissues, most notably on vascular endothelium; whereas PD-L2 is only detectably 
expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 


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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 [19]. 
 
1.6 
PD-1 Pathway and Cancer 
The importance of intact functions of immune surveillance in controlling neoplastic 
transformation of cells is well recognized [20].  The presence of T-cell infiltration of tumors, 
such as the presence of CD8+ T cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory 
T-cells (T regs), have been shown to correlate with improved prognosis and survival in multiple 
solid malignancies.  PD-L1 expression by tumors has been linked to the development of 
immunoresistance in cancer cells mediated by its interaction with T-cell PD-1 [21].  Although 
healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor.  High expression of PD-L1 on tumor cells has been found 
to correlate with poor prognosis and survival in multiple solid tumors [22-25]. PD-1 has also 
been suggested to regulate tumor-specific T-cell expansion in patients with melanoma [26].  The 
observed correlation of clinical prognosis with PD-L1 expression in multiple cancers suggests 
that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and is an attractive 
target for therapeutic intervention. 
 
1.7 
Corticosteroids and Immune Response 
Corticosteroids are known to have anti-inflammatory and immunosuppressive effects and are an 
effective therapy for inflammatory disorders, such as autoimmune disease, asthma, and allergies 
[27].  Several molecular mechanisms have been proposed for corticosteroids’ impact on the 
downregulation of T-cell activation, including modulation of activation-induced cell death and 
the inhibition of recruitment of neutrophils and monocytes to inflammatory sites [28].  In vitro 
studies have shown that dexamethasone leads to inactivation of T-cells through downregulation 
of the IL-2 receptors [27].  Glucocorticoids have also been shown to lead to expansion of 
regulatory T-cells mediated by production of TGF-β [29].  It is unclear whether steroid use 
impacts T-cell immune response to tumor cells in patients with cancer. Due to the 
downregulation of T-cell activation, concomitant corticosteroids could potentially blunt a desired 
immune response to anti PD-1 immunotherapy.  Corticosteroids have been successfully used for 
the treatment adverse effects of immunotherapy, such as autoimmune colitis and pneumonitis.   
 
1.8 
Clinical Activity of Immune Checkpoint Inhibitors 
Two phase III studies of ipilimumab, an anti-CTLA4 monoclonal antibody, have shown 
significant improvements in overall survival in patients with metastatic melanoma [30, 31].  
Blocking the PD-1/PD-L1 interaction with anti-PD-1 or anti-PD-L1 antibodies can also increase 
T-cell response to malignancy and lead to tumor cell death in patients with solid tumor 
malignancies, including lung cancer [32-36].  Nivolumab (BMS-936558), a monoclonal antibody 
against PD-1, showed an overall response rate of approximately 28% and 27% in patients with 
advanced melanoma and renal cell carcinoma, respectively [33].  An objective response rate of 
nearly 20% in patients with NSCLC has been observed by targeting PD-1 [33, 37].  
Pembrolizumab has shown an overall response rate of over 40% in patients with melanoma and 
over 20% in patients with NSCLC (Merck pembrolizumab Investigator Brochure). 
 
 
 


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1.9 
Pembrolizumab 
Pembrolizumab is a highly selective humanized mAb designed to block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4/kappa isotype with a 
stabilizing sequence alteration in the Fc region.  Pembrolizumab potently blocks binding to both 
ligands with half maximal inhibitory concentration (IC50) values below1 nM. Pembrolizumab 
enhances T cell responses in human donor blood cell cultures with an EC50 of ~0.1 to 0.3 nM.  
Pembrolizumab binds to cynomolgus PD-1 with similar affinity, blocking activity, and 
demonstrates equivalent enhancement of cynomolgus T cell responses. It does not cross-react 
with rodent PD-1 (Merck, Inc. pembrolizumab Investigator Brochure). 
 
Pembrolizumab strongly enhances T lymphocyte immune responses in cultured blood cells from 
healthy human donors, cancer patients, and primates. The antibody potentiates existing immune 
responses only in the presence of antigen-receptor stimulation and does not nonspecifically 
activate all T cells.  Using an anti-mouse PD-1 analog antibody, PD-1 blockade is demonstrated 
to significantly inhibit tumor growth in a variety of syngeneic murine tumor models. In 
experiments in mice, anti-PD-1 therapy is synergistic with chemotherapeutic agents such as 
gemcitabine and 5-FU and combination therapy results in increased efficacy and increased 
complete regression rates in vivo. In addition, there has been significant clinical experience with 
pembrolizumab (Merck, Inc. pembrolizumab Investigator Brochure).    
 
1.10 
Pembrolizumab Dose Selection Rationale 
The dose regimen of 200 mg Q3W of pembrolizumab is planned for all cancer trials. Available 
PK results in subjects with melanoma, NSCLC, and other solid tumor types support a lack of 
meaningful difference in PK exposures obtained at a given dose among tumor types. An open-
label Phase 1 trial (PN001) in melanoma subjects is being conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab.  The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors.  All three dose levels were well tolerated and no 
dose-limiting toxicities were observed.  This first in human study of pembrolizumab showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose levels 
(1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No maximum tolerated dose (MTD) has been 
identified. 
 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed.  The clinical 
efficacy and safety data demonstrate a lack of clinically important differences in efficacy 
response or safety profile at these doses.  For example, in Cohort B2, advanced melanoma 
subjects who had received prior ipilimumab therapy were randomized to receive pembrolizumab 
at 2 mg/kg versus 10 mg/kg Q3W.  The overall response rate (ORR) was 26% (21/81) in the 
2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set (FAS)).  The proportion 
of subjects with drug-related adverse events (AEs), grade 3-5 drug-related AEs, serious drug-
related AEs, death or discontinuation due to an AE was comparable between groups or lower in 
the 10 mg/kg group. 
 
 
 


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Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a given 
dose among tumor types.  Population PK analysis has been performed and has confirmed the 
expectation that intrinsic factors do not affect exposure to pembrolizumab to a clinically 
meaningful extent.  Taken together, these data support the use of lower doses (with similar 
exposure to 2 mg/kg Q3W) in all solid tumor indications.  2 mg/kg Q3W is being evaluated in 
NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated in head and 
neck cancer in PN012, which are expected to provide additional data supporting the dose 
selection. 
 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation 
results indicating that 200 mg will provide exposures that are reasonably consistent with those 
obtained with 2 mg/kg dose and importantly will maintain individual patient exposures within 
the exposure range established in melanoma as associated with maximal clinical response.  A 
population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed using available data from 476 subjects from PN001.   
The distribution of exposures from the 200 mg fixed dose are predicted to considerably overlap 
those obtained with the 2 mg/kg dose, with some tendency for individual values to range slightly 
higher with the 200 mg fixed dose.   The slight increase in PK variability predicted for the fixed 
dose relative to weight-based dosing is not expected to be clinically important given that the 
range of individual exposures is well contained within the range of exposures shown in the 
melanoma studies of 2 and 10 mg/kg to provide similar efficacy and safety.  The population PK 
evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there 
are no anticipated changes in exposure between different tumor types and indication settings. 
 
1.11 
Study Rationale 
Checkpoint inhibitors, specifically those targeting PD-1, have demonstrated striking efficacy in 
multiple solid tumors, including lung cancer.  These agents are particularly promising due to the 
potential of inducing prolonged responses in a disease that traditionally has very short 
progression-free intervals.  Pembrolizumab is a novel PD-1 inhibitor with demonstrated activity 
in lung cancer in the phase I setting.  Due to the potential of prolonged response, starting 
pembrolizumab in the first line setting combined with standard chemotherapy may maximize the 
potential benefit from this drug.   
 
Corticosteroids, often at high doses, are frequently administered in conjunction with cytotoxic 
chemotherapeutics, such as paclitaxel, as anti-emetic therapy or to prevent hypersensitivity.  
Unfortunately, corticosteroids are known to decrease T-cell mediated inflammation, and high 
doses of corticosteroids could lead to decreased efficacy of concomitant immunotherapy. Nab-
paclitaxel combined with carboplatin, unlike paclitaxel, does not require additional corticosteroid 
premedication that is required with paclitaxel.  
 
Nab-paclitaxel may have additional benefits when paired with immunotherapy beyond the ability 
to omit corticosteroid use.  Secreted protein acidic and rich in cysteine (SPARC) is responsible 
for maintaining extracellular matrix [38], has a high affinity for albumin, has been shown to be 
over-expressed in NSCLC, and may correlate with prognosis [39].  The recognition of SPARC 


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over-expression in NSCLC is important when targeting an immune response because the density 
and organization of the extracellular matrix may control migration of T cells to tumors [40].  
Nab-paclitaxel, due to its albumin-bound properties, may be better able to disrupt the 
extracellular matrix where SPARC is over-expressed and allow for better PD-1 inactivated T-cell 
migration to the tumor targets. In this phase II study, we propose the addition of pembrolizumab 
to standard induction chemotherapy with carboplatin and nab-paclitaxel without the use of 
corticosteroids for patients with advanced NSCLC. 
 
This Phase I/II trial will study the effects of pembrolizumab in combination with carboplatin 
/nab-paclitaxel for the first-line treatment of patients with advanced NSCLC. 
 
2. 
OBJECTIVES  
 
2.1 
Primary Objectives 
 
2.1.1 Phase I 
To determine the recommended Phase II dose (RP2D) and evaluate the safety and tolerability of 
the combination of pembrolizumab with carboplatin/nab-paclitaxel for the first line treatment of 
subjects with advanced NSCLC. 
 
2.1.2 Phase II 
To evaluate progression-free survival (PFS) and objective response for subjects receiving 
pembrolizumab and carboplatin/nab-paclitaxel for the first line treatment of advanced NSCLC. 
 
2.2 
Secondary Objectives 
 
2.2.1 Phase I  
To describe the following for subjects receiving pembrolizumab and carboplatin/nab-paclitaxel: 
• Progression-free survival (PFS) 
• Objective response  
• Anti-tumor activity 
• Overall survival (OS) 
• To evaluate the association of PD-L1 expression on PFS for subjects receiving 
pembrolizumab 
 
2.2.2 Phase II 
• To evaluate the following for subjects receiving pembrolizumab and 
carboplatin/nab-paclitaxel:  
o Overall survival (OS)  
o Anti-tumor activity 
o Safety and tolerability 
• To evaluate the association of PD-L1 expression on PFS for subjects receiving 
pembrolizumab 
 
 
 


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3 
SELECTION OF SUBJECTS 
Accrual will take place at Northwestern University (NU) and other sites in the Hoosier Cancer 
Research Network (HCRN). The study will enroll 12 to 24 subjects in the Phase I part and 43 
subjects in the phase II part for a total of 55 to 67 subjects.  It is estimated that 25 potentially 
eligible subjects may be evaluated per month, and approximately 6 will be enrolled per month.  It 
is estimated that accrual will be completed in one year and the total study duration will be 3 
years. 
 
3.1 
Inclusion Criteria 
 
1. Subjects must be willing and able to provide written informed consent for the trial and 
HIPAA authorization for release of protected health information. 
NOTE: HIPAA authorization may be included in the informed consent or obtained 
separately. 
2. Subjects must be ≥ 18 years of age. 
3. Individuals with stage IIIB or IV, unresectable non-small cell lung cancer (NSCLC) who 
have not received prior chemotherapy for Stage IIIB or IV disease, and who are not 
candidates for curative surgery or radiation therapy. 
4. ECOG performance status (PS) 0-1 
5. Measurable disease by RECIST v1.1 criteria 
6. Prior to registration, all subjects should have archival tissue available.  For subjects who 
have no archival tissue, but have PD-L1 testing results using the Dako 22C3 antibody, 
subjects will be permitted to enroll without submitting tissue.  If the patient has not had 
prior testing and no acceptable archival tissue is available, subjects must be willing to 
consent to providing a pre-treatment biopsy for PD-L1 testing.  Regardless of PD-L1 
testing status, archival tissue will be requested for research testing if available.  PD-L1 
status is required but does not need to be positive to be eligible for study. 
7. Phase II subjects must be willing to consent to providing a mandatory post-treatment core 
biopsy for research if clinically feasible. 
8. Women are eligible to participate if they are of non-childbearing potential or have 
documentation of a negative pregnancy test (serum or urine β-hCG) within 3 days of 
registration.  Sexually active pre-menopausal women of childbearing potential must agree 
to use adequate, highly effective contraceptive measures, starting with the first dose of 
study drug and for 120 days after the last dose of last study drug.  Effective birth control 
includes (a) intrauterine device (IUD) plus one barrier method; (b) oral, implantable, or 
injectable contraceptives plus one barrier method; or (c) 2 barrier methods.  Effective 
barrier methods are male or female condoms, diaphragms, and spermicides (creams or 
gels that contain a chemical to kill sperm). Women of childbearing potential are those 
who have not been surgically sterilized or have not been free from menses for ≥ 1 year.  
10. Male subjects should agree to use an adequate method of contraception starting with the 
first dose of study drug through 120 days after the last dose of last study drug. 
 
