Clinical trial NCT03425006
Conditions: Non Small Cell Lung Cancer
Sponsor: University of Pennsylvania
Start date: 2018-06-18; Completion date: 2021-10-11
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single center, single arm phase 2 study to establish the safety and efficacy of itacitinib (also known as INCB039110) administered in combination with pembrolizumab in patients with metastatic PD-L1 positive non-small cell lung cancer (NSCLC).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Itacitinib intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: a JAK 1 selective small molecule inhibitor intervention 2: a highly selective humanized monoclonal antibody (mAb)

Protocol documents:
Prot_SAP_000.pdf: 
Pembrolizumab and Itacitinib for NSCLC 
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Phase II Study of Pembrolizumab and Itacitinib (INCB039110) for First Line 
Treatment of Metastatic Non-Small Cell Lung Cancer Expressing PD-L1 
 
Principal Investigator 
 
 
Corey Langer, MD 
Department of Medicine 
University of Pennsylvania School of Medicine  
Regulatory Sponsor 
University of Pennsylvania  
Sponsor Medical Director 
Noelle Frey, MD 
Funding Sponsor 
Parker Institute for Cancer Immunotherapy 
Protocol Numbers 
UPCC# 09517; IRB#828910; NCT03425006 
Study Product(s) 
Itacitinib (INCB039110); Pembrolizumab 
IND number 
137721 
Correlative Laboratory Team 
Andy Minn, MD, PhD 
John Wherry, PhD 
Biostatistician 
Rosemarie Mick 
 
Date: 
Amended: 
V1.10-24-2017 
V2.01-16-2018 
V3.05-10-2019 
V4.03-11-2020 
V5.05-24-2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY .................................................................................................... 5 
2.0 
TRIAL DESIGN ......................................................................................................... 6 
2.1 
Trial Design .................................................................................................... 6 
3.0 
OBJECTIVES ............................................................................................................ 7 
3.1 
Primary Objectives & Hypotheses .................................................................. 7 
3.2 
Secondary Objectives .................................................................................... 8 
3.3 
Exploratory Objectives ................................................................................... 8 
4.0 
BACKGROUND & RATIONALE ............................................................................... 8 
4.1 
Background .................................................................................................... 8 
4.1.1 
Pharmaceutical and Therapeutic Background .................................... 8 
4.1.2 
Preclinical and Clinical Trial Data ....................................................... 9 
4.2 
Rationale ..................................................................................................... 10 
4.2.1 
Rationale for the Trial and Selected Subject Population ................... 10 
4.2.2 
Rationale for Dose Selection/Regimen/ Modification ........................ 11 
4.2.3 
Rationale for Endpoints .................................................................... 12 
5.0 
METHODOLOGY .................................................................................................... 13 
5.1 
Entry Criteria ................................................................................................ 13 
5.1.1 
Inclusion Criteria ............................................................................... 13 
5.1.2 
Exclusion Criteria ............................................................................. 14 
5.2 
Enrollment.................................................................................................... 15 
5.3 
Study Drugs ................................................................................................. 16 
5.3.1 
Dose Selection/Modification ............................................................. 16 
5.3.2 
Timing of Dose Administration .......................................................... 18 
5.4 
Concomitant Medications ............................................................................. 19 
5.4.1 
Acceptable Concomitant Medications ............................................... 19 
5.4.2 
Prohibited Concomitant Medications ................................................ 19 
5.5 
Rescue Medications & Supportive Care ....................................................... 20 
5.5.1 
Supportive Care Guidelines .............................................................. 20 
5.6 
Diet/Activity/Other Considerations ................................................................ 20 
5.6.1 
Diet ................................................................................................... 20 
5.6.2 
Contraception ................................................................................... 21 
5.6.3 
Use in Nursing Women ..................................................................... 21 
5.7 
Subject Withdrawal/Discontinuation ............................................................. 21 
5.8 
Subject Replacement Strategy ..................................................................... 22 
5.9 
Clinical Criteria for Early Trial Termination ................................................... 22 
5.10 
Clinical Criteria for Early Trial Termination due to Trial Conduct or Other 
Factors ......................................................................................................... 23 
6.0 
TRIAL FLOW CHART ............................................................................................. 24 
6.1 
Study Flow Chart ......................................................................................... 24 
7.0 
TRIAL PROCEDURES ............................................................................................ 27 
7.1 
Trial Procedures .......................................................................................... 27 
7.1.1 
Administrative Procedures ................................................................ 27 


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7.1.2 
Clinical Procedures/Assessments..................................................... 28 
7.1.3 
Archived Tumor Tissue Sample ........................................................ 29 
7.1.4 
Unscheduled Research Sample Collections ..................................... 29 
7.1.5 
Laboratory Procedures/Assessments ............................................... 30 
7.1.6 
Other Procedures ............................................................................. 31 
7.1.7 
Visit Requirements ........................................................................... 32 
7.1.8 
Definition of an Overdose for This Protocol and Reporting of 
Overdose to the Sponsor .................................................................. 32 
8.0 
STATISTICAL ANALYSIS PLAN ............................................................................ 33 
8.1 
Statistical Design ......................................................................................... 33 
8.2 
Statistical Analysis Plan ............................................................................... 33 
8.2.1 
Hypothesis/Evaluation ...................................................................... 34 
8.2.2 
Analysis Populations ........................................................................ 35 
8.2.3 
Statistical Methods ........................................................................... 35 
8.3 
Sample Size ................................................................................................. 36 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF STUDY DRUGS .......... 36 
9.1 
Itacitinib ....................................................................................................... 36 
9.1.1 
Availability ........................................................................................ 36 
9.1.2 
Preparation ....................................................................................... 36 
9.1.3 
Storage and Stability ........................................................................ 36 
9.1.4 
Product Handling and Labeling ......................................................... 36 
9.1.5 
Potential Toxicities ........................................................................... 36 
9.2 
Pembrolizumab ............................................................................................ 36 
9.3 
Returns and Reconciliation (Itacitinib) .......................................................... 36 
10.0 
SAFETY AND ADVERSE EVENTS ........................................................................ 37 
10.1 
Definitions .................................................................................................... 37 
10.2 
Recording of Adverse Events ....................................................................... 39 
10.3 
Reporting of Serious Adverse Events ........................................................... 40 
10.3.1 Investigator Reporting:  Local Regulatory Review Committees ......... 41 
10.3.2 Pregnancies ..................................................................................... 41 
10.4 
Protocol Exceptions and Deviations ............................................................. 41 
11.0 
DATA HANDLING AND RECORDKEEPING .......................................................... 42 
11.1 
Confidentiality .............................................................................................. 42 
11.2 
Source Documents ...................................................................................... 42 
11.3 
Case Report Forms ...................................................................................... 43 
11.4 
Records Retention ....................................................................................... 43 
12.0 
STUDY MONITORING, AUDITING, AND INSPECTING ......................................... 43 
12.1 
Study Monitoring Plan .................................................................................. 43 
12.2 
Auditing and Inspecting ................................................................................ 43 
13.0 
ETHICAL CONSIDERATIONS ................................................................................ 44 
14.0 
STUDY FINANCES ................................................................................................. 44 
14.1 
Funding Source ........................................................................................... 44 
14.2 
Conflict of Interest ........................................................................................ 44 
14.3 
Subject Stipends or Payments ..................................................................... 44 
14.4 
Study Discontinuation .................................................................................. 44 


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15.0 
PUBLICATION PLAN ............................................................................................. 44 
16.0 
APPENDICES ......................................................................................................... 45 
16.1 
ECOG Performance Status .......................................................................... 45 
16.2 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1- Criteria for 
Evaluating Response in Solid Tumors .......................................................... 45 
17.0 
REFERENCES ........................................................................................................ 46 
 
 
 
 


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1.0 
TRIAL SUMMARY 
Title: 
Phase II study of Pembrolizumab and Itacitinib (INCB039110) 
for First Line Treatment of Metastatic Non-Small Cell Lung 
Cancer Expressing PD-L1 
Abbreviated Title 
Pembrolizumab and itacitinib (INCB039110) for NSCLC 
Protocol Numbers 
UPCC#09517; IRB#828910; NCT03425006; IND#137721 
Trial Phase 
Phase II 
Study Center(s) 
University of Pennsylvania 
Study Population 
The first line treatment of patients with metastatic PD-L1 
positive non-small cell lung cancer (NSCLC) 
Methodology 
This is a single center, single arm phase 2 study to establish 
the safety and efficacy of itacitinib (also known as 
INCB039110) 
administered 
in 
combination 
with 
pembrolizumab in patients with metastatic PD-L1 positive 
non-small cell lung cancer (NSCLC). 
Study 
Drugs, 
Dose 
and 
Regimen 
Study Drug(s) 
• 
Itacitinib: a JAK 1 selective small molecule inhibitor; 
an investigational agent that is study supplied 
• 
Pembrolizumab: 
a 
highly 
selective 
humanized 
monoclonal antibody (mAb) 
 