 
 


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3.2 
Exclusion Criteria 
 
1. Individuals with the presence of symptomatic CNS metastases requiring radiation 
treatment, surgery, or ongoing use of corticosteroids. 
2. Untreated or brain metastasis causing any symptoms, such as neurologic deficits or 
headache. Individuals with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior 
to the first dose of study drug and any neurologic symptoms have returned to baseline 
and whole brain radiation or stereotactic radiosurgery completed over 4 weeks prior to 
registration), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to study treatment. 
3. History of solid organ or stem cell transplant requiring immunosuppressive medications. 
4. Any prior adjuvant cytotoxic chemotherapy within 12 months of registration.  Subjects 
who received chemotherapy for earlier stage disease more than 12 months prior to study 
registration are eligible for this trial. 
5. 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).  
6. Any radiotherapy within 2 weeks prior to registration (4 weeks for brain radiotherapy as 
noted above). 
7. 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. 
8. History of other invasive malignancy that is currently active and/or has been treated 
within 12 months of registration.  (Notable exceptions include: basal cell carcinoma, 
squamous cell carcinoma of the skin, localized prostate cancer, in situ carcinomas of the 
cervix and breast, and superficial bladder cancers [non-muscle-invasive]). 
9. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
10. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.    
11. Pulmonary conditions such as sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or 
hypersensitivity pneumonitis.  
12. Has a history of pneumonitis that required steroids or current pneumonitis. 
13. Pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE v 4 criteria. 
14. Known significant liver disease including viral, alcoholic, active hepatitis B or C, and/or 
cirrhosis. 
15. Abnormal liver or renal function as defined as: 
• Bilirubin ≥ 1.5 mg/dL 
• AST or ALT ≥ 2.5 x the ULN 
• Alkaline phosphatase > 2.5 x the ULN, there is no upper limit if bone metastasis 
is present in the absence of liver metastasis 
• Creatinine > 1.5 mg/dl 
 
 


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16. Abnormal baseline hematologic or coagulation parameters as defined as: 
• Absolute neutrophil count (ANC) <1.5 x 109/L 
• Hemoglobin < 9.0 g/dL; subjects may not be transfused to meet enrollment 
criteria 
• Platelets < 100 x 109/L 
• International Normalized Ratio (INR) of Prothrombin Time (PT) ≥1.5 x ULN 
unless subjects is receiving anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants 
• Activated Partial Thromboplastin Time (aPTT) ≥ 1.5 x ULN unless subjects is 
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
17. Has received a live vaccine within 30 days prior to the first dose of study drug.   
18. Known activating EGFR mutation or ALK translocation.  Testing is not required but 
should be performed if clinically indicated; results are not required prior to enrollment. 
19. 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 pembrolizumab. 
 
4 
SUBJECT REGISTRATION  
All subjects must be registered through the Hoosier Cancer Research Network (HCRN) 
electronic data capture (EDC) system.  A subject will be considered registered when they are 
given an “on study” date in the EDC system.  Subjects must be registered prior to starting 
protocol therapy and begin therapy within five business days of registration. 
 
5 
TREATMENT PLAN 
 
5.1 
Administration 
All subjects in both phases of this study will be treated in cycles lasting 21 days (3 weeks).  The 
drugs being used in this study include carboplatin, nab-paclitaxel, and pembrolizumab.  All 
subjects in both phases of the study will receive carboplatin/nab-paclitaxel and pembrolizumab 
as induction therapy.  Induction will continue for no more than 4 cycles of study treatment.  
Maintenance pembrolizumab will be continued for subjects without progression (complete 
response [CR], partial response [PR], or stable disease [SD] as defined by RECIST v1.1 criteria) 
after completion of 4 cycles of study treatment until the time of progression, unacceptable 
toxicity, or up to 2 years maximum from C1D1 (see Table 1).   
 
After completion of Phase I, the Phase II part of the study will begin with pembrolizumab at a 
dose of 200 mg in combination with chemotherapy.  
 
 
 


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Table 1: Treatment Schedules 
Abbreviations: IV-intravenous; mg-milligrams; kg-kilograms; m2-per meter squared 
*As additional data from ongoing trials becomes available, the dose of pembrolizumab may be adjusted.   
See section 5.1.2.1 below. 
 
5.1.1 Treatment Schedules 
 
5.1.1.1 
Phase I, Cohort 1 
Induction Therapy 
12 subjects will be enrolled to Cohort 1 and treated with carboplatin AUC 6 given IV on Day 1, 
nab-paclitaxel 100 mg/m2 given IV on Days 1, 8, and 15, and pembrolizumab 2* mg/kg IV on 
Day 1. Treatment will continue for a maximum duration of 4 cycles. 
 
Maintenance Therapy 
For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles study 
treatment, maintenance therapy with pembrolizumab 2* mg/kg will continue on Day 1 of each 
21-day cycle.  Treatment will continue until progression of disease, unacceptable toxicity, or for 
a maximum of 2 years from Cycle 1, Day 1.  Subjects who complete 24 months of treatment with 
pembrolizumab may be eligible for up to one year of additional study treatment if they progress 
after stopping study treatment provided they meet the requirements detailed in Section 3.1 
Inclusion Criteria. 
 
*As additional data from ongoing trials becomes available, the dose of pembrolizumab may be 
adjusted.  See section 5.1.2.1 below. 
 
Induction Therapy 
Maintenance if CR/PR/SD 
Phase I, 
Cohort 1 
1. carboplatin AUC 6 IV, Day 1 
2. nab-paclitaxel 100 mg/m2 IV,  
Days 1, 8, 15 
3. pembrolizumab 2* mg/kg IV,  
Day 1  
Cycle length: 21 days 
Duration: maximum 4 cycles 
 
pembrolizumab 2* mg/kg, Day 1  
Cycle length: 21 days 
 
Duration: until progressive disease, 
unacceptable toxicity, or up to 2 years 
maximum 
Phase I, 
Cohort 2  
(if necessary) 
1. carboplatin AUC 6 IV, Day 1 
2. nab-paclitaxel 100 mg/m2 IV, 
Days 1, 8, 15 
3. pembrolizumab 2* mg/kg IV,  
Day 1 (Cycle 2-4 only) 
Cycle length: 21 days 
Duration: maximum 4 cycles
pembrolizumab 2* mg/kg, Day 1 
Cycle length: 21 days 
 
Duration: until progressive disease, 
unacceptable toxicity, or up to 2 years 
maximum 
Phase II 
1. carboplatin AUC 6 IV, Day 1 
2. nab-paclitaxel 100 mg/m2 IV,  
Days 1, 8, 15 
3. pembrolizumab 200 mg IV Day 1 
of each cycle 
Cycle length: 21 days 
Duration: maximum 4 cycles of 
study treatment 
pembrolizumab 200 mg, Day 1 of  
Cycle 5 and beyond. 
Cycle length: 21 days 
Duration: until progressive disease, 
unacceptable toxicity or a maximum of 
2 years from C1D1. 


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5.1.1.2 
Phase I, Cohort 2 
Induction Therapy 
If unacceptable toxicity is seen in Phase I, Cohort 1, 12 additional subjects will be enrolled in 
Phase I, Cohort 2.  Subjects will be treated with carboplatin AUC 6 given IV on Day 1 and nab-
paclitaxel 100 mg/m2 given IV on Days 1, 8, and 15.  Pembrolizumab 2* mg/kg IV will be given 
on Day 1 starting in cycle 2. Treatment will continue for a maximum duration of 4 cycles 
(pembrolizumab given Cycles 2 to 4 only). 
 
Maintenance Therapy 
For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction 
therapy, maintenance therapy with pembrolizumab 2* mg/kg will continue on Day 1 of each 21-
day cycle.  Treatment will continue until progression of disease, unacceptable toxicity, or for a 
maximum of 2 years from Cycle 2, Day 1. Subjects who complete 24 months of treatment with 
pembrolizumab may be eligible for up to one year of additional study treatment if they progress 
after stopping study treatment provided they meet the requirements detailed in Section 3.1 
Inclusion Criteria. 
 
*As additional data from ongoing trials becomes available, the dose of pembrolizumab may be 
adjusted.  See section 5.1.2.1 below. 
 
5.1.1.3 
Phase II 
Induction Therapy Cycles 1-4 
Subjects will be treated with carboplatin AUC 6 given IV on Day 1, nab-paclitaxel 100 mg/m2 
given IV on Days 1, 8, and 15, and pembrolizumab 200 mg IV on Day 1. Treatment will 
continue for a maximum duration of 4 cycles of study treatment.  Each cycle starts when all the 
criteria to start a new cycle are met. A cycle is defined only when you can give all 3 drugs on 
Day 1, and it coincides with pembrolizumab.  Pembrolizumab should be given with carboplatin 
and nab-paclitaxel on day 1 of the cycle.  Chemotherapies may be withheld for six weeks, while 
pembrolizumab can be withheld for 12-weeks.  If there is a pembrolizumab-specific toxicity 
requiring pembrolizumab to be held, chemotherapy should be resumed without pembrolizumab 
within 6 weeks if it is felt that chemotherapy is safe by the site investigator. Delays in 
chemotherapy beyond 6 weeks require withdrawal from the study treatment.   
 
Maintenance Therapy 
For subjects who have confirmed CR, PR, or SD (non-progression) after 4 cycles of induction 
therapy, maintenance therapy with pembrolizumab 200 mg will continue on Day 1 of each 21-
day cycle. Treatment will continue until progression of disease, unacceptable toxicity, or for a 
maximum of 2 years from Cycle 1 Day 1.  Subjects who complete 24 months of treatment with 
pembrolizumab may be eligible for up to one year of additional study treatment if they progress 
after stopping study treatment provided they meet the requirements detailed in Section 3.1 
Inclusion Criteria. 
 
*As additional data from ongoing trials becomes available, the dose of pembrolizumab may be 
adjusted.  See section 5.1.2.1 below. 
 


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5.1.2 Dosing and route of administration 
 
5.1.2.1 
Pembrolizumab 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion on Day 1 of each cycle.  
Pembrolizumab, when given on the same day as chemotherapy, will be administered prior to 
other chemotherapy agents.  The dose of pembrolizumab used in the study may be adjusted 
based on emerging data provided by Merck.   
 
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 -five minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).   
 
5.1.2.2 
Nab-paclitaxel 
Nab-paclitaxel will be dosed at 100 mg/m2 and be administered as an intravenous (IV) infusion 
of reconstituted solution over 30 minutes.  The solution has a concentration of 5 mg/mL.  The 
total volume infused can be calculated as 20 mL/m2 based on body surface area (BSA) 
calculations for height and weight on Day 1 of each cycle.  Nab-paclitaxel dose should be 
completely administered before initiating carboplatin dose. 
 
5.1.2.3 
Carboplatin 
Carboplatin will be dosed at an AUC of 6 and given as an IV infusion in 250 mL of D5W or NS 
over 30 minutes.  
 
5.1.2.4 
Dose Calculations 
Body Surface Area (BSA) 
BSA calculations will be used for dosing of nab-paclitaxel.  BSA should be calculated on Day 1 
of each cycle based on the subject’s current height and weight using institutional standards. Dose 
modifications of all drugs should occur when the subject’s weight changes >5% from baseline. 
 
Area Under the Curve (AUC) 
Dosing of carboplatin will be calculated using the Calvert formula, using the target AUC and 
glomerular filtration rate (GFR) on Day 1 of each cycle.  This formula is as follows: mg = AUC 
x (GFR +25).  GFR should be calculated using the Cockroft & Gault method using the subject’s 
actual body weight.  For the dosing calculation, the maximum GFR should be capped at 125 
mL/min. 
 
5.2 
Dose Modifications 
All toxicities should be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 4, which can be located on the 
CTEP website at http://ctep.cancer.gov.   
 
All dose reductions of chemotherapy are considered permanent.  Once a dose of chemotherapy is 
reduced, it will not be increased to previous level, even if toxicity has resolved. Subjects who 
miss a treatment of chemotherapy and/or pembrolizumab for a reason unrelated to toxicity 
need to resume therapy ≤ 7 days of the originally planned treatment.  If a delay of more than 7 
days occurs, the subject will be taken off treatment.   


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5.2.1 Dosing Levels and Toxicity Management 
Table 2 should be used for all dosing adjustments based on the toxicities described in this 
section. 
 
Table 2: Dose Levels for carboplatin, nab-paclitaxel and Pembrolizumab 
 
Carboplatin 
Nab-paclitaxel 
Pembrolizumab 
Original Dose 
AUC 6 
100 mg/m2  
See below 
1st Dose Reduction 
AUC 4.5
75 mg/m2 
See below 
2nd Dose Reduction 
AUC 3 
50 mg/m2 
See below 
 
5.2.1.1 
Definition of Dose-limiting Toxicity (DLT) 
The occurrence of any of the following toxicities, which may be observed within the first 2 
cycles of treatment, will be considered a DLT, if judged by the site investigator to be possibly, 
probably or definitely related to pembrolizumab or the combination of pembrolizumab plus the 
cytotoxic chemotherapy regimen: 
• More than one missed dose of pembrolizumab (i.e., pembrolizumab not given during 2 or 
more cycles for any reason).  NOTE: a 1 week delay in starting a cycle for any 
hematologic toxicity (see section 5.2.1.3) does not count as a missed dose. 
• Any ≥ Grade 2 uveitis or eye pain that does not respond to topical therapy and does not 
improve to Grade 1 severity within the re-treatment period (≤ 6 weeks and/or prior to 
next pembrolizumab dose) OR requires systemic treatment. 
• Any ≥ Grade 2 pneumonitis or interstitial lung disease that does not resolve with dose 
delay and systemic steroids. The management algorithm for pneumonitis or pulmonary 
toxicity can be found in the current pembrolizumab Investigator Brochure. 
• Any ≥ Grade 3 febrile neutropenia. 
• Any Grade 3 non-skin, non-laboratory adverse event lasting ≥ 3 days despite optimal 
supportive care. Any ≥ Grade 4 adverse event including laboratory abnormalities, except 
Grade 4 leukopenia or neutropenia lasting < 7 days and not accompanied by fever. 
• Any liver function test (LFT) abnormality that meets the following criteria: 
o AST or ALT > 5 to 8 x ULN and/or total bilirubin > 3x ULN for > 2 weeks. 
o AST or ALT > 8 x ULN. 
o Total bilirubin > 5 x ULN. 
o ALT/AST > 3 x ULN and total bilirubin > 2 x ULN with alkaline phosphatase 
activity < 2 x ULN and no other reason can be found to explain the combination 
of elevations. 
• Grade 3 thrombocytopenia associated with bleeding. 
 
For the purposes of pembrolizumab dose decision-making, DLTs will be evaluated for the first 2 
cycles of pembrolizumab treatment.  Any AE with the potential to become a DLT based on the 
duration should be followed appropriately to accurately determine the duration of the event.  
Subjects should delay/interrupt or discontinue treatment if they experience any adverse event, 
laboratory abnormality or intercurrent illness (regardless of causality) which, in the opinion of 
the site investigator, presents a substantial clinical risk to the subject with continued dosing. Such 
delay/interruption or discontinuation, however, will not be considered a DLT unless it meets at 
least one of the DLT criteria defined above or if deemed dose-limiting by the DRC. 


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5.2.1.2 
Dose modifications specifically for pembrolizumab 
Subjects with evidence of PD by RECIST 1.1 criteria may continue to receive pembrolizumab 
beyond progression until confirmation scan is completed if they meet the following criteria:  
• Absence of clinical significant symptoms and signs (including worsening of laboratory 
values) indicating PD. 
• No decline in ECOG performance status (Appendix 16.2). 
• Absence of rapid progression of disease or progressive tumor at critical anatomical sites 
(e.g., cord compression) requiring urgent alternative medical intervention. 
 
In this scenario, pembrolizumab may continue for another 2 cycles for a repeat response 
assessment at 6 weeks later to evaluate response.  If progression is confirmed, the subject will 
discontinue treatment. 
 
If a dose of pembrolizumab is withheld for toxicity, then subjects may resume dosing with 
pembrolizumab if that is appropriate at their next scheduled appointment or when toxicity has 
improved as described below.   
 
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-
threatening AEs as per Table 3 below. Table 16.3 Chemotherapy Dose Modification and 
Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
should be utilized as appropriate. 
 
In the case that toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, study 
therapy should be discontinued after consultation with the sponsor-investigator (NOTE: this 
only applies to subjects on maintenance pembrolizumab alone.  For delays ≥ 3 weeks from a 
scheduled Day 1 carboplatin dose (i.e., 6 weeks from last carboplatin dose), all treatments will be 
discontinued.  Subjects who require corticosteroids to manage pembrolizumab-related AEs must 
be at an equivalent dose of ≤ 10 mg per day of prednisone to resume dosing with 
pembrolizumab.  Furthermore, an inability to reduce the corticosteroid dose for managing a 
drug-related adverse event to the equivalent of ≤ 10 mg prednisone per day within 12 weeks of 
the last pembrolizumab dose should prompt discussion between the site investigator and sponsor-
investigator regarding the subject’s ability to continue on treatment in the study.  With site 
investigator and sponsor-investigator agreement, subjects with a laboratory adverse event still at 
Grade 2 after 12 weeks may continue treatment in the study only if asymptomatic and controlled.  
 
In subjects who continue on pembrolizumab having experienced a Grade 3, Grade 4, or 
persistent (> 4 weeks) Grade 2 pembrolizumab-related AE, dosing should be held until the AE 
resolves to Grade 0-1 or baseline and dosing should be resumed at 2 mg/kg every 3 weeks for 
Phase I subjects and 200 mg every 3 weeks for Phase II subjects.   
 
However, in subjects who experience Grade 3 or 4 pneumonitis, or recurrent persistent  
(> 4 weeks) Grade 2 drug-related pneumonitis after re-challenge from a prior episode of 
persistent (> 4 weeks) Grade 2 drug-related pneumonitis, pembrolizumab must be permanently 
discontinued. 
 


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Table 3 Dose Modification Guidelines for Pembrolizumab Drug-Related Adverse Events 
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 6 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent 
per day within 6 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 6 
weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or 3-4 
Hold pembrolizumab for 
new onset Type 1 diabetes 
mellitus or Grade 3-4 
hyperglycemia associated 
with evidence of beta cell 
failure. 
Resume pembrolizumab when 
subjects 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 6 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent 
per day within 6 weeks. 
Hyperthyroidis
m  
3 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 6 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent 
per day within 6 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
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 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 6 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent 
per day within 6 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
 
 


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Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 6 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent 
per day within 6 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related 
Toxicity2 
3 or Severe 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 6 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent 
per day within 6 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. 
1 For subjects 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 subjects 
should be discontinued. 
2 Subjects 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 6 weeks of the 
last dose. 
 
5.2.1.3 
Dose Modifications for Hematologic Toxicity 
A CBC with differential will be obtained on Day 1 of each cycle and each day the subject 
receives nab-paclitaxel.  Day 1 carboplatin and nab-paclitaxel may only be given if the platelets 
count ≥ 100 x 109/L and ANC ≥ 1.5 x 109/L.  A CBC with differential will also be obtained on 
Day 8 and Day 15 prior to nab-paclitaxel dosing. Filgrastim support per FDA labeled guidelines 
may be utilized Cycle 2 or subsequent Cycles if warranted by neutropenic fever or neutrophil 
count causing delay or dose reduction in chemotherapy. 
 
Hematologic toxicities requiring dose modification of carboplatin and nab-paclitaxel are as 
follows (see also 5.2.1.1). These are considered a DLT if occurring during the first 2 cycles: 
 Grade 4 hematologic toxicity: 
o Lasting ≥ 7 days OR 
 Febrile neutropenia Grade 3 or Grade 4: 
o Grade 3 is defined as ANC < 1000/mm3 with a single temperature of > 38.3 
degrees C (101° F) or a sustained temperature of ≥ 38 degrees C (100.4° degrees 
F) for > 1 hour. 
o Grade 4 is defined as ANC < 1000/mm3 with a single temperature of > 38.3 
degrees C (101° F) or a sustained temperature of ≥ 38 degrees C (100.4° F) for 
more > 1 hour, with life-threatening consequences and urgent intervention 
indicated 
 Grade 3 or Grade 4 thrombocytopenia if associated with: 
o A bleeding event which does not result in hemodynamic instability but requires an 
elective platelet transfusion, or 
o A life-threatening bleeding event which results in urgent intervention and 
admission to an Intensive Care Unit 
 


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All other hematologic toxicities that do not meet the above specifications are not considered a 
DLT. 
 
For Day 1 hematologic toxicities occurring for cycles 1-4, the current cycle should be delayed by 
1 week. A cycle is defined only when you can give all 3 drugs on Day 1, and it coincides with 
pembrolizumab.  A CBC with differential should be checked at least once a week if carboplatin, 
nab-paclitaxel, or pembrolizumab is not given on Day 1. Study treatment may be resumed after a 
1 week delay if the platelet count is ≥ 100 x 109/L and ANC is ≥ 1.5 x 109/L.  Continuation at the 
same dose or at a reduced dose is based on investigator discretion unless the above criteria 
requiring dose reduction is met.  If chemotherapy is delayed more than 1 week, dose reductions 
should occur.  Refer to nab-paclitaxel product label for guidance.  
• If platelets remain < 100 x 109/L and/or ANC < 1.5 x 109/L and chemotherapy cannot 
resume within 6 weeks of last chemotherapy, all treatments should be discontinued. 
 
Special consideration for weekly nab-paclitaxel dosing on Day 8 and Day 15: 
• For hematologic toxicities occurring on Day 8 or 15 of the cycle, treatment can be held or 
dose reduced based on site investigator discretion.  If there is concern regarding ability to 
dose on Day 8 or Day 15, labs may be obtained locally within 48 hours prior to the dose 
of nab-paclitaxel for subject convenience. If the subject does not receive dosing on Day 8 
or Day 15, due to counts or for other reasons, an AE assessment should be done via 
telephone call by research staff. If clinical concerns arise regarding AEs, the patient 
should be seen in a clinic for further AE assessment and treatment as clinically indicated. 
If the criteria requiring dose reductions for hematologic toxicities listed above are not 
met, a dose reduction is not required, but is permissible based on site investigator 
discretion.  Refer to nab-paclitaxel product label for guidance. If a dose reduction is 
indicated, permanently reduce nab-paclitaxel and carboplatin doses as specified in Table 
4.   
 
Table 4: Dose Reductions for Hematologic Toxicity 
*Episodes = febrile neutropenia, severe neutropenia, or platelet nadir < 25 x 109/L 
 
5.2.1.4 
Dose Modifications for Renal Toxicity 
Glomerular filtration rate (GFR) as calculated by the standard Cockcroft and Gault formula must 
be used to calculate creatinine clearance (CrCl) prior to each dose of carboplatin on Day 1 of 
each cycle.  Only subjects with a CrCl of ≥ 30 mL/min will be treated.   
• If CrCl < 30 mL/min, carboplatin, nab-paclitaxel, and pembrolizumab should be held. 
 
Carboplatin 
Nab-paclitaxel
Pembrolizumab
1st 
episode* 
Dose reduce to AUC 4.5 
Dose reduce to 75 mg/m2 
No adjustments 
2nd 
episode 
Dose reduce to AUC 3 
Dose reduce to 50 mg/m2 
No adjustments 
3rd 
episode 
Discontinue 
Discontinue 
Discontinue 
Anemia 
No adjustments 
No adjustments 
No adjustments 


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• If a Grade 3 or Grade 4 toxicity (Table 5) occurs, carboplatin and pembrolizumab should 
be held. 
 
Table 5: CTCAE Grading of Renal Toxicity 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Creatinine 
increased 
> 1 - 1.5 x baseline;  
> ULN - 1.5 x ULN 
> 1.5 - 3.0 x baseline; 
> 1.5 - 3.0 x ULN 
> 3.0 x baseline; 
> 3.0 - 6.0 x ULN 
> 6.0 x ULN 
Abbreviations: ULN, upper limit of normal 
 
If medications are held, a serum chemistry should be checked and CrCl calculated at least once a 
week.  Carboplatin may be resumed at one dose level lower (See Table 2) once the CrCl returns 
to ≥ 30 mL/min or returns to Grade 1 toxicity level.  Pembrolizumab can be resumed at standard 
dose. 
• If CrCl remains < 30 mL/min or > Grade 1 toxicity for ≥ 3 weeks after last dose of 
carboplatin or pembrolizumab, all treatments should be discontinued and the subject will 
come off study. 
 
5.2.1.5 
Dose Modifications for Hepatic Toxicity 
Hepatic function labs should be assessed on Day 1 of each cycle.  Laboratory criteria for dose 
reductions are detailed in Table 6.  If any medications are required to be held, hepatic function 
labs should be repeated once a week.  Treatment can be resumed once liver function tests return 
to acceptable levels.   
• If liver function tests remain elevated (AST > 10 x ULN and Alk Phos > 10 x ULN or 
Bilirubin > 5 x ULN) for ≥ 3 weeks after last dose of nab-paclitaxel or pembrolizumab, 
all treatments should be discontinued. 
 
Table 6: Dose Reductions for Hepatic Toxicity 
AST/ALT 
 
Alkaline 
phosphatase 
 
Bilirubin 
Nab-paclitaxel Pembrolizumab
< 10 x 
ULN 
and 
< 5 x ULN 
and 
> ULN- 
1.25 x ULN
100% 
100% 
< 10 x 
ULN 
and 
< 5 x ULN 
or 
> 1.25- 
2 x ULN
Reduce to  
75 mg/m2
100% 
< 10 x 
ULN 
and 
< 10 x ULN 
or 
> 2-5 x ULN 
Reduce to  
50 mg/m2
Discontinue* 
> 10 x 
ULN 
or  
> 10 x ULN 
or 
> 5 x ULN 
Discontinue 
Discontinue 
*See specific recommendations for immune-related hepatic toxicity. 
 
5.2.1.6 
Dose Modifications for Sensory Peripheral Neuropathy Toxicity 
Sensory peripheral neuropathy assessment will be conducted at screening by history and graded 
by CTCAE v4.  Withhold nab-paclitaxel and carboplatin for Grade 3-4 sensory peripheral 
neuropathy.  Resume nab-paclitaxel and carboplatin at reduced doses (see Table 7 below) when 
sensory peripheral neuropathy improves to Grade 1 or completely resolves. 
 
 
 


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Table 7: Dose Reductions for Sensory Peripheral Neuropathy 
 
Occurrence 
Nab-paclitaxel  
Carboplatin 
Sensory Neuropathy 
Grades 3-4 
First 
Dose reduce to 75 mg/m2 
Dose reduce to AUC 4.5 
Second 
Dose reduce to 50 mg/m2
Dose reduce to AUC 3 
Third 
Discontinue 
Discontinue 
 
5.3 
Rescue Medications and Supportive Care 
 
5.3.1 Nausea/vomiting  
Nausea and vomiting should be treated aggressively, and consideration should be given in 
subsequent cycles to the administration of prophylactic antiemetic therapy according to standard 
institutional practice.  Subjects should be strongly encouraged to maintain liberal oral fluid 
intake. 
 
5.3.1.1 
Carboplatin and nab-paclitaxel 
Steroids should be avoided as premedication for chemotherapy, especially in subjects 
receiving pembrolizumab.  Suggested anti-emetic prophylaxis for carboplatin and nab-
paclitaxel is as follows: 
• Palonosetron 0.25 mg IV Day 1 only 
o OR: ondansetron 16-24 mg PO or 8-16 mg IV followed by ondansetron 8 
mg PO or IV every 8-12 hours through Day 3 
• Aprepitant 125 mg PO Day 1 and 80 mg PO daily for Days 2-3 
o OR: fosaprepitant 150 mg IV Day 1 
• As needed: 
o Ondansetron 8 mg PO or IV every 8 hours (starting Day 4 for subjects who 
receive palonosetron on Day 1) 
o Prochlorperazine 10 mg PO or IV every 6 hours 
o Lorazepam 0.5-2 mg PO or IV every 4-6 hours 
 
5.3.1.1.1 Nab-paclitaxel alone 
When receiving nab-paclitaxel alone, NCCN guidelines for low emetic risk intravenous 
chemotherapy can be followed, which may include: 
• Metoclopramide 10-40 mg PO or IV 
• Prochlorperazine 10 mg PO or IV 
• Ondansetron 8 mg PO or IV 
• As needed medications as described above 
 
5.3.1.2 
Pembrolizumab alone 
No anti-emetic prophylaxis required 
 


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5.3.2 Anemia 
Transfusions and/or erythropoietin may be utilized as clinically indicated for the treatment of 
anemia, but should be clearly noted as concurrent medications.  Consider a potential 
immunologic etiology. 
 
5.3.3 Neutropenia 
Prophylactic use of colony-stimulating factors including Granulocyte Colony-Stimulating Factor 
(G-CSF), pegylated G-CSF or Granulocyte Macrophage Colony-Stimulating Factor GM CSF is 
not allowed in this study.  Therapeutic use of G-CSF is allowed in subjects with Grade 3-4 
febrile neutropenia.  Consider a potential immunologic etiology. 
 