Dose and Route of Administration 
• 
Itacitinib: 200mg PO (extended release formulation) 
• 
Pembrolizumab: 200mg IV infusion over 30 minutes 
  
Regimen 
• 
Treatment = 3 week (Q3W) dosing cycles 
• 
Itacitinib: Once daily for Cycle 3 and Cycle 4 (up to 6 
weeks) 
• 
Pembrolizumab: Q3 week cycles of treatment 
beginning at Day 1; if the PI considers it beneficial for 
the subject, a fifth cycle may be administered prior to 
EOS visit. 
Number of trial subjects 
Up to 48 evaluable subjects 
Estimated duration of trial 
Approximately 48 months 
 
 
 
 
 


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2.0 
TRIAL DESIGN 
2.1 
Trial Design 
This is an optimal 3-stage Phase II trial of trial of pembrolizumab and itacitinib for first line 
treatment of PD-L1 positive metastatic NSCLC. Up to 48 evaluable subjects will be enrolled to 
examine the efficacy of adding itacitinib to pembrolizumab among patients with previously 
untreated metastatic NSCLC with tumor PD-L1 expression greater than or equal to 50%. Subjects 
will receive 2 cycles of pembrolizumab (200mg every 3 weeks), and then undergo repeat imaging 
and tumor biopsy. Beginning on the Day 1 of Cycle 3 the subject will receive itacitinib (selective 
JAK1 inhibitor) 200 mg daily for 6 weeks. Pembrolizumab will be continued at the same dose and 
frequency.  After 6 weeks of treatment (week 12 of treatment overall) with itacitinib, repeat imaging 
and tumor biopsy will be performed. The scan is purely for biopsy planning, and no treatment 
decisions will be made based upon the results (Figure 1). Objective response by RECIST 1.1 will 
be determined based on the week 12 scan.  Subjects who either experience documented 
progressive disease during the first 12 weeks of treatment or complete the first 12 weeks of 
treatment and undergo re-staging (i.e., PET/CT scan) will be considered evaluable for objective 
response evaluation.  Subjects who are withdrawn from study (due to toxicity or other reasons) in 
the first 12 weeks of treatment and who do not undergo re-staging will be considered unevaluable 
for objective response evaluation but will be included in the safety analyses. These subjects will 
be replaced. Objective response rate (ORR) is defined as the proportion of evaluable subjects 
who achieve a complete or partial response according to RECIST 1.1 criteria. 
 
The ORR for pembrolizumab in untreated PD-L1 positive advanced NSCLC was recently reported 
to be 45% (95% CI 37-53%) [1]. The 3-stage optimal design tests the null hypothesis that the 
ORR ≤ 35% (clearly inferior to pembrolizumab) versus the alternative that the ORR > 55% (clearly 
superior to pembrolizumab) [2]. Eleven evaluable subjects will be entered into the first stage of 
the study. If 2 or fewer of these 11 subjects respond, then the trial will be terminated. If at least 3 
of these subjects respond, then an additional 19 evaluable subjects will be entered into the second 
stage of the study. If 12 or fewer of these 30 subjects respond, then the trial will be terminated. If 
at least 13 of these subjects respond, then an additional 18 evaluable subjects will be entered 
into the third stage of the study. If 20 or fewer of these 48 subjects respond, then it will be 
concluded that the regimen does not merit further investigation. If at least 21 of these 48 subjects 
respond, then it will be concluded that the regimen merits further investigation. If the true objective 
response rate is 35%, then the probability of recommending the regimen for further investigation 
(false positive error), is 0.100. If the true objective response rate is 55%, then the probability of 
recommending the regimen for further investigation (power), is 0.906. If the true objective 
response rate is 35%, then the probability of early termination of the trial by the end of the second 
stage is 0.786. The software program, PASS v14 was employed to define this 3-stage design. 
 
As of Protocol Amendment V5, subjects will continue on study treatment for up to 12 weeks (4 
treatment cycles), followed by an End of Study Visit (EOS) at Week 16.  If the PI considers it 
beneficial fo the subject, a fifth cycle may be administered prior to the EOS visit.  Subjects who 
remained on study treatment beyond Week 16 prior to the approval of Protocol Amendment V5, 
will be asked to undergo an End of Study Visit at their next clinic appointment.  
 
Investigators will make treatment-based decisions using RECIST 1.1. Adverse events will be 
monitored throughout the subjects’ participation in the trial and graded in severity according to 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 per protocol 
Section 10.1.  
 


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The primary objectives of the trial include determination of ORR per RECIST 1.1 for the 
combination of pembrolizumab and itacitinib and the safety of this combination, as assessed by 
CTCAE.  Pre-specified adverse events of clinical interest include the following events: 1) Grade 
≥ 3 diarrhea 2) Grade ≥ 2 colitis, 3) Grade ≥ 2 pneumonitis, 4) Grade ≥ 3 hypo- or hyperthyroidism, 
5) Grade ≥ 2 hypophysitis, 6) Grade ≥ 2 uveitis, 7) Grade ≥ 2 nephritis, 8) Grade ≥ 3 anemia, 9) 
Grade ≥ 3 thrombocytopenia, and 10) Grade ≥ 3 neutropenia.  
 
The secondary objective of this trial is to collect paired tumor biopsies and peripheral blood to 
characterize immune biomarkers of response to treatment with pembrolizumab and itacitinib. 
Additional secondary objectives include determination of progression free survival, duration of 
response and overall survival, up to week 16 when the subject reaches end of study.  
 
Figure 1. Study Schema 
 
3.0 
OBJECTIVES  
3.1 
Primary Objectives & Hypotheses 
1) To determine the objective response rate at 12 weeks according to RECIST 1.1 for the 
combination of pembrolizumab and itacitinib among patients with previously untreated, 
PD-L1 positive metastatic NSCLC.  Responses will be compared to the subject’s 
baseline assessment and historical controls using pembrolizumab monotherapy.  
2) To evaluate toxicities (CTCAE v5.0 scoring) of pembrolizumab and itacitinib in patients 
with previously untreated, PD-L1 positive metastatic NSCLC 
 


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3.2 
Secondary Objectives  
1) To collect paired blood and tumor tissue samples in order to perform mechanistic studies 
on treatment-related changes in the subject and tumor immune profiles 
 
2) To determine the median progression free survival (PFS) and duration of response 
(DOR) at week 12 as well as overall survival (OS) for subjects treated with 
pembrolizumab and itacitinib, up week 16.  
 
3.3 
Exploratory Objectives 
1) To perform analyses of tumor infiltrating lymphocytes (TILs) to identify changes in 
functional markers in response to the addition of itacitinib to pembrolizumab. 
 
2) To perform gene expression studies of tumor tissue using Nanostring to characterize 
genetic effects in response to immunotherapy. 
4.0 
BACKGROUND & RATIONALE 
4.1 
Background  
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the United States [3].  
More than half of patients present with metastatic disease, and are thus considered incurable [4].  
Until very recently, the standard first-line treatment for NSCLC not harboring a targetable mutation 
was platinum doublet chemotherapy.  While supportive care measures for patients receiving 
cytotoxic chemotherapy have improved markedly, the side effects of these agents can be 
substantial [5, 6].  Immunotherapy, most commonly using PD-1 inhibitors, is now known to have 
significant activity in NSCLC with a very favorable side effect profile [7-9]. Most recently, the 
KEYNOTE 024 study revealed that among patients with PD-L1 expression greater than or equal 
to 50%, pembrolizumab was associated with superior overall and progression free survival when 
compared with platinum doublet chemotherapy [1].  
 
4.1.1 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation 
has been known for decades [10].  Accumulating evidence shows a correlation between tumor-
infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies 
[11-15].  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells to 
FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in 
many solid tumors. 
 