5.3.4 Thrombocytopenia 
Transfusion of platelets may be used if clinically indicated.  Idiopathic Thrombocytopenic 
Purpura (ITP) should be ruled out before initiation of platelet transfusion. 
 
5.3.5 Anti-infective 
Subjects with a documented infectious complication should receive oral or IV antibiotics or other 
anti-infective agents as considered appropriate by the site investigator for a given infectious 
condition, according to standard institutional practice. 
 
5.3.6 Pneumonitis 
• 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. 
• For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
• Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
5.3.7 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).  
• 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. 
• For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
• For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids.   
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
 


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5.3.8 Type 1 diabetes mellitus (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 
o Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
o Evaluate subjects with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
5.3.9 Hypophysitis 
• 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. 
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. 
 
5.3.10 Hyperthyroidism or Hypothyroidism  
Thyroid disorders can occur at any time during treatment. Monitor subjects 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. 
• Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy. 
o In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
• Grade 3-4 hyperthyroidism  
o 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. 
 
5.3.11 Hepatic 
• For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
o Treat with IV or oral corticosteroids 
• For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
• When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
5.3.12 Renal Failure or Nephritis 
• For Grade 2 events, treat with corticosteroids. 
• For Grade 3-4 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.  


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5.3.13 Management of Infusion Reactions  
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Table 9 below shows treatment guidelines 
for subjects who experience an infusion reaction associated with administration of 
pembrolizumab (MK-3475). 
 
Table 9 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for < =24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids  
Antihistamines  
NSAIDS 
Acetaminophen  
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
trial treatment administration.
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 
 
Diphenhydramine 50 mg p.o. 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
p.o. (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
 
5.3.14 
Other toxicities 
For all Grade 3 or Grade 4 clinically significant toxicities, all drugs should be held.  Medications 
should be delayed until resolution to ≤ Grade 1 or baseline grade at the time of registration, 
before proceeding. Use of supportive therapies is encouraged (i.e., anti-emetics for 
nausea/vomiting, anti-diarrheal medications for diarrhea).  Upon resolution, carboplatin or nab-
paclitaxel should be resumed at 1 dose level lower (Table 2) if toxicity is felt to be related to 
either of these medications.  If toxicity is felt to be related to pembrolizumab, it should be 
restarted at the same dose level. 
 
5.4 
Duration of Therapy 
Therapy with pembrolizumab will continue until disease progression by RECIST v1.1 criteria, 
unacceptable toxicity, or for a maximum of 2 years.  Subjects who complete 24 months of 
treatment with pembrolizumab may be eligible for up to one year of additional study treatment if 
they progress after stopping study treatment provided they meet the requirements detailed in 
Section 3.1 Inclusion Criteria. 
 
5.4.1 Reasons for withdrawal from treatment 
• Any clinically significant Grade 3 or 4 non-hematologic toxicity that persists for ≥ 3 
weeks 
• 3rd episode of hematologic toxicity after appropriate dose reductions. Hematologic 
toxicity defined as:  
o Febrile neutropenia (Grade 3) 
 neutrophil count < 1.0 x 109/L and  
 a single oral temperature of > 38.3°C (101°F) or a temperature of ≥ 38.0°C 
(100.4°F) sustained for > 1 hour 
o Severe neutropenia  
 Neutrophil count < 0.50 x 109/L ≥ 1 week  
• Creatinine clearance < 30 ml/min for ≥ 3 weeks 
• AST/ALT and Alk Phos > 10 x ULN for ≥ 3 weeks 
• Bilirubin > 5 x ULN for ≥ 3 weeks 
• Grade ≥ 3 pneumonitis or second episode of Grade ≥ 2 pneumonitis 
• Pneumonitis that persists for ≥ 12 weeks 
• Grade 3 or Grade 4 AE that requires 10 mg of prednisone equivalent or > 12 weeks from 
time of onset 
• In case a grade 3 or grade 4 toxicity does not resolve to Grade 0-1 within 12 weeks after 
last infusion, study therapy should be discontinued after consultation with the sponsor-
investigator.  In cases of laboratory grade 2 toxicity only, subjects may be permitted to 
continue on study with sponsor-investigator approval. 
• Palliative RT involving target lesions is required.  Of note, palliative RT to non-target 
lesions in the absence of progression by RECIST v1.1 criteria is permitted. 


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• Subject withdraws consent  
• Subject becomes pregnant or is unwilling to use appropriate birth control techniques as 
outlined in inclusion criteria (Section 3.1 Inclusion Criteria) 
• Serious illness that prevents safe continuation of therapy, for example mechanical 
ventilation, septic shock requiring treatment in the intensive care unit, or ECOG 
performance status 4 for > 2 weeks. 
• Two years of uninterrupted delivery of pembrolizumab every 3 weeks and no 
documented progression of disease.  NOTE: 24 months of study medication is calculated 
from the date of first dose. Subjects who stop pembrolizumab after 24 months may be 
eligible for up to one year of additional study treatment if they progress after stopping 
study treatment provided they meet the requirements detailed in Section 3.1 Inclusion 
Criteria. 
 
6 
RESPONSE ASSESSMENT 
 
6.1 
Timing of Response Assessment 
A baseline CT scan of the chest and upper abdomen (must include liver and adrenals) with IV 
contrast and an MRI brain are required prior to enrollment on study. Response by CT of 
measurable disease will be assessed after every 2 chemotherapy cycles.  If there are treatment 
delays, the scans will be adjusted to coincide with completion of 2 cycles of chemotherapy each 
time for all subjects on study.  Subjects may have other imaging performed at other intervals for 
other reasons, such as the evaluation of new symptoms, and the results of these tests should be 
documented and may be used to determine progression of disease (see Section 6.2.4 Response 
Criteria).   
 
After documented progression by RECIST v1.1 criteria, if subjects are clinically stable, 
treatment with pembrolizumab may continue for another 2 cycles for a repeat response 
assessment at 6 weeks later to evaluate response as delayed response has been previously 
described in Section 5.2.1.2. 
 
6.2 
Methods of Response Assessment 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST v1.1 criteria.   
 
6.2.1 Definitions 
 
Evaluable for toxicity 
All subjects will be evaluable for toxicity from the time of their first treatment on Cycle 1 Day 1. 
 
Evaluable for objective response 
Only those subjects who have measurable disease present at baseline, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response.  These subjects will have their response classified according to the definitions stated 


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below.  (Note:  Subjects who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.) 
 
Evaluable Non-Target Disease Response 
Subjects who have lesions present at baseline that are evaluable but do not meet the definitions 
of measurable disease, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease.  The response assessment is based 
on the presence, absence, or unequivocal progression of the lesions.  
 
6.2.2 Disease Parameters 
 
Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded as ≥ 10 mm with CT scan, MRI, or calipers by 
clinical exam.  All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
NOTE:  Tumor lesions that are situated in a previously irradiated area might be considered 
measurable if disease progression has been previously documented. 
 
Malignant lymph nodes 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
 
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ and up to 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements.  It may be the case that, on 


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occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline.  
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
 
6.2.3 Response Criteria 
 
6.2.3.1 
Evaluation of Target Lesions 
 
Complete Response (CR) 
Disappearance of all target lesions.  Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to < 10 mm. 
 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the 
baseline sum diameters. 
 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm.  (Note:  the appearance of one or more new lesions is also considered progression). 
 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study. 
 
6.2.3.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
 
NOTE:  If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response. 
 
 
 


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Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above 
the normal limits. 
 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or sponsor-investigator). 
 
6.2.3.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The subject's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
Table 10: RECIST v1.1 Criteria for Evaluation of Subjects with Measurable Disease 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No
CR
> 4 wks. Confirmation**
CR 
Non-CR/Non-PD 
No
PR
> 4 wks. Confirmation** 
CR 
Not evaluated 
No
PR
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once > 4 
wks. from baseline**
PD 
Any 
Yes or No
PD
no prior SD, PR or CR 
Any 
PD*** 
Yes or No
PD
Any 
Any 
Yes
PD
∗ 
See RECIST v1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease   
progression. 
Note:  Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
 
 


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6.2.4 Duration of Response 
 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements.  
 
6.2.5 Progression-Free Survival 
PFS is defined as the duration of time from date of registration to time of progression or death, 
whichever occurs first. 
 
6.2.6 Overall Survival 
Overall survival is defined as the duration of time from date of registration to the time of death. 


 
 
 
 
 
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7. STUDY PARAMETERS 
 
 
Induction Phase 
Maintenance Phase 
Examination 
Screening
-28 days 
C1D1 
C1-C4 
Day8 
±1 day 
C1-C4 
Day 15 
±1 day 
C2D1   
±1 day 
C3D1 
±1 day 
C4D1 
±1 day 
C5+D1 
(odd # 
cycles) 
C6+D1 
(even # 
cycles) 
EOT14 
30 days 
(±7) from 
last dose
REQUIRED ASSESSMENTS 
Informed consent and 
eligibility confirmation 
X 
 
 
 
 
 
 
 
 
 
Pathology Review1 
X 
Tumor Biopsy2   
X 
X
 
Medical History including 
smoking history 
X 
 
 
 
 
 
 
 
 
 
Physical exam, Vitals, 
ECOG PS3  
X 
X 
X16 
X16 
X 
X 
X 
X 
X 
X 
Review Adverse Events, 
ECIs and con meds 
 
X 
X16 
X16 
X 
X 
X 
X 
X 
X 
Sensory neuropathy test 
X 
LABORATORY ASSESSMENTS 
CBC with differential4 
X11 
X 
X16 
X16 
X 
X 
X 
X 
X 
X 
Chemistry panel (and 
liver function)5 
X11 
X 
BMP16 
BMP16 
X 
X 
X 
X 
X 
X 
Thyroid Function6 
X11 
 
X 
X 
 
X 
X 
Pregnancy test7 
X 
PT/INR, PTT 
X11 
X
 
 
DISEASE ASSESSMENT 
CT Chest 
X12 
X13 
X13
X13
CT Abd 
X12 
X13 
X13
X13
MRI Brain 
X12 
X13 
X13
X13
Other Imaging8 
X 
X13 
X13
X13
TREATMENT EXPOSURE 
Carboplatin9 
 
X
X
X 
X
Nab-paclitaxel9 
 
X
X16 
X16 
X
X 
X
 
Pembrolizumab 
 
X10 
X
X 
X
X10 
X10 
FOLLOW UP 
Follow-up15 
 
X15 
 
 
 
 
 


 
 
 
 
 
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Footnotes: 
1: A pathology report confirming diagnosis of advanced stage NSCLC is required. For subjects with early stage disease that later developed 
metastatic disease, a biopsy confirmation of the metastatic disease is required. 
 
2: Adequate archival tissue or available PD-L1 testing results using the Dako 22C3 antibody are required for enrollment. If the patient has not had 
prior testing and no acceptable archival tissue is available, subjects must be willing to consent to providing a pre-treatment biopsy for PD-L1 
testing.  This biopsy is to be obtained within 28 days prior to registration.  Phase II subjects are required to provide a post-treatment tumor biopsy 
after completion of 4 cycles of study treatment or at progression.  The progression biopsy should be performed once confirmed by second scan 
unless unequivocal progression that requires the subject come off study treatment prior to confirmation scan. In the event that a subject has had a 
complete response or there is no disease feasible to biopsy, no biopsy will be obtained at that time. In this case, the subject will have the option to 
undergo a biopsy at progression. Window for tumor biopsies ±10 days to allow for scheduling conflicts (weekends/holidays).  Acceptable biopsies 
will be obtained via transcutaneous core needle biopsies or surgical biopsies.  At least 3 cores of tissue will be required.  FNAs are NOT 
acceptable.  See CLM (Correlative Laboratory Manual) for details regarding collection and shipping of sample. 
 
3: Subjects are assessed for physical examination (includes height and weight), vital signs and ECOG PS. 
 
4: CBC with differential is checked at screening and prior to chemotherapy on Day 1 of each cycle.  Repeat CBC on Days 8 & 15 of C1-C4. CBC 
is required prior to post-treatment biopsy for Phase II subjects. 
 
5: Comprehensive chemistry (including liver function) checked at screening and prior to chemo on Day 1 of each cycle.  Repeat basic chemistry 
(include electrolytes & creatinine) on Days 8 & 15 of C1-C4. 
 
6: Thyroid function assessment includes TSH, T3, and free T4. This test will be done at screening, Cycle 2, and every other cycle thereafter). 
 
7: Women of childbearing potential must have a negative serum or urine β-hCG pregnancy test obtained within 3 days of registration.    
 
8: Not required; other imaging may be done at physician discretion prior to registration to identify other areas of known or expected disease based 
on subject symptoms. 
 
9: Induction Cycles 1-4: Subjects will be treated with carboplatin AUC 6 given IV on Day 1, nab-paclitaxel 100 mg/m2 given IV on Days 1, 8 and 
15. 
 
10: Induction: Phase I Cohort 1 will begin Pembrolizumab on C1D1.  Phase II treatment; Induction: pembrolizumab will be administered Day 1 of 
each cycle.  Maintenance: pembrolizumab will be given on Day 1 of Cycles 5+ for a maximum duration of 2 years from Cycle 1 Day 1.  Cycle 5 
will begin once all 4 cycles of chemotherapy are complete. 
 
11: Tests must be obtained within 10 days of registration. 
 
 
 


 
 
 
 
 
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12: Tests must be obtained within 4 weeks of registration.  A CT scan with IV contrast of the chest and upper abdomen to include liver and 
adrenals is required. A CT abdomen may be completed as a separate study or as part of the CT chest study as long as the liver and bilateral adrenal 
glands are included per institutional standards.  Oral contrast is not necessary. CT Pelvis should be obtained if clinically indicated or if there is 
known disease in the pelvis. 
 
13: Initial post treatment scans will be done after completion of 2 cycles of chemotherapy.  The next set of scans will be performed after 
completion of 4 cycles of chemotherapy (need to be complete prior to Cycle 5 Day 1).  Thereafter, scans will be every 6 weeks beginning with 
Cycle 7.  The method of radiology imaging should remain the same throughout the treatment process.  If new symptoms have developed, 
additional radiology imaging should be performed as clinically indicated per the investigator’s discretion. MRI of the brain is to be done at 
screening per Footnote 12 for all patients. For those subjects with documented brain involvement, an MRI of the brain should be performed at a 
minimum of every 3 months. Brain imaging may be repeated when clinically indicated if there is a concern for brain metastasis. A ± 7-day 
window may be applied to all scans. 
 
14: End of treatment visit to include; physical exam, vital signs, ECOG PS, AEs and concomitant medications, CBC, CMP, TSH.  Imaging if 
clinically indicated. 
 
15: Subjects who discontinue treatment without evidence of progression will have repeat imaging every 6 weeks the first year off treatment (± 7 
days), every 9 weeks the second year after treatment (± 14 days). After the second year of treatment, radiology imaging should be completed at 
regular intervals (every 3-6 months suggested; ± 12 weeks) at the investigator’s discretion. Subjects will be followed for survival once progression 
is confirmed or another anti-cancer treatment is initiated.  The subject will be followed for survival once progression is confirmed or another anti-
cancer treatment is initiated.  Follow up for survival will occur every three months and may be accomplished via email, phone or other means as 
appropriate. 
16: Circumstances may occur based on laboratory/clinical trends where the ability to dose nab-paclitaxel on Day 8 or Day 15 is in question. In these 
circumstances, labs may be obtained locally within 48 hours prior to the dose of nab-paclitaxel to lessen the burden on the subject. If the subject does not 
receive dosing on Day 8 or Day 15, due to counts or for other reasons, an AE assessment should be done via telephone call by research staff. If treatment is 
not administered, physical exam, vital signs and ECOG status are not required. If clinical concerns arise regarding AEs, the patient should be seen in a 
clinic for further AE assessment and treatment as clinically indicated. 
 
 


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7.1 
Screening Assessments 
A signed informed consent will be obtained before any screening procedures are performed. 
Subjects who are considered for eligibility but do not meet all criteria will be considered 
screening failures.  Reasons for screen failures will be documented for those subjects who do not 
meet inclusion/exclusion criteria. Clinical data collected on these subjects will be entered into the 
database.  
 
7.1.1 Within 28 days of registration 
• Collect signed and dated informed consent statement (ICS).  
• Pathologic confirmation of NSCLC diagnosis (see Section 14.1 Pathology Requirements 
for Enrollment) 
• Document relevant medical history including history of their lung cancer and prior 
treatments, other past medical and surgical histories, current medications, allergies, social 
history including smoking history, and family history.  
• Physical exam (includes height and weight), vital signs (oral temperature, blood pressure, 
heart rate, respiratory rate and pulse oximetry) and ECOG PS (Appendix 16.2) 
• Sensory neuropathy assessment by history and graded by CTCAE v4. 
• Collect unstained slides from an archived tumor tissue. Note: if adequate tissue is 
unavailable, a pre-treatment biopsy for research purposes is required.  
• Baseline scans including; CT scan with IV contrast of the chest and upper abdomen to 
include liver and adrenals is required unless medically contraindicated and MRI of the 
brain. Note: Additional other imaging may be used at the discretion of the treating 
physician to assess other areas based on previously known disease or suspicion of new 
areas of involvement due to the subject’s complaints. These baseline tests will be used to 
determine the location(s) of baseline disease that may be used for responses assessment 
(see Section 6.0 Response Assessment). 
 
7.1.2 Within 28 days of registration 
• Adequate archival tissue or available PD-L1 testing results using the Dako 22C3 antibody 
are required for enrollment. If the patient has not had prior testing and no acceptable 
archival tissue is available, subjects must be willing to consent to providing a pre-
treatment biopsy for PD-L1 testing.  This biopsy is to be obtained within 28 days prior to 
registration.  Acceptable biopsies will be obtained via transcutaneous core needle 
biopsies or surgical biopsies.  At least 3 cores of tissue will be required.  FNAs are NOT 
acceptable.  See CLM (Correlative Laboratory Manual) for details regarding collection 
and shipping of sample. Window for tumor biopsies ±10 days to allow for scheduling 
conflicts (weekends/holidays).  
 
7.1.3 Within 10 days of registration 
• CBC with differential  
• Comprehensive chemistry panel  
• Liver function tests (AST, ALT, Alkaline phosphatase, bilirubin)  
• Thyroid function test including; TSH, T3 and free T4  
• PT/INR, PTT (± 5 days) 
 
 


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7.1.4 Within 3 days of registration 
• Collect serum or urine β-hCG pregnancy test (within 3 days of registration) for pre-
menopausal women (i.e., last menstrual period ≤ 12 months ago) and women < 1 years 
after onset of menopause. Menopause is defined as the time at which fertility ceases, 
where a woman has had no menstruation for > 12 months. 
 
7.2 
On Treatment Assessments 
The following assessments will be completed prior to chemotherapy treatment. Lab values will 
be recorded and checked for toxicity that would necessitate a dose reduction (most notably white 
blood count and differential to calculate absolute neutrophil count (ANC), platelet count, 
creatinine, AST, ALT, Alk Phos, and bilirubin). Grading of all toxicities will be according to 
CTCAE v4. Dosing of carboplatin, nab-paclitaxel, and pembrolizumab will be based on height 
and weight on the day of treatment (see Section 5.1.2.4 Dose Calculations). 
 
7.2.1 Day 1 of each cycle (± 1 day) unless otherwise specified 
• Physical exam (includes weight), vital signs (oral temperature, blood pressure, heart rate, 
respiratory rate and pulse oximetry) and ECOG PS (Appendix 16.2) 
• AE assessment including ECIs and concomitant medications 
• CBC with differential and platelet count 
• Comprehensive chemistry panel 
• Liver function tests (AST, ALT, Alkaline phosphatase, bilirubin) 
• Thyroid function test including; TSH, T3 and free T4 (Cycle 2 and every other cycle 
thereafter) 
• A CT scan with IV contrast of the chest and upper abdomen to include liver and adrenals 
is required unless medically contraindicated (Cycle 3 and odd number cycles thereafter). 
Repeat all other imaging studies at these same intervals if disease was identified at 
baseline. Additional imaging studies may be obtained at these intervals or at any time if 
clinically indicated and at site investigator discretion. Results from all imaging, whether 
at the scheduled interval or otherwise, should be recorded and used for response 
assessments (see Section 6.0 Response Assessment).  Window of ± 7 days. 
Phase II subjects are required to provide a post-treatment tumor biopsy after completion 
of 4 cycles of study treatment (or at progression, whichever comes first).  In the event 
that a subject has had a complete response and there is no evidence of disease feasible to 
biopsy, no post-treatment biopsy will be obtained. Window for tumor biopsies ±10 days 
to allow for scheduling conflicts (weekends/holidays).  Acceptable biopsies will be 
obtained via transcutaneous core needle biopsies or surgical biopsies.  At least 3 cores of 
tissue will be required.  FNAs are NOT acceptable.  See CLM (Correlative Laboratory 
Manual) for details regarding collection and shipping of sample. 
 
7.2.2 Days 8 & 15 Cycles 1-4 (±1 day) 
• Physical exam (includes weight), vital signs (oral temperature, blood pressure, heart rate, 
respiratory rate and pulse oximetry) and ECOG PS (Appendix 16.2) 
• AE assessment including ECIs and concomitant medications 
• CBC with differential and platelet count  
• Basic chemistry panel including electrolytes and creatinine 


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• Circumstances may occur based on laboratory/clinical trends where the ability to dose 
Nab-paclitaxel on Day 8 or Day 15 is in question. In these circumstances, labs may be 
obtained locally within 48 hours prior to the dose of nab-paclitaxel to lessen the burden 
on the subject. If the subject does not receive dosing on Day 8 or Day 15, due to counts 
or for other reasons, an AE assessment should be done via telephone call by research 
staff. If treatment is not administered, physical exam, vital signs and ECOG status are not 
required. If clinical concerns arise regarding AEs, the subject should be seen in a clinic 
for further AE assessment and treatment as clinically indicated. 
 
7.3 
Off Treatment Assessments 
 
7.3.1 End of treatment (30 days from last dose of study treatment ± 7 days) 
• Physical exam (includes weight), vital signs (oral temperature, blood pressure, heart rate, 
respiratory rate and pulse oximetry) and ECOG PS (Appendix 16.2) 
• AE assessment including ECIs and concomitant medications 
• CBC with differential and platelet count  
• Basic chemistry panel including electrolytes and creatinine 
• TSH 
• Repeat imaging if clinically indicated and at the discretion of the site investigator 
 
7.3.2 Follow-up  
• Subjects who discontinue treatment without evidence of progression will have repeat 
imaging every 6 weeks the first year off treatment, then every 3 months thereafter. 
• The subject will be followed for survival once progression is confirmed or another anti-
cancer treatment is initiated.  Follow up for survival will occur every three months and 
may be accomplished via email, phone or other means as appropriate. 
 
7.4 
Tumor Biopsy parameters  
Adequate archival tissue or available PD-L1 testing results using the Dako 22C3 antibody are 
required for enrollment. If the patient has not had prior testing and no acceptable archival tissue 
is available, subjects must be willing to consent to providing a pre-treatment biopsy for PD-L1 
testing.  This biopsy is to be obtained within 28 days prior to registration.  Phase II subjects are 
required to provide a post-treatment tumor biopsy after completion of 4 cycles of study treatment 
or at progression.  The progression biopsy should be performed once confirmed by second scan 
unless unequivocal progression that requires the subject come off study treatment prior to 
confirmation scan. In the event that a subject has had a complete response or there is no disease 
feasible to biopsy, no biopsy will be obtained at that time. In this case, the subject will have the 
option to undergo a biopsy at progression. Window for tumor biopsies ±10 days to allow for 
scheduling conflicts (weekends/holidays).  Acceptable biopsies will be obtained via 
transcutaneous core needle biopsies or surgical biopsies.  At least 3 cores of tissue will be 
required.  FNAs are NOT acceptable.  See CLM (Correlative Laboratory Manual) for details 
regarding collection and shipping of sample. 
 
 


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7.4.1 Pre-treatment biopsy (- 28 days) 
The pre-treatment biopsy is required only if adequate tissue is not available prior to registration 
(at least 5 unstained slides).  Prior to the biopsy, baseline complete blood count (CBC) and 
PT/PTT will be reviewed to confirm the safety of this invasive procedure.  The treating 
physician, in consultation with an interventional radiologist and/or surgeon, will determine the 
most accessible tumor for biopsy.  The best candidate lesions for biopsy are those that are 
measurable and identified as target lesions (see Section 6.2.2 Disease Parameters) whenever 
possible.  Lymph nodes measuring less than 2 cm diameter and bone lesions should not be 
selected as candidate lesions for biopsy.  The location that is selected for biopsy will be 
documented.  Acceptable biopsies will be obtained via transcutaneous core needle biopsies, 
surgical biopsies.  At least 3 cores of tissue will be required.  If a tumor biopsy was obtained of a 
target lesion during eligibility assessment, it is preferred to obtain a new baseline scan. The 
tissue sample should have proper size to enable multiple planned biomarker analyses, but not 
artificially decrease the longest diameter of the lesion. Biopsy of lesions on study should be 
limited to non-target lesions or new lesions if their pathologic etiology is ambiguous. 
 
7.4.2 Post-treatment biopsy ± 10 days (Phase II only)  
Phase II subjects are required to provide a post-treatment tumor biopsy after completion of 4 
cycles of study treatment or at progression.  The progression biopsy should be performed once 
confirmed by second scan unless unequivocal progression that requires the subject come off 
study treatment prior to confirmation scan. Window for tumor biopsies ±10 days to allow for 
scheduling conflicts (weekends/holidays).  Acceptable biopsies will be obtained via 
transcutaneous core needle biopsies or surgical biopsies.  At least 3 cores of tissue will be 
required.  FNAs are NOT acceptable.   A CBC and PT/PTT is required before the biopsy to 
confirm the safety of this invasive procedure.  The same procedure and requirements for biopsy 
will be used.  Whenever possible, the same lesion that was biopsied pre-treatment should be 
biopsied post-treatment. Target lesions should not be biopsied as that would compromise the 
ability to monitor and measure them effectively. Only non-target lesions should be biopsied. If 
the subject has had a complete response in that particular lesion, another similar lesion should be 
biopsied, preferably one that has had a partial response.   
 
In the event that a subject has had a complete response or disease is not feasible to biopsy 
per site investigator discretion, no post-treatment biopsy will be obtained at that time. In 
this case, the subject will have the option to undergo a biopsy at progression. Acceptable 
biopsies will be obtained via transcutaneous core needle biopsies or surgical biopsies.  At least 3 
cores of tissue will be required.  Fine-needle aspirate biopsies are NOT acceptable. See CLM for 
collection, labeling and shipping instructions. 
 
7.4.3 Tumor biopsy analysis 
Pre-treatment and post-treatment biopsies will be processed by the local study site pathology 
department and paraffin embedded.  PD-L1 expression in pre-treatment and post-treatment tumor 
biopsies will be analyzed at a central lab using a Merck-specified assay. See CLM for collection, 
labeling and shipping instructions.  
 
 
 


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7.5 
Laboratory Tests parameters  
 
7.5.1 Labs prior to tumor biopsies 
Subjects undergoing tumor biopsies are required to have a CBC and PT/INR, and PTT prior to 
tumor biopsies.  Subjects with platelets < 50 x 109 or an INR > 1.5 will not be permitted to 
undergo biopsies.  Platelets and/or fresh frozen plasma (FFP) should be transfused to correct the 
underlying abnormality at the treating physician’s discretion in order to decrease the risk of 
bleeding complications during the tumor biopsy. 
 
7.6 
Imaging Tests parameters (window of ± 7 days) 
 
7.6.1 Baseline imaging 
All subjects will have baseline imaging including, but not limited to, a CT of the Chest and upper 
abdomen to include liver and bilateral adrenal glands with IV contrast, and an MRI of the brain.  
Additional imaging tests may be used at the discretion of the treating physician to image other 
areas based on previously known disease or suspicion of new areas of involvement due to subject 
complaints.  These baseline tests will be used to determine the location(s) of baseline disease that 
may be used for response assessment (see Section 6.0 Response Assessment). 
 