The PD-1 receptor-ligand interaction between tumor cells and the immune system is a major 
pathway hijacked by tumors to suppress immune control.  The normal function of PD-1, expressed 
on the cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted 
or excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene 
Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or 
PD-L2) [16, 17].  The structure of murine PD-1 has been resolved [18].  PD-1 and family members 
are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of 
signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based 


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switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-
1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling 
cascade [19-22].  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 [23, 24].  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells [25, 26].  Expression has also 
been shown during thymic development on CD4-CD8- (double negative) T-cells as well as 
subsets of macrophages and dendritic cells [17].  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic 
tissues as well as in various tumors [23, 27-29].  Both ligands are type I transmembrane receptors 
containing both IgV- and IgC-like domains in the extracellular region and contain short 
cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits 
T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at low levels on various 
non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only 
detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments.  PD-L2 is thought to control immune T-cell activation in lymphoid 
organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues [23]. 
Although healthy organs express little (if any) PD-L1, a variety of cancers have been 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma (MEL) [30]. This suggests 
that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be 
considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab (previously known as MK-3475 and SCH 900475) is a potent and highly selective 
humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2.   
 
Interferons are known to have an important role early in generating anti-tumor T cell responses.  
However, interferons are also involved in the development of adaptive immune resistance [31, 
32].  Signaling through the JAK-STAT pathway, interferons regulate PD-L1 expression as well as 
multiple other negative feedback effects on the immune response through pathways that would 
not be inhibited by PD-1 blockade alone [33].  Interferon signaling has been theorized as an 
explanation for the observation that elevated PD-L1 expression is not universally associated with 
response to pembrolizumab and may also be responsible for primary or secondary  treatment 
resistance [1, 34].  JAK1 is a tyrosine kinase necessary for signaling downstream of both type I 
and II interferon receptors, as well as multiple other inflammatory cytokines.  JAK/STAT signaling 
has been proposed to promote tumor growth in part by promoting an inflammatory 
microenvironment that limits CD8+ T cell activity [35].  
 
Itacitinib is a potent JAK1 selective small molecule inhibitor (half maximal inhibitory concentration 
[IC50] = 3.6 nM), with 22 to 500-fold greater selectivity for JAK1 compared to other JAK family 
members including JAK2, JAK3 and TYK2.  
 
4.1.2 
Preclinical and Clinical Trial Data 
Previous work in a mouse melanoma model showed that tumor intrinsic interferon signaling 
promotes resistance to immune checkpoint blockade [36].  Knocking out type I and II interferon 
receptors on melanoma cells sensitizes them to immune checkpoint blockade, markedly 
improving treatment response and survival in pre-clinical models.  T cells from these mice express 
higher proliferative and cytotoxic markers after immune checkpoint blockade.   


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Preclinical studies utilizing a JAK1/2 inhibitor to block interferon signaling revealed the following 
observations that can be translated to human trials: 
• 
JAK inhibition reduced tumor growth in response to immune checkpoint blockade and 
flow cytometry analysis of tumor cells demonstrated decreased surface expression of 
multiple inhibitory receptor ligands, which generally are associated with immune 
suppression.   
• 
As prolonged JAK inhibition can have side effects, we tested a short course of JAK 
inhibitor therapy and still observed consistent improvements in tumor regression.   
• 
When JAK inhibition began concurrently with checkpoint blockade, no improvement was 
seen in tumor regression relative to checkpoint blockade alone. 
• 
When JAK inhibition was started after an induction phase of checkpoint blockade, 
however, a marked increase in tumor regression was seen.  The selective benefit of 
sequential, as opposed to concurrent therapy initiation is consistent with 1) the 
immunostimulatory role of interferon signaling in early events of dendritic cell activation 
and T cell priming, and 2) the feedback inhibition and immunosuppressive role that 
occurs with prolonged interferon signaling.   
 
The importance of the timing of JAK inhibition is also implied by studies in chronic viral infections. 
Blocking interferon signaling late in infection improves viral control, while earlier inhibition is not 
beneficial[37, 38].  In this study, we aim to extend these findings to patients by testing the addition 
of JAK inhibition to ongoing anti-PD-1 therapy. We hypothesize that combined treatment with 
pembrolizumab and itacitinib will be associated with an overall response rate of at least 55%.  
Moreover, using paired blood and tissue-based biomarkers during the course of treatment we 
hope to better understand the dynamics of response to immunotherapy among patients with 
NSCLC.   
 
The combination of itacitinib and pembrolizumab is being evaluated in a phase I study in patients 
with advanced solid tumors. Data from this trial have not been presented or published. To date, 
35 subjects have been treated in the dose escalation and expansion cohorts. No dose-limiting 
toxicities were noted.  The risks of using itacitinib in combination with pembrolizumab are 
unknown at this time. We anticipate the risk profile of these agents when given in combination will 
be similar to that of the risk profile of each drug when given alone. Efficacy data is currently not 
available for this combination.  
 
Refer to the Investigator’s Brochure of itacitinib and the pembrolizumab package insert for 
additional Preclinical and Clinical data including information on potential toxicities. 
 
4.2 
Rationale 
4.2.1 
Rationale for the Trial and Selected Subject Population 
The therapeutic benefit of immune checkpoint blockade has now been seen in multiple 
malignancies, with durable responses observed in a subset of patients [1, 9, 34, 39]. In spite of 
these exciting results, only a limited number of patients respond to PD-1 blockade, with response 
rates of approximately 20% in an unselected population.  PD-L1 expression is the best-studied 
predictive biomarker for response to checkpoint blockade in NSCLC [40].  While PD-L1 is an 
imperfect biomarker, with significant dynamism and heterogeneity, a recent study of patients with 
tumors expressing a high level of PD-L1 (>50%) pembrolizumab was found to improve overall 


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survival and progression free survival over platinum doublet chemotherapy in the first line 
treatment of NSCLC [1, 41]  Even in this population enriched for patients likely to respond to PD-
1 inhibition, the response rate to pembrolizumab was only 44.8%.  While this is a great advance, 
there is clearly room for improvement as we attempt to extend the benefits of anti-PD-1 therapy 
to a larger patient population.   
 
Patients with newly diagnosed stage IV or metastatic NSCLC with tumor PD-L1 expression 
greater than or equal to 50% will be enrolled in this study prior to any systemic therapy for 
metastatic disease.  This patient population is selected because 1) PD-L1 is itself upregulated by 
interferon signaling and could serve as a biomarker for JAK1 inhibition, and 2) we hypothesize 
that in a proportion of patients with PD-L1+ tumors, feedback inhibition that occurs with prolonged 
interferon signaling limits response.  Thus, patients with high levels of PD-L1 expression may be 
more likely to benefit from the combination of pembrolizumab and itacitinib. 
 
4.2.2 
Rationale for Dose Selection/Regimen/ Modification 
The currently approved dose for pembrolizumab in patients with NSCLC is 200mg every 3 
weeks. The 200mg every 3 week dose was also shown to be safe and effective in a first line 
treatment trial for patients with PD-L1 positive NSCLC [1]. At this time, the duration of treatment 
with pembrolizumab in patients with a clinical benefit is not clear but a standard practice is to 
continue treatment in the absence of adverse effects and/or clinical and radiographic disease 
progression. Therefore treatment with pembrolizumab will continue indefinitely in the absence of 
(1) documented disease progression per RECIST 1.1, (2) unacceptable adverse event(s), (3) 
intercurrent illness that prevents further administration of treatment, (4) investigator’s decision to 
withdraw the subject, (5) subject withdrawal of consent, (6) pregnancy of the subject, (7) 
noncompliance with trial treatment or procedure requirements, (8) institution of alternative 
systemic treatment, or (9) other administrative reasons. Pembrolizumab may also continue at 
the physician investigator’s discretion if the subject continues to benefit clinically from treatment.   
  
In study INCB039110-107, 35 subjects with advanced solid tumors have been treated with 
itacitinib in combination with pembrolizumab (8 subjects in Part 1a [dose escalation] and 27 
subjects in Part 1b [dose expansion]).  The most frequently reported treatment-emergent adverse 
events (TEAEs) in Part 1a were anemia, fatigue, disease progression (50% each) and nausea, 
decreased appetite, and decreased weight (37.5% each).  The most frequent TEAE in Part 1b 
were fatigue and nausea (37.0% each).  There were no dose-limiting toxicities (DLTs) in Part 1a.  
The dose expansion cohort was treated with 300mg daily of itacitinib.  Serious adverse events 
(SAE) were reported in 6 subjects in the expansion cohort and include disease progression (2 
subjects, 7.4%) and abdominal pain, gastric obstruction, pancreatitis, pyrexia, urinary tract 
infection and pulmonary embolism (1 subject each, 3.7%). Only pyrexia was considered to be a 
treatment-related SAE.  
 