7.6.2 Response assessment imaging 
A CT of the Chest/upper abdomen to include liver and bilateral adrenal glands with IV contrast 
is repeated on Day 1 (±3 days) of Cycle 3 and the odd numbered cycles thereafter.  Any other 
baseline imaging studies that identified areas of disease should also be repeated at these same 
time intervals for the entire duration the subject remains on study.  Additional studies may be 
obtained at these intervals or at any time if new areas of disease are suspected at the site 
investigator’s discretion.  Results from all imaging, whether at the scheduled time interval or 
otherwise, should be recorded and used for response assessments using RECIST v1.1 criteria 
(see Section 6.0 Response Assessment). 
 
7.6.3 Post-progression imaging  
This study will use RECIST 1.1 to capture all outcomes.  However, the study will allow patients 
to receive treatment beyond progression at the discretion of the site investigator given the unique 
tumor response seen in this class of therapeutics. 
 
After the first documentation of progression per RECIST 1.1, if the subject is clinically stable, 
confirmatory scans should be performed 6 weeks later. It is at the discretion of the site 
investigator to keep a clinically stable subject on study therapy or to stop study therapy until 
repeat imaging performed.   
 
Clinical Stability is defined as: 
1) Absence of symptoms and signs indicating clinical significant progression of disease 
(including worsening of laboratory values) indicating disease progression. 
2) No decline in ECOG performance status (Appendix 16.2). 
3) Absence of rapid progression of disease or progressive tumor at critical anatomical sites 
(e.g., cord compression) requiring urgent alternative medical intervention. 
 


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Subjects that are deemed clinically unstable are not required to have repeat imaging for 
confirmation.  
 
If progression is confirmed, then the subject will be discontinued from study therapy.  If 
progression is not confirmed, then the subject should resume/continue study therapy and 
continue scans every 6 weeks. The previous response assessments based on RECIST 1.1 for 
these patients will not be re-categorized for purposes of the study endpoints.  For patients that 
continue on study drug treatment, all aspects of the protocol will continue to be followed. 
 
When feasible, subjects should not be discontinued until progression is confirmed. 
 
7.6.4 Confirmation of response for CR and PR 
After the first documentation of CR or PR per RECIST 1.1, confirmatory scans will be obtained 
at the next regularly scheduled assessment on the odd number cycles (6 weeks).  Repeat 
assessment for progression will continue every 6 weeks thereafter. 
 
8. 
DRUG FORMULATION AND PROCUREMENT 
 
8.1 
Carboplatin 
Please see product package insert for complete details regarding Carboplatin. 
 
8.1.1 Availability  
Carboplatin is commercially available  
 
8.1.2 Chemical Name  
Carboplatin (carboplatin for injection or platinum diamine [1,1-cyclobutane- decarbozxylate 
(2—0,0’)-,(SP-4-2)]) is a platinum compound used as a chemotherapeutic agent. It will be 
supplied commercially.  
 
8.1.3 Formulation  
Carboplatin is available as a sterile lyophilized powder in single-dose vials containing 50 mg, 
150 mg, or 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and 
mannitol. Commercial supplies of carboplatin will be used in this study.  
 
8.1.4 Preparation 
Immediately before use, the contents of a carboplatin vial must be reconstituted with either 
sterile water for injection, USP, 5% dextrose in water, or 0.9% sodium chloride injection, USP. 
The following shows the proper diluent volumes to be used to obtain a carboplatin concentration 
of 10 mg/mL. Carboplatin solution can be further diluted to concentrations as low as 0.5 mg/mL 
with D5W or 0.9% normal saline. Carboplatin reacts with aluminum to form a precipitate and 
cause a loss of potency. Therefore, needles or intravenous sets containing aluminum parts that 
may come in contact with the drug must not be used for the preparation or administration of 
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8.1.5 Storage and Stability 
Intact vials of carboplatin are stable for the period indicated on the package when stored at room 
temperature (15-30°C or 59-86°F) and protected from light.  When prepared as described above, 
carboplatin solutions are stable for 8 hours at room temperature if protected from light. The 
solution should be discarded after 8 hours since no antibacterial preservative is contained in the 
formulation. 
 
8.1.6 Adverse Events Associated with Carboplatin 
Incidence rates of adverse events associated with carboplatin are provided in the product package 
insert. Some of the adverse events expected with Carboplatin treatment are listed below. 
 
Hematologic: Myelosuppression is the major dose-limiting toxicity. Thrombocytopenia, 
neutropenia, leukopenia, and anemia are common, but typically resolve by Day 28 when 
carboplatin is given as a single agent. 
 
Allergic Reactions: Hypersensitivity to carboplatin has been reported in 2% of subjects receiving 
the drug. Symptoms include rash, urticaria, erythema, pruritus, and rarely bronchospasm and 
hypotension. The reactions can be successfully managed with standard epinephrine, 
corticosteroid, and antihistamine therapy. 
 
Neurologic: Peripheral neuropathies have been observed in 4% of subjects receiving carboplatin 
with mild paresthesia being the most common. 
 
Gastrointestinal: Nausea and vomiting are the most common GI events; both usually resolve 
within 24 hours and respond to antiemetics. Other GI events include diarrhea, weight loss, 
constipation, and gastrointestinal pain. 
 
Hepatic Toxicity: Elevated alkaline phosphatase, total bilirubin, and SGOT have been observed. 
 
Other:  Pain and asthenia are the most common miscellaneous adverse events. Alopecia has been 
reported in 3% of the subjects taking carboplatin. 
 
8.2 
nab-Paclitaxel 
Please see product package insert for complete details regarding nab-Paclitaxel. 
 
8.2.1 Availability 
Nab-paclitaxel is commercially available. 
 
8.2.2 Chemical Name 
The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-
one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine. 
 
8.2.3 Formulation 
Nab-paclitaxel is supplied as a white to yellow, sterile, lyophilized powder for reconstitution 
with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-
use vial contains 100 mg of paclitaxel (bound to human albumin) and approximately 900 mg of 


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human albumin (containing sodium caprylate and sodium acetyltryptophanate). Each milliliter 
(mL) of reconstituted suspension contains 5 mg paclitaxel. nab-paclitaxel is free of solvents. 
 
8.2.4 Preparation and Administration Precautions  
Nab-paclitaxel is a cytotoxic drug and, as with other potentially toxic paclitaxel compounds, 
caution should be exercised in handling nab-paclitaxel. The use of gloves is recommended. If 
nab-paclitaxel (lyophilized cake or reconstituted suspension) contacts the skin, wash the skin 
immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, 
events may include tingling, burning and redness. If nab-paclitaxel contacts mucous membranes, 
the membranes should be flushed thoroughly with water.  
 
Given the possibility of extravasation, it is advisable to closely monitor the infusion site for 
possible infiltration during drug administration. Limiting the infusion of nab-paclitaxel to 30 
minutes, as directed, reduces the likelihood of infusion-related reactions.  
 
Premedication to prevent hypersensitivity reactions is generally not needed prior to the 
administration of nab-paclitaxel. Premedication may be needed in subjects who have had prior 
hypersensitivity reactions to nab-paclitaxel. Subjects who experience a severe hypersensitivity 
reaction to nab-paclitaxel should not be re-challenged with this drug.  
 
8.2.5 Preparation for Intravenous Administration  
Nab-paclitaxel is supplied as a sterile lyophilized powder for reconstitution before use. Avoid 
errors, read entire preparation instructions prior to reconstitution.  
 
1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, 
USP.  
2. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 
minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE 
VIAL.  
3. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized 
cake as this will result in foaming.  
4. 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.  
5. 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.  
6. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides. 
 
8.2.6 How Supplied  
Product No.: 103450  
NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a 
carton.  
 
8.2.7 Storage  
Store the vials in original cartons at 20ºC to 25ºC (68º F to 77ºF). Retain in the original package 
to protect from bright light.  
 


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8.2.8 Handling and Disposal  
Procedures for proper handling and disposal of anticancer drugs should be considered. Several 
guidelines on this subject have been published. There is no general agreement that all of the 
procedures recommended in the guidelines are necessary or appropriate. 
 
8.2.9 Adverse Events Associated with nab-Paclitaxel 
Please see product package insert for complete details regarding adverse events associated with 
nab-Paclitaxel.  
 
Hematologic Disorders  
Neutropenia was dose dependent and reversible. Among subjects with metastatic breast cancer in 
the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the 
subjects treated with a dose of 260 mg/m2 compared to 22% in subjects receiving paclitaxel 
injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials.  
Infections  
Infectious episodes were reported in 24% of the subjects treated with nab-paclitaxel. Oral 
candidiasis, respiratory tract infections and pneumonia were the most frequently reported 
infectious complications.  
 
Hypersensitivity Reactions (HSRs)  
Grade 1 or 2 HSRs occurred on the day of nab-paclitaxel administration and consisted of 
dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of nab-
paclitaxel in subjects previously exhibiting hypersensitivity to paclitaxel injection or human 
albumin has not been studied.  
 
Cardiovascular  
Hypotension, during the 30-minute infusion, occurred in 5% of subjects. Bradycardia, during the 
30-minute infusion, occurred in <1% of subjects. These vital sign changes most often caused no 
symptoms and required neither specific therapy nor treatment discontinuation.  
 
Severe cardiovascular events possibly related to single-agent nab-paclitaxel occurred in 
approximately 3% of subjects. These events included cardiac ischemia/infarction, chest pain, 
cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, 
pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient 
ischemic attacks have been reported.  
 
Electrocardiogram (ECG) abnormalities were common among subjects at baseline. ECG 
abnormalities on study did not usually result in symptoms, were not dose-limiting, and required 
no intervention. ECG abnormalities were noted in 60% of subjects. Among subjects with a 
normal ECG prior to study entry, 35% of all subjects developed an abnormal tracing while on 
study. The most frequently reported ECG modifications were non-specific repolarization 
abnormalities, sinus bradycardia, and sinus tachycardia.  
 
Respiratory  
Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment 
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Neurologic  
The frequency and severity of sensory neuropathy increased with cumulative dose. 
Sensory neuropathy was the cause of nab-paclitaxel discontinuation in 7/229 (3%) 
subjects. Twenty-four subjects (10%) treated with nab-paclitaxel developed Grade 3 
peripheral neuropathy; of these subjects, 14 had documented improvement after a median 
of 22 days; 10 subjects resumed treatment at a reduced dose of nab-paclitaxel and 2 
discontinued due to peripheral neuropathy. Of the 10 subjects without documented 
improvement, 4 discontinued the study due to peripheral neuropathy.  
 
No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy 
(Grade 2) was observed in either arm of the controlled trial.  
 
Vision Disorders  
Ocular/visual disturbances occurred in 13% of all subjects (n=366) treated with nab-paclitaxel 
and 1% were severe. The severe cases (keratitis and blurred vision) were reported in subjects 
who received higher doses than those recommended (300 or 375 mg/m2). These effects generally 
have been reversible.  
 
Arthralgia/Myalgia  
The symptoms were usually transient, occurred two or three days after nab-paclitaxel 
administration, and resolved within a few days. 
 
8.3 
Pembrolizumab 
Please see Investigator’s Brochure for detailed information regarding Pembrolizumab 
 
8.3.1 Availability 
Pembrolizumab is an investigational drug in this setting and not available outside of a clinical 
trial. 
 
The site investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
 
8.3.2 Chemical Properties 
Pembrolizumab is a humanized anti-PD-1 mAb of the IgG4/kappa isotype with a stabilizing 
S228P sequence alteration in the fragment crystallizable (Fc) region. Pembrolizumab binds to 
human PD-1 and blocks the interaction between PD-1 and its ligands. 
 
8.3.3 Product Descriptions 
Clinical Supplies will be provided by Merck as summarized in Table 11. 
 
Table 11 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 


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8.3.4 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 
8.3.5 Clinical Supplies Disclosure 
This study is open-label; therefore, the subject, the study site personnel, the site investigator 
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. 
 
8.3.6 Adverse Events 
Please see Investigator’s Brochure for complete details regarding adverse events related to 
Pembrolizumab. 
 
Pembrolizumab is generally well tolerated and demonstrates a favorable safety profile in 
comparison to chemotherapy. Pembrolizumab is an immunomodulatory agent, and based on this 
mechanism of action, immune mediated adverse events are of primary concern.  Important 
identified risks for pembrolizumab are of an immune mediate nature, including: pneumonitis, 
colitis, hypophysitis (including hypothyroidism or hyperthyroidism), hepatitis, Type I diabetes 
mellitus, uveitis, and nephritis, myositis, Guillain-Barre syndrome, pancreatitis, and severe skin 
reaction toxic epidermal necrolysis (TEN), some with fatal outcome. A new important risk of 
myocarditis has been identified; cases with fatal outcome have been reported.  
 
The majority of immune-mediated adverse events were mild to moderate in severity, were 
manageable with appropriate care, and rarely required discontinuation of therapy. In addition to 
the previously noted identified risks, infusion-related reactions are a risk but are not considered 
immune mediated; these are also further described in the current IB. 
 
9. 
STATISTICAL CONSIDERATIONS  
 
9.1 
Study Design  
This is a Phase I/II study for previously untreated subjects with advanced NSCLC.  The study 
will take place in two phases.  First, a cohort of twelve subjects will be enrolled in the Phase I 
part and will be treated with carboplatin, nab-paclitaxel, and pembrolizumab.  A cohort of twelve 
subjects will be evaluated for safety and tolerability after 2 cycles of therapy.  All subjects who 
receive either nab-paclitaxel or pembrolizumab will be evaluable. If 33% of subjects or less have 
unacceptable toxicity in the first cohort or any subsequent cohort (if necessary), the study will 
proceed to the Phase II part.  If more than 33% have unacceptable toxicity, 12 additional subjects 
will be enrolled in a second cohort, if necessary.  If unacceptable toxicity is seen in more than 
33% in Cohort 2, the study will end due to unacceptable toxicity of this drug combination.   
 
During the phase I portion of the study, there will be weekly teleconferences to review toxicities 
for all subjects on study.  If at any point more than 4 subjects experience a DLT, enrollment to 
the current cohort will end.  These ongoing assessments will occur throughout phase I for both 
cohort 1 and cohort 2 (if necessary).  For example, if all 5 of the first 5 subjects enrolled have a 
DLT, no more subjects will be enrolled to that Phase I cohort or treated.  If this occurs during 
cohort 2, the trial will end. 
 


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The Phase II part of the study is a single arm study.  All subjects will be treated with carboplatin, 
nab-paclitaxel, and pembrolizumab in 21-day cycles for up to 4 cycles.   
 
Mandatory pre-treatment tumor biopsies will be obtained prior to initiating treatment for all 
subjects (only if adequate archived samples are unavailable).  Mandatory tumor biopsies will be 
obtained in the Phase II part of the study after 4 cycles of study treatment or at the time of 
progression, whichever comes first.  
 
For subjects without progression of disease after Cycle 4, pembrolizumab will continue every 3 
weeks for up to 2 years or until unacceptable toxicity.   
 
9.2 
Phase I 
 
9.2.1 Definition of primary outcomes/endpoints  
Recommended Phase II dose (RP2D) 
RP2DS is defined as the dosing schedule of pembrolizumab resulting in less than 33% 
toxicity rate as assessed after completion of 2 cycles. Unacceptable toxicity will be 
defined as any non-hematologic toxicity Grade ≥ 3 or any hematologic toxicity Grade ≥ 4 
as defined in greater detail in section 5.2.1.1.  Toxicities are graded according to CTCAE 
v4. 
 
Safety and Tolerability  
Safety and tolerability is defined as rates of Grade 1-5 toxicity according to CTCAE v4.  
 
9.2.2 Definition of secondary outcomes/endpoints 
PFS  
PFS is defined as the time from registration to progressive disease according to RECIST v1.1 
criteria or death from any cause. 
 
Response  
Response is defined as partial response [PR] or complete response [CR] according to RECIST 
v1.1 criteria.  
 
OS 
OS is defined as the time from registration until death from any cause. 
 
PD-L1 expression  
PD-L1 expression is defined as positive if ≥ 1% of tissue stains positive for PD-L1 by IHC.  
 
Anti-tumor activity 
Defined as the change in the sum of the dimensions of all measurable lesions as defined by 
RECIST 1.1 criteria. 
 
 
 


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9.2.3 Analytic plan for primary objective 
 
Cohort 1 
All subjects who receive treatment will be evaluated for toxicity. Toxicities by type and grade 
will be summarized overall and by dose level.  During the phase I portion of the study, there will 
be weekly teleconferences to review toxicities for all subjects on study.  If at any point more than 
4 subjects experience a DLT, we stop accrual to Cohort 1.  For example, if all 5 of the first 5 
subjects enrolled have a DLT, no more subjects will be enrolled to that Phase I cohort or treated.  
The same process will apply for cohort 2 (below).  After 12 subjects in Cohort 1 are treated, if 
the rates of unacceptable toxicity after 2 cycles of pembrolizumab, defined as Grade ≥ 3 non-
hematologic or Grade ≥ 4 hematologic toxicity, are ≤ 33% of subjects (≤ 4 of 12), the 
recommended Phase II dose (RP2D) of pembrolizumab will be 2 mg/kg and the study will 
advance to the Phase II part of study.  If unacceptable toxicity occurs in > 33% of subjects (≥ 5 
of 12), a second cohort of subjects will be enrolled.  
 
Cohort 2 (if necessary) 
Twelve subjects will be treated with delayed initiation of pembrolizumab 2 mg/kg.  
Pembrolizumab will be omitted for Cycle 1 and start on Day 1 of Cycle 2.  Ongoing 
assessments will occur as described above in cohort 1.  At any point that 5 subjects have 
unacceptable toxicity, the trial will end.  Presuming all 12 subjects are treated in the cohort, if ≤ 
33% of subjects have unacceptable toxicity (as defined above) at this dose level, 2 mg/kg starting 
Cycle 2, Day 1 will be the RP2D and schedule and the study will proceed to the Phase II part of 
the study.  If > 33% of subjects (≥ 5 of 12) have unacceptable toxicity at this level, the study will 
be discontinued due to unacceptable toxicity of this drug combination. 
 
9.2.4 Analytic plan for secondary objectives   
Median PFS and median OS outcomes will be described using KM method and two-sided 80% 
confidence intervals will be calculated.   
 
Response will be reported as a percentage of subjects registered to the study. 
 
PD-L1 expression will be categorized as positive (≥ 1% expression) or negative (< 1% 
expression) from pre-treatment biopsies.  Positive PD-L1 expression rates are estimated to be 
70% based on preliminary data from pembrolizumab PN 001. The distribution of PFS will be 
summarized by PD-L1 expression using Kaplan-Meier method and PFS will be compared using 
one-sided logrank test.  Nominal p-values will be reported to measure the strength of the 
differences tested. 
 
Anti-tumor activity will be reported as a percentage change in the sum of the dimensions of all 
measurable lesions as defined by RECIST 1.1 criteria.  The baseline imaging before treatment 
will be compared to each subsequent imaging assessment.  The maximum anti-tumor activity 
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9.2.5 Sample size justification   
Table 12 indicates the probability of a dose proceeding to Phase II (observe ≤ 4 of 12 
unacceptable toxicities) for a range of true unacceptable toxicity rates; there is a high probability 
(72%) if there is truly a 30% rate of unacceptable toxicity, and a low probability (19%) if there is 
truly a 50% rate of unacceptable toxicity. 
 
Table 12: Probability of dose proceeding to Phase II 
 
True Probability of Unacceptable toxicity at Current Dose
 
0.10 
0.20
0.30
0.40
0.50
0.60 
0.70
Probability that dose 
proceeds to Phase II 
0.99 
0.93
0.72
0.44
0.19
0.06 
0.01
 
9.3 
Phase 2 
 
9.3.1 Definition of primary outcomes/endpoints  
Progression-free survival (PFS)  
PFS is defined as the time from registration until progression of disease, as defined by RECIST 
v1.1 criteria, or death from any cause.  
 
Response (PR or CR)  
PR or CR is defined according to RECIST v1.1 criteria.  
 
9.3.2 Definition of secondary outcomes/endpoints 
OS  
OS is defined as the time from registration until death from any cause.  
 
Safety and Tolerability  
Safety and tolerability is defined as rates of Grade 1-5 toxicity according to CTCAE v4.  
 
PD-L1 expression  
PD-L1 expression is defined as positive if ≥ 1% of tissue stains positive for PD-L1 by IHC.  
 
Anti-tumor activity 
Defined as the change in the sum of the dimensions of all measurable lesions as defined 
by RECIST 1.1 criteria. 
 
9.3.3 Analytic plan for primary objective 
Recruitment of 43 subjects will last approximately 12 months and subjects will be followed until 
39 PFS events occur or a maximum of 2 years from registration of the last subject.  The 
estimated study duration is 3 years.  Two co-primary outcomes are chosen – PFS based on 
mechanism of action, and RR based on acknowledgement of ‘traditional’ single arm studies.  
 
For the first co-primary outcome, PFS, assumptions are that the addition of pembrolizumab will 
increase PFS by 50% to 9.0 months compared to historical control of 6.0 months.  After 
completion of the study, or when 39 or more subjects have experienced a PFS event, the 
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reported. A one-sided 5% type I error, 20% type II error and exponential distribution of PFS 
were assumed. Success will be defined as a lower 95% one sided confidence limit for the median 
(Brookmeyer, R. and Crowley, J. (1982), “A Confidence Interval for the Median Survival Time,” 
Biometrics, 38, 29–41.) being greater than 6 months. 
 
For the second co-primary outcome, response rate, a single stage single arm design will assume a 
historical control response rate of 31% and a hypothesized study rate of 50%.  This effect size 
may be detected with 80% power, a one-sided 5% type I error rate and a 20% type II error rate.  
Success will be defined as the number of responses being greater than or equal to 19 out of 43. 
 
The analysis of both co-primary outcomes will use the intention-to-treat approach from the time 
of registration.   
 
9.3.4 Analytic plan for secondary objectives 
• OS outcomes will be summarized using KM method.    
• Safety and tolerability will be reported as rates of Grade 1-5 toxicity by CTCAE v4 
criteria for all events with a frequency of ≥ 1%. 
• PD-L1 expression will be categorized as positive or negative from pre-treatment and 
post-treatment biopsies.  Positive PD-L1 expression rates are estimated to be 70%, based 
on preliminary data from pembrolizumab PN 001. The distribution of PFS will be 
summarized by PD-L1 expression using Kaplan-Meier method and PFS will be compared 
using one-sided logrank test.  Nominal p-values will be reported to measure the strength 
of the differences tested. 
• Anti-tumor activity will be reported as a percentage change in the sum of dimensions of 
all measurable lesions as defined by RECIST 1.1 criteria.  The baseline imaging before 
treatment will be compared to each subsequent imaging assessment.  The maximum anti-
tumor activity will be reported using the assessment with the smallest sum of dimensions 
(maximum response). 
 
9.3.5 Sample size justification 
As described above, sample size calculations indicated that 43 subjects were needed to meet the 
co-primary endpoint PFS goal of 9.0 months compared to a retrospective cohort with a median 
PFS of 6.0 months.  This sample size would also have 80% power to meet the co-primary 
endpoint of a 50% response rate versus an historic control rate of 31%.  An alpha of 0.05 and 
beta of 0.20 were used for each primary endpoint, resulting in an overall type I error rate of 0.10.   
 
9.3.6 Subject Accrual  
Twenty-five potentially eligible subjects are expected to be identified per month and 6 subjects 
per month registered to the study.  It is estimated it will take approximately 12 months to register 
43 subjects.  Subjects will be followed until 39 PFS events occur or a maximum of 2 years from 
registration of the last subject. 
 
 
 


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9.3.7 Reporting and Exclusions 
 
9.3.7.1 
Evaluation of toxicity   
All subjects will be evaluable for toxicity from the time of their first treatment on study. 
 
9.3.7.2 
Evaluation of Response  
All subjects included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each subject will be assigned one 
of the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
 
All of the subjects who met the eligibility criteria should be included in the main analysis of the 
response rate.  An incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate.   
 
All conclusions will be based on all eligible subjects.  Sub-analyses may then be performed on 
the basis of a subset of subjects, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these sub-analyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding subjects from the 
analysis should be clearly reported. 
 
10. 
ADVERSE EVENT REQUIREMENTS 
The descriptions and grading scales found in the NCI CTCAE v4 will be utilized for AE 
assessment. A copy of the CTCAE v4 can be downloaded from the CTEP website at 
http://ctep.cancer.gov. 
 
10.1 
Definitions 
 
10.1.1 Adverse Event (AE) 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the administration, at any 
dose, or a medicinal or therapeutic product whether or not considered related to that product.  All 
abnormal laboratory values or diagnostic test results during the phase I portion constitute adverse 
events and will be reported during the Phase I portion of the study.  During the Phase II portion, 
abnormal laboratory values or diagnostic test results constitute adverse events only if they induce 
clinical signs or symptoms or require treatment or further diagnostic tests. 
 
10.1.2 Serious Adverse Event (SAE) 
A serious adverse event (SAE) is any adverse event occurring at any dose or during study 
therapy that: 
• Death. NOTE: Death due to disease progression should not be reported as a SAE, unless 
it is attributable by the site investigator to the study therapy 


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• Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
• Is a new cancer 
• Overdose; see 10.3 
• Pregnancy; see 10.4 
 
10.1.3 Expectedness 
Expected adverse event 
Expected AE are those events that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an AE is considered expected when it 
appears in the current AE list, the Investigator’s Brochure (IB), the package insert or is included 
in the informed consent document as a potential risk. 
 
Unexpected adverse event 
For the purposes of this study, an AE is considered unexpected when it varies in nature, intensity 
or frequency from information provided in the current AE list, the IB, the package insert or when 
it is not included in the informed consent document as a potential risk. 
 
10.1.4 Attribution 
Attribution is the relationship between an AE or SAE and the study treatment. Attribution will be 
assigned as follows: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 


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10.2 
Reporting 
 
10.2.1 Adverse Events  
• Adverse events should be recorded from the start of treatment through a minimum of 30 
days post-operative (or in unresected subjects 30 days past the date of the restaging scan 
or the attempted surgery).  
• AEs will be recorded regardless of whether or not they are considered related to the study 
drug.   
• AEs considered related to study drug will be followed until resolution to ≤ Grade 1 or 
baseline, deemed clinically insignificant, and/or until a new anti-cancer treatment starts, 
whichever is earlier. 
• After initiation of neoadjuvant treatment, all adverse events will be reported according to 
the guidelines in the following sections. Throughout the study, site investigators should 
report any deaths, serious adverse events, or other adverse events of concern that are 
believed to be related to the investigational intervention. 
 
10.2.2 Site Requirements for Reporting SAEs 
 
PLEASE NOTE: Robert H. Lurie Comprehensive Cancer Center at Northwestern University 
has specific reporting instructions to Celgene.  Please see Section 10.2.3.2. 
 
Site investigators will assess the occurrence of SAEs at all subject evaluation time points during 
the study. 
 
Site investigators and other site personnel must report any SAE both related and unrelated 
occurring from the time of informed consent signature to 90 days following cessation of 
treatment or 30 days following cessation of treatment if the subject initiate new anticancer 
therapy, whichever is earlier.  The SAE should be reported on the SAE/ECI Submission Form 
within 24 hours of discovery of the event. 
 
Additionally, any serious adverse event, considered by a site investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the site investigator at 
any time outside of the time period specified in the previous paragraph also must be reported to 
HCRN.   
 
The completed SAE/ECI Submission Form must be sent electronically to Hoosier Cancer 
Research Network at safety@hoosiercancer.org. The site investigator is responsible for 
informing the IRB of the SAE per local requirements. The original copy of the SAE/ECI 
Submission Form and the fax confirmation sheet must be kept at the study site. 
 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode within one business day of the site investigator receiving the follow-
up information.   
 