Itacitinib is also being evaluated in combination with other immunotherapies in research studies.  
In personal communications with Incyte (the sponsor of these trials), they decided that based 
upon proprietary information, the recommended phase 2 dose for future study is 200mg/daily.  As 
more precise data become available, the protocol and consent will be updated to better 
characterize adverse events. 
 


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4.2.3 
Rationale for Endpoints 
 Efficacy Endpoints 
4.2.3.1.1 Primary 
Objective response rate, defined as the percentage of evaluable subjects who achieve a complete 
or partial clinical response at 12 weeks, according to RECIST 1.1 is the primary endpoint of this 
study. Given that this is a first line study of a novel combination, ORR was chosen as an earlier 
indicator of efficacy of the combination and to limit the number of subjects exposed if improved 
efficacy is not observed.  Morever, based on the mechanism of action, JAK1 inhibition would be 
predicted to improve the response rate in a population of patients with PD-L1 positive tumors by 
reducing the expression of additional immune inhibitory pathways in the tumor microenvironment.  
Responses will be compared to the subject’s baseline assessment and historical controls using 
pembrolizumab monotherapy. 
4.2.3.1.2 Secondary 
Peripheral blood immune profiling will provide important mechanistic information on how PD-1 
blockade and itacitinib function in human subjects.  By studying treatment related changes in 
blood and tumor, and correlate these with response or resistance, superior and perhaps tailored 
combination treatment strategies could potentially be developed in the future. Correlative samples 
will be banked upon receipt and correlative assays performed in the following priority order.  
High priority assays: 
1. Multiparametric flow cytometry analysis of peripheral blood mononuclear cells to analyze 
T cell subsets and markers of functionality.  T cell subsets will be determined using 
transcription factors and surface markers subsets. Functionality will be measured by 
examining activation markers, cytokines, effector molecules, and proliferation markers.  
2. Transcriptomic analyses of tumor specimens to identify changes in gene expression 
after the addition of itacitinib to pembrolizumab. In particular, we will examine a subset of 
interferon-stimulated genes (ISGs) associated with resistance to checkpoint blockade in 
pre-clinical models. 
3. Measurement of inflammatory cytokine or chemokine levels in subject serum. In 
particular, we will examine interferon levels and other cytokines regulated by the JAK1 
pathway as biomarkers for both on-target drug activity and response. 
Second priority assays: 
1. Measurement of inflammatory cytokine or chemokine levels in subject serum. Circulating 
tumor cell (CTC) and circulating tumor DNA (ctDNA) measurements and profiling.   
Additional secondary endpoints include progression free survival (PFS), overall survival (OS) 
and duration of response (DOR).  PFS is defined as days from initiation of study therapy to first 
documented disease progression, death due to any cause or last subject contact which 
documents progression-free status. Those patients who are currently on-study and progression-
free at 16 weeks, will no longer be followed and will be censored for PFS and OS at week 16. 
DOR is defined as the time from first documentation of partial or complete response to first 
documented disease progression. Those patients who are currently on-study and progression-
free at 16 weeks, will no longer be followed and will be censored for PFS and OS at week 16. 


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OS is defined as days from initiation of study therapy to death due to any cause or last subject 
contact.  Those patients who are currently on-study and progression-free at 16 weeks, will no 
longer be followed and will be censored for PFS and OS at week 16. 
 Exploratory objectives 
Perform analyses of tumor infiltrating lymphocytes (TILs) to identify changes in functional markers 
in response to the addition of itacitinib to pembrolizumab. This study will be a pilot feasibility study 
of performing multiparametric analysis of TILs, particularly CD8+ T cells, from patients with 
metastatic 
NSCLC 
using 
approaches 
such 
as 
flow 
cytometry 
and 
multicolor 
immunohistochemistry.  
 
Given the potential role for chronic interferon signaling as well as other inflammatory cytokines 
regulated by JAK/STAT signaling in impairing T cell function, we anticipate that response to 
itacitinib and pembrolizumab will be associated with 1) sustained activation of PD1+ T cells after 
an initial proliferative burst as measured by Ki67, 2) high pre-treatment interferon levels that is 
suppressed during treatment, and 3) high gene expression levels of resistance-associated ISGs. 
We hypothesize that subjects failing to respond to treatment will show initial proliferative burst in 
PD1+ T cells that is not sustained despite continued pembrolizumab, and 2) decreased 
expression of various other markers of T cell activation. 
 
Additionally, deep sequencing of the T cell receptor (TCR) in tumor and blood will be performed 
as feasible to identify clones that expand after treatment and monitor their persistence over time. 
These are non-biased approaches to identify tumor reactive T cells in subjects where the specific 
neoantigen is not known.  
5.0 
METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 
Inclusion Criteria 
1. Stage IV or metastatic non-small cell lung cancer (NSCLC) 
 
2. Provide written informed consent for the trial. 
 
3.  Patients ≥ 18 years of age  
 
4. Tumor PD-L1≥ 50% as assessed by the PD-L1 IHC 22C3 pharmDx assay (Dako 
North America). 
 
5. Subject must have adequate tumor burden at a safely accessible site for biopsy. 
NOTE: If sites chosen for biopsy were previously irradiated, there must be 
evidence of tumor growth/viable tumor as assessed by the investigator. 
 
6. At least one measurable lesion according to Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 
 
7. ECOG performance status 0 or 1  
 
8. Adequate organ function as defined in Table 1  


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Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) ≥1,250/mcL 
Platelets ≥100,000/mcL 
Hemoglobin ≥9 g/dL or ≥5.6 mmol/L  
Renal 
 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥50 mL/min for subject with creatinine levels > 
1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin ≤ 1.5 X ULN OR 
 Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
aCreatinine clearance should be calculated per institutional standard. 
 
9. Subjects of reproductive potential must agree to use acceptable birth control 
methods as described in protocol Section 5.6.2. 
 
5.1.2 
Exclusion Criteria 
1. Sensitizing mutations in Epidermal growth factor receptor (EGFR) or anaplastic 
lymphoma kinase (ALK) or ROS1 proto-oncogene receptor tyrosine kinase 
(ROS1) translocations 
2. Currently participating in or has participated in a study of an investigational agent 
or anticipated use of an investigational device within 4 weeks of the first dose of 
study treatment. 
3. Untreated symptomatic central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  
4. Received prior systemic cytotoxic chemotherapy, biologic therapy, targeted 
therapy or immunotherapy for incurable (metastatic) NSCLC.   
5. Diagnosis of immunodeficiency within 7 days prior to eligibility confirmation by the 
physician-investigator.  
6. Prior monoclonal antibodies used for the treatment of NSCLC within 4 weeks prior 
to eligibility confirmation by the physician-investigator, or individuals who have not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier.  


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7. Known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, non-invasive bladder tumors, or in situ cervical cancer  
8. Active autoimmune disease requiring systemic immunosuppressive treatment 
within the past 3 months prior to eligibility confirmation by the physician-
investigator. Subjects that require intermittent use of steroid-containing 
bronchodilators or local steroid injections or topical steroid medications are not 
excluded from the study.  Subjects with hypothyroidism stable on hormone 
replacement or Sjogren’s syndrome are not excluded from the study. 
9. Interstitial lung disease or history of pneumonitis that has required oral or IV 
steroids 
10. Active infection requiring systemic therapy with IV antibiotics 
11. History or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.   
12. Known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
13. Pregnant or breastfeeding women 
14. 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). 
15. Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
16. Known active Hepatitis B (e.g., HBsAg positive or HBV DNA detectable) or 
Hepatitis C (e.g., HCV RNA [qualitative] is detected). 
17. Anticipated receipt of any live vaccine within 30 days prior to the first dose of trial 
treatment.   
Note: For the purposes of determining eligibility above, enrollment is defined as the date of subject 
consent. 
5.2 
Enrollment 
The Subject Number consists of the Protocol Number with a sequential subject number affixed to 
it.  Assignment of subject numbers will occur at the time of consent and occur in ascending order 
(i.e. 09517-01, 09517-02, etc).  No numbers will be omitted.  Subject numbers will thereafter be 
used on all study documentation. 
At the time a subject consents to participate in this study, a Consent Notification Form should be 
completed.  When eligibility of the subject is confirmed by a physician-investigator, an Enrollment 
Notification should be completed.  Both completed forms should be emailed in real-time to the 
Protocol Monitoring and Sponsor Project Manager. 


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5.3 
Study Drugs 
The treatments to be used in this trial are outlined below in Table 2. 
Table 21: Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen 
Use 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 
3-week cycle; 
up to 4 study 
treatment 
cycles* 
Per label- with the 
exception of the 
drug being 
administered with 
itacitinib 
Itacitinib 
(INCB039110) 
200 mg 
Once Daily 
Oral 
Daily for cycles 
3-4 (q3 weeks); 
up to 42 days 
of therapy 
Investigational 
The pembrolizumab dosing interval may be modified as per package insert. 
*If the PI considers it beneficial for the subject, a fifth cycle may be administered prior to EOS visit.   
 
5.3.1 
Dose Selection/Modification 
 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
 Dose Modifications 
Pembrolizumab  
Please refer to the pembrolizumab package insert.   


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Itacitinib  
Table 3: Dose modification guidelines for itacitinib-related adverse events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment1 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
itacitinib (after 
consultation 
with the 
Sponsor 
Medical 
Director)2 
Hematological 
Toxicity  
1, 2 
No 
N/A 
N/A 
N/A 
3, 4 
Yes 
Toxicity 
improves 
to Grade 0-
2 or 
baseline 
 
Reduce 
itacitinib by 1 
dose level (100 
mg daily) 
 
If second dose  
reduction is 
necessary 
subject will be 
discontinued 
from itacitinib 
treatment. 
Toxicity does 
not resolve 
within 2 weeks 
of last dose. 
 
If second dose 
reduction is 
necessary 
subject will be 
discontinued 
from itacitinib 
treatment. 
Thrombocytopenia 
with bleeding 
 
1, 2 
 
 
 
No- but 
dose 
reduce 
 
N/A 
Reduce 
itacitinib by 1 
dose level (100 
mg daily) 
 
If second dose 
reduction is 
necessary 
subject will be 
discontinued 
from itacitinib 
treatment. 
If second dose 
reduction is 
necessary 
subject will be 
discontinued 
from itacitinib 
treatment. 
3, 4 
 
 
 
Yes 
Toxicity 
improves 
to Grade 0-
2 or 
baseline 
Hold itacitinib 
until count 
recovery. 
 
If second dose 
hold is 
necessary 
subject will be 
discontinued 
from itacitinib 
treatment. 
Toxicity does 
not resolve 
within 2 weeks 
of last dose. 
 
If second dose 
hold is 
necessary 
subject will be 
discontinued 
from itacitinib 
treatment. 


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Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment1 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
itacitinib (after 
consultation 
with the 
Sponsor 
Medical 
Director)2 
Febrile 
neutropenia 
3 
Yes 
N/A 
N/A 
Discontinue 
itacitinib 
Infection 
3,4 
Yes 
Completion 
of IV 
antibiotics 
Reduce 
itacitinib by 1 
dose level (100 
mg daily) 
Toxicity does 
not resolve with 
typical antibiotic 
course 
Non-
hematological 
toxicity 
 
Note:  Exceptions 
to be treated 
similar to grade 1 
toxicity  
• Grade 2 
alopecia 
• Grade 2 
fatigue 
 
 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for 
clinically 
significant 
symptoms 
Toxicity 
improves 
to Grade 0-
1 or 
baseline 
Same dose and 
schedule 
 
 
N/A 
3, 4 
 
Yes 
 
Toxicity 
improves 
to Grade 0-
1 or 
baseline 
 
Reduce 
itacitinib by 1 
dose level (100 
mg daily) 
 
If second dose 
reduction is 
necessary 
subject will be 
discontinued 
from itacitinib 
treatment. 
Toxicity does 
not resolve 
within 2 weeks 
of last dose. 
 
If second dose 
reduction is 
necessary 
subject will be 
discontinued 
from itacitinib 
treatment. 
 
 
Hepatic Toxicity 
Bilirubin ≥ 2 x 
ULN AND 
Grade 3 
AST/ALT (≥ 
3 x ULN)  
Yes 
N/A 
N/A 
Discontinue 
itacitinib 
* N/A = Not applicable 
1- Missed doses will not be made up.  The subject may receive up to 42 days of itacitinib therapy.  
2- If a subject discontinues itacitinib therapy, they may continue on pembrolizumab treatment and 
may remain on study.  
5.3.2 
Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be 


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administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab will be administered q3 weeks as a 30 minute IV infusion.  Up to 4 cycles of 
pembrolizumab will be administered as part of this study.  If the PI considers it beneficial for the 
subject, a fifth cycle may be administered prior to EOS visit.  Pembrolizumab treatment cycle 
intervals may be increased due to toxicity as per package insert.  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, a window of +/- 10 minutes is permitted. 
Itacitinib will be administered daily starting at Cycle 3/Day 1 and continue for a total of 6 weeks 
(42 days).  Itacitinib should be taken orally by the subject at the prescribed dose- 200 mg QD (2 
x 100 mg tablets).  If dose reductions are required due to toxicity, the prescribed dose may be 
reduced to 100 mg QD (1 x 100 mg tablet). Itacitinib should be taken with water, and may be 
taken without regard to food.  If itacitinib doses are missed due to toxicity (per Table 3) or if 
vomiting occurs, these missed doses will not be made up.  
5.4 
Concomitant Medications 
All concomitant medications received within 28 days before the first dose of trial treatment and 
Week 12 (End of Treatment Safety Follow-up Visit) should be recorded.  Anticancer therapies 
administered after the End of Treatment Safety Follow-up Visit will continue to be recorded until 
the end of study visit (Week 16). 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy may be 
required.  The investigator should discuss any questions regarding this with the Sponsor.  The 
final decision on any supportive therapy or vaccination rests with the investigator and/or the 
subject's primary physician.  However, the decision to continue the subject on trial therapy will 
rest with the Sponsor. 
5.4.1 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medications will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  Subjects may receive other medications that the investigator deems to be medically 
necessary unless specified in Section 5.4.2 below.  
5.4.2 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial: 
• 
Systemic corticosteroid therapy or any other form of immunosuppressive therapy is 
prohibited within 7 days prior to study treatment. (Nasal or oral inhalers are permissible).  
Physiologic replacement doses of steroids (mineralocorticoid or less than or equal to a 
prednisone 10 mg daily dose) will also be permitted. 


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• 
Anti-cancer systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab and itacitinib 
• 
Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed per physician-investigator discretion, but would be regarded as a disease 
progression event for the primary endpoint. However as per Section 4.2.2, 
subjects may continue to receive pembrolizumab at the physician-investigator’s 
discretion if the subject continues to benefit clinically from treatment. 
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid 
(oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live 
attenuated vaccines and are not allowed.  
• 
Glucocorticoids, in excess of physiologic doses (prednisone >10 mg per day equivalent), 
for any purpose other than an abbreviated course to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology.  
• 
CYP3A4 inhibitors and dual CYP3A4/2C9 
• 
Fluconazole (>200mg doses) 
5.5 
Rescue Medications & Supportive Care 
5.5.1 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Please refer to the pembrolizumab package insert for supportive care 
guidelines related to pembrolizumab administration.  
Toxicity management considerations for itacitinib are outlined below.  
• 
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. 
• 
Anti-infectives: Subjects with a documented infectious complication should receive oral 
or IV antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional practice. 
5.6 
Diet/Activity/Other Considerations 
5.6.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 


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5.6.2 
Contraception 
Pembrolizumab and/or itacitinib may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab and/or itacitinib have transient adverse effects on the composition of 
sperm.  Therefore while enrolled, all subjects must agree not to participate in a conception process 
(i.e. active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization, 
etc).   
 
Female subjects of reproductive potential (women who have reached menarche or women who 
have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses 
within the preceding 24 months, or have not undergone a sterilization procedure [hysterectomy 
or bilateral oophorectomy]) must have a negative serum or urine pregnancy test performed within 
72 hours of Cycle 1/Day 1 as per the Trial Flow Chart. 
 