 
 


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Follow-up information will be sent electronically to HCRN at safety@hoosiercancer.org using 
the SAE/ECI Submission Form stating that this is a follow-up to a previously reported SAE. The 
follow-up information should describe whether the event has resolved or continues, if and how it 
was treated, and whether the subject continued or withdrew from study participation.   
 
All AEs and SAEs whether reported by the subject, discovered during questioning, directly 
observed or detected by physical examination, laboratory test or other means, will be recorded in 
the subject’s medical record and on the appropriate study specific eCRF forms within the EDC 
system.   
 
10.2.3 Reporting requirements 
The study must be conducted in compliance with FDA regulations, local safety reporting 
requirements and reporting requirements of the sponsor-investigator. Progress reports and 
notifications of serious unexpected adverse drug reactions will be provided to the IRB according 
to local regulations and guidelines. These reports will be reviewed by the sponsor-investigator 
and those considered unexpected and possibly related to study drug plus all deaths within 90 
days of discontinuing treatment will be forwarded to participating sites for submission to their 
Institutional Review Boards per their guidelines.  All other events will be held and submitted to 
the sites for continuing review. 
 
10.2.4 Hoosier Cancer Research Network Requirements for Reporting SAEs 
 
10.2.4.1 
Reporting to Merck 
HCRN will report any serious adverse event, or follow up to a serious adverse event whether or 
not related to Merck product that occurs to any subject from the time the consent is signed 
through 90 days following cessation of treatment or 30 days following cessation of treatment if 
the subject initiate new anticancer therapy, whichever is earlier.  The SAE/ECI Submission Form 
should be sent to Merck within one business day of receipt from the site. HCRN will provide 
follow-up information as reasonably requested. 
 
Hoosier Cancer Research Network will fax the SAE/ECI Submission Form and any other 
relevant safety information to Merck GS at +1-215-993-1220.  
 
10.2.4.2 
Reporting to Celgene 
Robert H. Lurie Comprehensive Cancer Center at Northwestern University will report to 
Celgene and HCRN concurrently in writing using a Celgene SAE form any SAE within 24 
hours of becoming aware of the event.  SAEs received from other participating sites will be sent 
to HCRN and HCRN will report to Celgene by within 24 hours of HCRN becoming aware of 
the event.  HCRN will report to Celgene using a MEDWATCH 3500A form.  Celgene will 
communicate directly with HCRN regarding SAE follow up questions and HCRN will respond 
to those questions within 5 days.   
 
The initial report will be as complete as possible, including an assessment of the causal 
relationship between the event and the investigational product(s), if available.  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) will be documented on a follow-up report.  A final report to 


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document resolution of the SAE is required.  The Celgene tracking number (AX-CL-NSCLC-PI-
004076) 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 study records. 
 
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 
 
10.2.4.3 
Reporting to the Northwestern QAM 
All SAEs, including deaths must be reported to the assigned Northwestern QAM. The completed 
SAE Submission Form must be emailed to croqualityassurance@northwestern.edu within one 
business day of discovery of the event.  See Section 11 for additional reporting information. 
 
10.2.4.4 
Reporting to the Food and Drug Administration (FDA) 
This study was determined to be exempt by the FDA on 1.28.15.  HCRN will continue to 
facilitate compliance of applicable requirements for the sponsor-investigator in relation to this 
study. This includes but is not limited to 21 CFR 50.20 informed consent, 21 CFR Part 56 IRB, 
and pertinent sections of the Public Health Service Act and FDAAA. 
 
10.3 
Definition of an Overdose  
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.   
 
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. 
 
10.4 
Reporting of Pregnancy and Lactation  
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial. 


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Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization 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.   
 
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of the study drugs, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported by 
the investigator.  All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported 
as serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
 
10.5 
Events of Clinical Interest (ECI) 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the SAE/ECI Submission Form.  ECIs (both non-serious 
and serious adverse events) identified from the date of first dose through 90 days following 
cessation of treatment, or 30 days after the initiation of a new anticancer therapy, whichever is 
earlier, will be reported from the site to HCRN within one business day.  HCRN will report to 
Merck within one business day. 
 
Events of clinical interest for this trial include: 
1. an overdose of Pembrolizumab, as defined in Section 10.3 - Definition of an Overdose 
and Reporting Guidelines, 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.  The trial site guidance for assessment and follow up of 
these criteria can be found in the Investigator Trial Master File (or equivalent). 
 
11. 
TRIAL MANAGEMENT 
The Robert H. Lurie Comprehensive Cancer Center’s Data Monitoring Committee (DMC) will 
provide study oversight activities as outlined in Section 11.2. This study will be conducted with 
guidance from the Data and Safety Monitoring Plan of the Robert H. Lurie Comprehensive 
Cancer Center, a copy of which can be found at:  
https://www.cancer.northwestern.edu/research/clinical-trials-office/research-oversight.html  
 
 
 


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11.1 
HCRN oversight activities include 
• Review and processing of all adverse events requiring expedited reporting as defined in 
the protocol 
• Provide trial accrual progress, safety information and data summary reports to the 
sponsor-investigator  
• Submit data summary reports to the lead institution DMC and attend DMC reviews: 
o during the Phase I portion of the study, semi-monthly to present safety summary 
reports 
o during the Phase II portion of the study, as applicable: following any reports of 
protocol deviations or SAEs; and overall study data delinquency that exceeds 
10% incomplete forms or sites with data delinquency that are not responding 
sufficiently to the HCRN data delinquency escalation process   
o throughout the study, semi-annual comprehensive DMC review  
• During the Phase I portion of the study there will be weekly Phase I safety calls with all 
participating institutions 
 
11.2 
Robert H. Lurie Comprehensive Cancer Center’s Data Monitoring Committee 
(DMC) 
HCRN will provide the following for the Robert H. Lurie Comprehensive Cancer Center’s 
DMC to review: 
• Adverse event summary report 
• Monitoring reports 
• Audit results if applicable 
• Study accrual patterns 
• Data delinquency  
• Protocol deviations 
 
The Robert H. Lurie Comprehensive Cancer Center’s DMC will conduct a comprehensive study 
review semi-annually.  Documentation of DMC reviews will be provided to sponsor-investigator 
and HCRN.  Issues of immediate concern by the DMC will be brought to the attention of the 
sponsor-investigator and other regulatory bodies as appropriate.  The sponsor-investigator will 
work with HCRN to address the DMC’s concerns.   
 
11.3 
Data Quality Oversight Activities 
 
11.3.1 Onsite Monitoring 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed.  For cause visits may occur as necessary. Selected source 
documents will be reviewed for verification of agreement with data entered into the EDC system.  
It is important for the site investigator and their relevant personnel to be available for a sufficient 
amount of time during the monitoring visits or audit, if applicable. The site investigator and 
institution guarantee access to source documents by HCRN or its designee. 
 
The trial site may also be subject to quality assurance audit by Merck or Celgene or its designee 
as well as inspection by appropriate regulatory agencies. 
 


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11.3.2 Remote Data Validation 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study.  The data entry completion status of each participating site will be 
reviewed on a weekly basis to ensure timeliness of data entry.  Electronic Case Report Form 
(eCRF) constraints will be utilized to prevent data entry errors and ensure complete data entry.  
Automated bi-weekly edit check programs will check for errors in accuracy, validity, and 
consistency in the data.  Listings from the edit check programs will be used to generate queries in 
the EDC system. Corrections will be made in a timely manner by the study site personnel.  
 
11.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information.   
 
12. 
DATA HANDLING AND RECORD KEEPING 
 
12.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based electronic data capture system (EDC), a system compliant with Good 
Clinical Practices and Federal Rules and Regulations.  HCRN personnel will coordinate and 
manage data for quality and integrity. All data will be collected and entered into EDC system by 
study site personnel from participating institutions.   
 
12.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in EDC system or other secure database(s). If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in EDC system, according to study-
specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
 
12.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 


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retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
12.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Merck, Celgene, IRB, or government agencies, like the 
FDA, may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
13. 
ETHICS 
 
13.1 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved by an IRB.  The site investigator must submit written approval to HCRN before he/she 
can register any subject to the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements.  In addition, the IRB must approve all advertising used to 
recruit subjects for the study.  The protocol must be re-approved by the IRB annually, as local 
regulations require.  
 
13.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements. 
 
13.3 
Informed Consent 
The site investigator will ensure the subjects is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study.  The site investigator must store all original, signed 
Informed Consent Forms.  A copy of the signed Informed Consent Form must be given to the 
subject. 
 
 
 


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14. 
PATHOLOGY REQUIREMENTS 
 
14.1 
Pathology Requirements for Enrollment 
 
14.1.1 Source of specimen 
A pathology report confirming the diagnosis of advanced stage non-small cell lung cancer 
(NSCLC) must be available at the time of enrollment on study.  For subjects with locally 
advanced or metastatic disease at the time of diagnosis, the original pathology from this 
diagnosis is sufficient.  For subjects with early stage disease who later developed metastatic 
disease, biopsy confirmation of the metastatic disease is required.  All biopsies done at other 
institutions should be reviewed and confirmed by a pathologist at the local study site. 
 
14.1.2 Adequacy of available specimen 
For all subjects, unstained slides from an archived tumor block must be available prior to 
registration, with the exception for subjects who have had prior PD-L1 testing using the Dako 
22C3 antibody and insufficient tissue for additional studies.  Adequacy of tissue samples will be 
determined by the Merck & Co. laboratory responsible for doing correlative studies.  If adequate 
tissue samples are not available, additional biopsy will be required.  Acceptable biopsies will be 
obtained via transcutaneous core needle biopsies or surgical biopsies.  At least 3 cores of tissue 
will be required.   
 
14.1.3 Histology 
The following histology is eligible  
• Adenocarcinoma 
• Large cell carcinoma 
• Poorly differentiated carcinoma 
• NSCLC, not otherwise specified 
• Squamous Cell Carcinoma 
 
14.2 
Pathology Requirements for Study Biopsies  
 
14.2.1 Subject selection for biopsies 
Adequate archival tissue or available PD-L1 testing results using the Dako 22C3 antibody are 
required for enrollment. If the patient has not had prior testing and no acceptable archival tissue 
is available, subjects must be willing to consent to providing a pre-treatment biopsy for PD-L1 
testing.  This biopsy is to be obtained within 28 days prior to registration.  Phase II subjects are 
required to provide a post-treatment tumor biopsy after completion of 4 cycles of study treatment 
or at progression.  The progression biopsy should be performed once confirmed by second scan 
unless unequivocal progression that requires the subject come off study treatment prior to 
confirmation scan. In the event that a subject has had a complete response or there is no disease 
feasible to biopsy, no biopsy will be obtained at that time. In this case, the subject will have the 
option to undergo a biopsy at progression. Window for tumor biopsies ±10 days to allow for 
scheduling conflicts (weekends/holidays).  Acceptable biopsies will be obtained via 
transcutaneous core needle biopsies or surgical biopsies.  At least 3 cores of tissue will be 
required.  FNAs are NOT acceptable.  See CLM (Correlative Laboratory Manual) for details 
regarding collection and shipping of sample. 


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14.2.2 Preparation and shipment of specimen 
All biopsies, whether obtained in Interventional Radiology, or in the operating room, should be 
processed by the local study site’s pathology lab.   See CLM for collection, labeling and shipping 
of samples.  
 
 


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33. Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in 
cancer. N Engl J Med, 2012. 366(26): p. 2443-54. 
34. Ribas, A., Tumor immunotherapy directed at PD-1. N Engl J Med, 2012. 366(26): p. 2517-9. 
35. Brahmer, J.R., et al., Survival and long-term follow-up of the phase I trial of nivolumab 
(Anti-PD-1; BMS-936558, ONO-4538) in patients (pts) with previously treated advanced 
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Melanoma. N Engl J Med, 2013. 


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37. Brahmer, J.R., et al., Phase I study of single-agent anti-programmed death-1 (MDX-1106) in 
refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic 
correlates. J Clin Oncol, 2010. 28(19): p. 3167-75. 
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modulation of integrin-linked kinase activity. J Biol Chem, 2005. 280(43): p. 36483-93. 
39. Huang, Y., et al., SPARC expression and prognostic value in non-small cell lung cancer. 
Chin J Cancer, 2012. 31(11): p. 541-8. 
40. Salmon, H., et al., Matrix architecture defines the preferential localization and migration of 
T cells into the stroma of human lung tumors. J Clin Invest, 2012. 122(3): p. 899-910. 
41. Mosteller, R.D., Simplified calculation of body-surface area. N Engl J Med, 1987. 317(17): 
p. 1098. 
 
 
 


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16. 
APPENDICES 
 
16.1 
Robert H. Lurie CCC DSMP  
This study will be conducted in accordance with the Data and Safety Monitoring Plan of the 
Robert H. Lurie Comprehensive Cancer Center, a copy of which can be found at: 
http://cancer.northwestern.edu/cro/library.cfm#CPSRMS 
 
16.2 
ECOG Performance status 
 
Table 13: ECOG Performance Status 
Grade 
Description 
Grade 0 
Fully active, able to carry on all pre-disease performance without restriction
Grade 1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work
Grade 2 
Ambulatory and capable of all self care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
Grade 3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours 
Grade 4 
Completely disabled. Cannot carry on any self care. Totally confined to bed 
or chair 
 
 
 
 
 
 
 


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Table 16.3 Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab  
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of pneumonitis 
• 
Evaluate 
participants 
with 
suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add 
prophylactic 
antibiotics 
for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus). 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting 
colitis 
should 
consider 
GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
Grade 4 
Permanently 
discontinue 


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feasible, fluid and electrolytes should be 
substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement therapy 
for participants with T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers 
(eg, 
propranolol) 
or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate 
thyroid 
replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer 
corticosteroids 
(prednisone 
1-2 
mg/kg 
or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE administer 
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Grade 3 or 4 
Permanently 
discontinue 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).