All participants participating in sexual activity that could lead to pregnancy must agree to use two 
methods of birth control. The two birth control methods can be either two barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from screening throughout the study period up to 120 days after the last dose of study 
therapy.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).  Male sterilization (i.e. vasectomy) is also considered an acceptable 
method of birth control as long as a barrier method is also utilized.  
 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study they must adhere to the contraception requirement above. If there is any question that a 
subject will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
 
5.6.3 
Use in Nursing Women 
It is unknown whether the study drugs are excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment. 
5.7 
Subject Withdrawal/Discontinuation  
A subject may be prematurely discontinued from study treatment for any of the following 
reasons: 
• 
Withdrawal of consent 
• 
Confirmed radiographic disease progression per RECIST 1.1; (as per standard of care, a 
patient receiving pembrolizumab who experiences asymptomatic progression of disease 
may be continued on therapy until progression is confirmed with a subsequent scan). 
• 
Unacceptable adverse experiences or toxicities (see Section 5.3.1.2) 
• 
Intercurrent illness that prevents further administration of treatment 


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• 
Investigator’s decision to withdraw the subject 
• 
Confirmed positive serum pregnancy test  
• 
Noncompliance with trial treatment or procedure requirements 
• 
Institution of alternative systemic treatment 
• 
Other Administrative reasons 
Subjects who discontinue from study treatment will complete and End of Study Visit per the Trial 
Flow Chart in Section 6.0.   
5.8 
Subject Replacement Strategy 
Subjects who either experience documented progressive disease during the first 12 weeks of 
treatment or complete the first 12 weeks of treatment and undergo re-staging are considered 
evaluable and will not be replaced.  Subjects who complete study treatments but are unable to 
complete planned biopsies will also be considered evaluable for response and adverse events.  
All other subjects will be considered non-evaluable and will be replaced. 
5.9 
Clinical Criteria for Early Trial Termination 
The 3-stage optimal design tests the null hypothesis that the ORR ≤ 35% (clearly inferior to 
pembrolizumab) versus the alternative that the ORR ≥ 55% (clearly superior to pembrolizumab) 
[2]. ORR will include both subjects with partial responses and complete responses, per RECIST 
1.1.  Stable disease will not be considered a response.  Eleven evaluable subjects will be entered 
into the first stage of the study. If 2 or fewer of these 11 subjects respond, then the trial will be 
terminated. If at least 3 of these subjects respond, then an additional 19 evaluable subjects will 
be entered into the second stage of the study. If 12 or fewer of these 30 subjects respond, then 
the trial will be terminated. If at least 13 of these subjects respond, then an additional 18 evaluable 
subjects will be entered into the third stage of the study. If 20 or fewer of these 48 subjects 
respond, then it will be concluded that the regimen does not merit further investigation. If at least 
21 of these 48 subjects respond, then it will be concluded that the regimen merits further 
investigation. If the true objective response rate is 35%, then the probability of recommending the 
regimen for further investigation (false positive error), is 0.100. While if the true objective response 
rate is 55%, then the probability of recommending the regimen for further investigation (power), 
is 0.906. If the true objective response rate is 35%, then the probability of early termination of the 
trial by the end of the second stage is 0.786. The software program, PASS v14 was employed to 
define this 3-stage design. 
 
A Bayesian termination rule for unacceptable toxicity (defined in Section 8.1) will be employed to 
monitor safety. Assuming a minimally informative beta (1,5) prior, which is information equivalent 
to 1 of 6 treated subjects with unacceptable toxicity. If the number of subjects with unacceptable 
toxicity in the first stage of 2-stage design is: ≥2 in first 3 subjects, ≥3 in first 6, ≥4 in first 9, or in 
the second stage of the design is: ≥ 5 in first 12, ≥6 in first 15, ≥7 in first 18, ≥9 in first 25 subjects, 
≥10 in first 30 or in the third stage of the design is: ≥12 in first 35, ≥13 in first 40 and ≥14 in first 
45, then termination will be considered as it is likely that the rate of unacceptable toxicity is >25%.  


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5.10 Clinical Criteria for Early Trial Termination due to Trial Conduct or Other 
Factors 
Early trial termination will occur for any of the following: 
1. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects 
2. Plans to modify or discontinue the development of the study drug 


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6.0 
TRIAL FLOW CHART 
6.1 
Study Flow Chart  
Trial Period: 
Treatment Cycles (q3 weeks) 
End of Study 
Treatment6 
End of Study6  
Treatment Cycle/Title: 
Screening 
Visit 
Cycle1 
Cycle 2 
Cycle 3 
Cycle 4 
EOT Safety 
Follow-up 
Visit 
 
Scheduling Window (Days): 
-28 to -1 
Wk1 
Wk 3 (± 3) 
Wk 6 (± 3) Wk 9 (± 3) Week 12 (±5) 
Week 16(±10) 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
Assessment 
X 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
X 
X--------------------------------------------------X 
X 
 
Pembrolizumab Administration 
 
X 
X 
X 
X 
 
 
Itacitinib Administration 
 
 
 
X 
X 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
X 
X 
Adverse Event Assessment 
X 
X--------------------------------------------------X 
X 
X 
Full Physical Examination 
X 
 
 
 
X 
X 
 
Directed Physical Examination4 
 
X 
X 
X 
 
 
X 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test – Urine or Serum β-
HCG3 
X 
X3 
 
 
 
 
 
PT/INR and aPTT 
X9 
 
 
 
 
 
 
CBC with Differential8 
X9 
 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry 
Panel8 
X9 
 
X 
X 
X 
X 
X 


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Trial Period: 
Treatment Cycles (q3 weeks) 
End of Study 
Treatment6 
End of Study6  
Treatment Cycle/Title: 
Screening 
Visit 
Cycle1 
Cycle 2 
Cycle 3 
Cycle 4 
EOT Safety 
Follow-up 
Visit 
 
Scheduling Window (Days): 
-28 to -1 
Wk1 
Wk 3 (± 3) 
Wk 6 (± 3) Wk 9 (± 3) Week 12 (±5) 
Week 16(±10) 
TSH8 
X9 
 
X 
 
 
X 
 
Tumor Imaging5 
X7 
 
X10 
 
X11 
 
 
Tumor Biopsies1 
  
 
X10 
 
X11 
 
 
Archived Tumor Tissue Sample 
Collection 
X12 
 
 
 
 
 
 
Research Blood Collection2 
X 
X 
X 
X 
X 
X 
 
1. The order of preference for biopsy site, if safely accessible, is primary tumor > solid organ metastasis (including 
thoracentesis) > lymph node metastasis.  Preference will be made to biopsy the same site for both biopsies, if safe and 
feasible.  
2. Up to 78mL of blood will be collected for research studies. Please refer to the Study Laboratory Manual for additional details 
related to sample collection and handling. 
3. Female subjects of reproductive potential only.  A negative pregnancy test is required within 72 hours of Cycle 1/Day 1. 
4. Directed physical examinations will be symptom and disease driven based on physician discretion.  
5. RECIST 1.1 will be used in this study for assessment of tumor response. While either CT or MRI may be utilized, as per 
RECIST 1.1, CT is the preferred imaging technique in this study.  Tumor imaging timing should follow calendar days and 
should not be adjusted for delays in cycle starts or extension of pembrolizumab cycle duration. 
6. The End of Treatment (EOT) Safety Follow-up Visit will occur at Week 12 (+/-5d). The End of Study (EOS) Visit will occur at 
Week 16 (+/-10d).  If the PI considers it beneficial for the subject, a fifth cycle may be administered prior to EOS visit.  
Subjects who remained on study treatment beyond Week 16 prior to the approval of Protocol Amendment V5, will be asked to 
undergo an End of Study Visit at their next clinic appointment prior to being withdrawn from the study.  Please refer to 
Section 7.1.6.1 for how to handle subjects who prematurely discontinue from study treatment.  
7. Baseline tumor imaging to be performed within 30 days prior to Cycle 1/Day 1.  A PET/CT may be used to fulfill baseline 
imaging requirements, however a PET/CT cannot be substituted for post-infusion imaging. Please refer to Section 7.1.2.6 for 
additional information.  


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8. Please refer to Table 4 for additional information.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 
hours prior to dosing.  Results must be reviewed by the investigator or qualified designee and found to be acceptable prior to 
each dose of trial treatment.  
9. Screening laboratory tests are to be performed within 10 days prior to Cycle 1/Day 1.  
10. Performed 7-14 days after Cycle 2 of pembrolizumab. Tumor imaging will be used for biopsy planning only, and no treatment 
decisions will be made based upon the results.  
11. Performed at the end of Cycle 4, before the end of study visit.  Imaging performed at this timepoint will be used to evaluate 
objective response by RECIST 1.1. 
12. An archived tumor tissue sample may be collected for exploratory analysis if available. Subjects will not undergo an additional 
procedure to obtain this sample. Please refer to the Lab Manual for additional instructions. 


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7.0 
TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor for 
reasons related to subject safety. In these cases, such evaluations/testing will be performed 
in accordance with those regulations. 
7.1.1 
Administrative Procedures 
 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.  Copies of the informed consent form must be placed in the 
electronic medical record as well as study folder. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature. 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the physician-investigator to ensure that 
the subject qualifies for the trial.    
 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 


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for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   
 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 
days before starting the trial.  Treatment for the disease for which the subject has enrolled in 
this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medications, if any, taken by the subject 
during the trial.   
 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review/document all new anti-neoplastic therapy 
initiated after the last dose of trial treatment.   
 Trial Compliance (Medication/Diet/Activity/Other) 
Please refer to Table 3 for additional information on dose modification guidelines for 
itacitinib-related adverse events. 
 
7.1.2 
Clinical Procedures/Assessments 
 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 5.0.  Toxicities will be characterized in 
terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment. Please refer to Section 10 for additional information on the assessment and 
recording of adverse events.  
 Full Physical Exam 
The investigator or licensed medical professional will perform a complete physical exam 
during the screening period.  Clinically significant abnormal findings should be recorded as 
medical history.  A full physical exam should be performed during screening,  


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 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.  Directed physical examinations will be symptoms and disease 
driven based on physician discretion.  
 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to beginning each 
treatment cycle and at treatment discontinuation as specified in the Trial Flow Chart (Section 
6.0).  Vital signs should include temperature, pulse, weight and blood pressure.  Height will 
be measured at screening only. 
 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 16.1) as 
specified in the Trial Flow Chart.   
 Tumor Imaging and Assessment of Disease 
The initial tumor imaging will be performed within 30 days prior to the first dose of trial 
treatment. Scans performed as part of routine clinical management are acceptable for use as 
the screening scan if they are of diagnostic quality and performed within 30 days prior to the 
first dose of trial treatment. A PET/CT may be used to fulfill baseline imaging requirements; 
however a PET/CT cannot be substituted for post-infusion imaging.  
 
As responses to immunotherapy may be delayed, no subjects should have treatment 
decisions modified by the week 6 scan (42 ± 7 days) alone – this is intended as a research 
scan to guide biopsies.  A repeat scan at 12 weeks (performed at the end of Cycle 4 prior to 
end of study visit) is intended for the primary outcome and clinical decision-making.  Tumor 
imaging timing should follow calendar days and should not be adjusted for delays in cycle 
starts or extension of pembrolizumab cycle duration. 
 
If a subject demonstrates radiographic progression at Week 12, repeat imaging may be 
performed at least 28 days later at the discretion of the treating investigator in order to confirm 
radiographic progression.  
 
The same imaging techniques should be used to follow a subject throughout the trial.  For 
subjects with brain metastases, MRI brain should be included in the imaging follow up prior to 
treatment and at any time when a subject develops new neurologic symptoms.  
 
7.1.3 
Archived Tumor Tissue Sample 
If available, an archived tumor tissue sample will be requested for exploratory analysis after 
informed consent is obtained. Subjects will not be asked to undergo an additional procedure 
to obtain this sample. 
7.1.4 
Unscheduled Research Sample Collections 
Beyond the research sample collections scheduled for specific time points, up to 30 mL (2 
tablespoons) of additional peripheral blood may be drawn once per week to better 
characterize correlates of clinical events. In addition, samples obtained during procedures 
performed for standard clinical indications (e.g., clinical tumor biopsies, etc) may be diverted 


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for research use if such diversion does not substantially increase the risk of the procedure or 
compromise standard clinical diagnostic studies. 
7.1.5 
Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below in Table 4.  The total amount of blood/tissue to be drawn/collected over the 
course of the trial (from pre-trial to post-trial visits), including approximate blood/tissue 
volumes drawn/collected by visit and by sample type per subject may vary depending upon 
clinical course of the subject and length of time on trial.  
 
 


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Table 4  Laboratory Tests 
Hematology 
Chemistry 
Other 
Hematocrit 
Albumin 
Serum β-human chorionic 
gonadotropin(β-hCG)† 
Hemoglobin 
Alkaline phosphatase 
Urine pregnancy test † 
Platelet count 
Alanine aminotransferase (ALT) 
PT (INR) 
WBC (total and 
differential) 
Aspartate aminotransferase (AST) 
aPTT 
Red Blood Cell 
Count 
 Total protein 
Total thriiodothyronine (T3) 
Absolute 
Neutrophil Count 
Carbon Dioxide  
Free tyroxine (T4) 
 
Blood Urea Nitrogen 
Thyroid stimulating hormone (TSH) 
 
Calcium 
 
 
Chloride 
 
 
Creatinine 
 
 
Glucose 
  
 
Phosphorus 
  
 
Potassium   
  
 
Sodium 
  
 
Magnesium 
  
 
Total Bilirubin 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of normal) 
 
† Performed on women of childbearing potential only. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test will be required.   
After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing.  
Results must be reviewed by the investigator or qualified designee and found to be acceptable 
prior to each dose of trial treatment.  
7.1.6 
Other Procedures 
 Withdrawal/Discontinuation 
When a subject prematurely discontinues from study treatment, all applicable activities scheduled 
for the End of Treatment Safety Follow-up Visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 10. Subsequent to the 
End of Treatment Safety Follow-up Visits, subjects will be asked to return for an End of Study 
Visit as per the Trial Flow Chart in Section 6.0. 
 Blinding/Unblinding 
Study treatment is open label for this study. 


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7.1.7 
Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
 Screening 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
 
Prior to treatment initiation, potential subjects will be evaluated to determine that they fulfill the 
entry requirements as set forth in Section 5.1. Screening procedures may be repeated. 
 
Written informed consent must be obtained prior to performing any tests/procedures for research 
purposes.  Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified 
time frame.  
 
 Treatment Period 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
 
7.1.7.2.1 End of Treatment Safety Follow-Up Visit 
The End of Treatment Safety Follow-Up Visit will occur at Week 12 (+/- 5d) in accordance with 
the the Trial Flow Chart in Section 6.0.  If the PI considers it beneficial for the subject, a fifth cycle 
may be administered prior to EOS visit. If a subject prematurely discontinues from study 
treatment, all applicable activities scheduled for the End of Treatment Safety Follow-up Visit 
should be performed at the time of discontinuation.   
 
AEs will continue to be followed through the End of Treatment Safety Follow-Up Visit in 
accordance with the safety requirements outlined in Section 10.  .   
 
 
 End of Study Visit 
The End of Study Visit will occur at Week 16 (+/-10d).  If the PI considers it beneficial for the 
subject, a fifth cycle may be administered prior to EOS visit.  Subjects who remained on study 
treatment beyond Week 16 prior to the approval of Protocol Amendment V5, will be asked to 
undergo an End of Study Visit at their next clinic appointment prior to being withdrawn from the 
study.   
 
Any SAEs experienced after this visit must be reported to the sponsor if the investigator suspects 
a causal relationship to the study treatment. Once an adverse event is detected, it should be 
followed until its resolution or until it is judged to be permanent.   
 
7.1.8 
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor 
Pembrolizumab 
Please refer to package insert.  


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Itacitinib 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose 
of itacitinib.  There is no clinical experience with overdosage of itacitinib. In clinical studies, the 
highest total daily dose was 1200mg and no adverse events were associated with this dose.  
Treatment of overdose will include supportive care. 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor.  
8.0 
STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Design 
3-stage optimal design. The ORR for pembrolizumab in untreated PD-L1 positive advanced 
NSCLC was recently reported (Reck NEJM Oct 2016) to be 45% (95% CI 37-53%). The 3-stage 
optimal design (TT Chen, Statistics in Medicine 16:2701-2711,1997) tests the null hypothesis that 
the ORR ≤ 35% (clearly inferior to pembrolizumab) versus the alternative that the ORR > 55% 
(clearly superior to pembrolizumab). Eleven evaluable subjects will be entered into the first stage 
of the study. If 2 or fewer of these 11 subjects respond, then the trial will be terminated. If at least 
3 of these subjects respond, then an additional 19 evaluable subjects will be entered into the 
second stage of the study. If 12 or fewer of these 30 subjects respond, then the trial will be 
terminated. If at least 13 of these subjects respond, then an additional 18 evaluable subjects will 
be entered into the third stage of the study. If 20 or fewer of these 48 subjects respond, then it 
will be concluded that the regimen does not merit further investigation. If at least 21 of these 48 
subjects respond, then it will be concluded that the regimen merits further investigation. If the true 
objective response rate is 35%, then the probability of recommending the regimen for further 
investigation (false positive error), is 0.100. While if the true objective response rate is 55%, then 
the probability of recommending the regimen for further investigation (power), is 0.906. If the true 
objective response rate is 35%, then the probability of early termination of the trial by the end of 
the second stage is 0.786. The software program, PASS v14 was employed to define this 3-stage 
design. 
8.2 
Statistical Analysis Plan 
Based on evaluable subjects, the objective response rate and 95% confidence interval will be 
calculated. Duration of remission, progression-free survival and overall survival will be estimated 
by the method of Kaplan and Meier. Median values and 95% confidence intervals will be 
calculated. All observed toxicities will be graded and tabled. Toxicity tables will be separately 
constructed for cycles with pembrolizumab alone (cycles 1-2 and cycle >5) or pembrolizumab and 
itacitinib (cycles 3-4). Changes in immune pharmacodynamic biomarkers will be examined with 
scatter plots and summary statistics. Fold changes from baseline values will be estimated and 
summarized. Sample Size: The required sample size ranges from 11 to 48 evaluable subjects. 
In the event that 5% of subjects are not evaluable for objective response evaluation, the maximum 
sample size is 50 subjects. Study Duration: With an estimated accrual of 2 patients per month, 
it is anticipated that accrual will continue for approximately 24 months and subject follow-up will 
continue for up to year post Cycle 1/Day 1 (initiation of study treatment)  for a total study duration 
of up to 36 months. 


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8.2.1 
Hypothesis/Evaluation 
Study Objectives are stated in Section 3.0.  
Hypotheses 
• 
Pembrolizumab and itacitinib will be associated with an ORR of at least 55% among 
patients with previously untreated, PD-L1 positive metastatic NSCLC. 
 
• 
Pembrolizumab and itacitinib will be well tolerated among patients with previously 
untreated, PD-L1 positive metastatic NSCLC. 
 
• 
The addition of itacitinib to pembrolizumab will result in increased T cell activation in the 
peripheral blood and decreased interferon signaling in tumor tissue in the week 12 
biopsy, compared to the week 6 biopsy.   
 
Analysis Endpoints 
Primary 
There are two primary endpoints of this study: objective response rate (ORR) and tolerability of 
therapy. 
Objective response rate 
Objective response rate (ORR) is defined as the percentage of evaluable subjects who achieve 
a complete or partial clinical response according to RECIST criteria  
Tolerability of Therapy 
Tolerability of therapy will be determined on the basis of CTCAE adverse event reporting. 
Secondary 
Immune biomarkers 
Priority assays for research blood collection will be multiparametric flow cytometry analysis of T 
cell subsets for changes in markers of exhaustion/activation. Additional assays include 
measurement of serum cytokines, circulating tumor cells and circulating DNA.  
Tumor tissue will be analyzed by immunohistochemical, transcriptomic and genomic approaches.  
Overall Survival 
Overall Survival (OS) is defined as the time from initiation of study therapy to death due to any 
cause or last subject contact.  Subjects without documented death at the time of the final analysis 
will be censored at the date of the last follow-up. Those patients who are currently on-study and 
progression-free at 16 weeks, will no longer be followed and will be censored for OS at week 16. 
Progression Free Survival (PFS)  


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Progression-free survival (PFS) is defined as days from initiation of study therapy to first 
documented disease progression, death due to any cause or last subject contact which 
documents progression-free status. Those patients who are currently on-study and progression-
free at 16 weeks, will no longer be followed and will be censored for PFS at week 16. 
Duration of response (DOR) 
Duration of response (DOR) is defined as days from first documented complete or partial clinical 
response to first documented disease progression. Those patients who are currently on-study 
and progression-free at 16 weeks, will no longer be followed and will be censored for DOR at 
week 16. 
8.2.2 
Analysis Populations 
 Efficacy Analysis Populations 
Subjects who either experience documented progressive disease during the first 12 weeks of 
treatment or complete the first 12 weeks of treatment and undergo re-staging are considered 
evaluable for objective response evaluation.  Subjects who are withdrawn from study (due to 
toxicity or other reasons) in the first 12 weeks of treatment and who do not undergo re-staging 
will be considered unevaluable for objective response evaluation but will be included in the safety 
analyses. The All Patients as Treated population will be used for estimation of PFS and OS. 
 
 Safety Analysis Populations 
The All Patients as Treated (APaT) population will be used for the analysis of safety data in this 
study. The APaT population consists of all enrolled subjects who received at least one dose of 
study treatment with either itacitinib or pembrolizumab. At least one laboratory or vital sign 
measurement obtained subsequent to at least one dose of trial treatment is required for inclusion 
in the analysis of each specific parameter. To assess change from baseline, a baseline 
measurement is also required. 
 
8.2.3 
Statistical Methods 
Primary Objectives 
1. Based on evaluable subjects, the objective response rate and 95% confidence interval 
will be calculated. 
2. Toxicities will be graded, categorized and tabled. Toxicity tables will be separately 
constructed for cycles with pembrolizumab alone (cycles 1-2 and cycle >5) or 
pembrolizumab and itacitinib (cycles 3-4). 
 
Secondary Objectives 
1. Changes in immune pharmacodynamic biomarkers will be examined with scatter plots 
and summary statistics.  Fold changes from baseline values will be estimated and 
summarized. 
2. Duration of response, progression-free survival and overall survival will be estimated by 
the method of Kaplan and Meier.  Median values and 95% confidence intervals will be 
calculated.  
 


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8.3 
Sample Size 
The required sample size ranges from 11 to 48 evaluable subjects.  In the event that 5% of 
subjects are not evaluable for objective response evaluation, the maximum sample size is 50 
subjects. 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF STUDY 
DRUGS 
9.1 
Itacitinib 
9.1.1 
Availability 
Study drug supplied by Incyte.  Provided as 100 mg (free base equivalent) sustained-release 
tablets.   
9.1.2 
Preparation 
None 
9.1.3 
Storage and Stability 
Itacitinib should be stored in a secure, limited-access location at ambient conditions (15°C to 
30°C, or 59°F to 86°F). 
9.1.4 
Product Handling and Labeling 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. All study drug dispensed will be affixed with a clinical label in accordance with regulatory 
requirements. Subjects will be instructed to bring all used/unused study medications to the site at 
each study visit. Subjects will also be asked to document administration on a study-supplied pill 
diary.  
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.1.5 
Potential Toxicities 
Please refer to the itacitinib Investigator Brochure. 
9.2 
Pembrolizumab 
Commercially available and administered per package insert with the exception of the drug will 
be administered with another drug, itacitinib.  Please refer to the pembrolizumab package insert 
for additional information.  
9.3 
Returns and Reconciliation (Itacitinib) 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Incyte, the amount dispensed to and returned by the subjects, and the amount remaining at the 
conclusion of the trial.  


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Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed and/or returned as per instructions from the sponsor.  It is the 
Investigator’s responsibility to arrange for appropriate disposal according to applicable federal, 
state, local and institutional guidelines and procedures, and maintain appropriate records of 
disposal. 
10.0 SAFETY AND ADVERSE EVENTS 
10.1 Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  Intercurrent illnesses or injuries should be 
regarded as adverse events. 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
• 
fatal 
• 
life-threatening 
• 
requires or prolongs hospital stay 
• 
leads to a persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
 
Hospitalizations that meet the following criteria should not be reported as serious adverse events: 
• 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, such as preplanned study visits and preplanned hospitalizations 
for study procedures or treatment administration 
• 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• 
Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
 
Note:  Treatment on an emergency outpatient basis that does not result in hospital admission and 
involves an event not fulfilling any of the definitions of a SAE given above is not a serious adverse 
event.  
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, 
a seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  


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Unexpected adverse events 
An adverse event is considered unexpected if the event, the severity of the event (grade), and/or 
the frequency of the event is not consistent with the risk information described in the investigator 
brochure, package insert, or protocol.   Please refer to the itacitinib investigator brochure and 
pembrolizumab package insert for additional detail related to severity and/or frequency of a 
particular event. 
 
Related adverse events 
An adverse event is considered related to participation in the research if there is a reasonable 
possibility that an event was caused by an investigational product, intervention, or research-
required procedures.  For the purposes of this study, "reasonable possibility" means there is 
evidence to suggest a causal relationship. The relationship of the event to the study will be classified 
as possibly related, probably related, and definitely related. 
• 
Possibly Related: There is some evidence to suggest a causal relationship, however 
other factors may have contributed to the event. 
• 
Probably Related: There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely.  
• 
Definitely Related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out.  
 
Adverse Event Reporting Period 
Collection of adverse events will begin at the time of consent and continue through the End of 
Study Visit. 
 
After the End of Study Visit, any SAE that the investigator becomes aware of must be reported to 
the sponsor if the investigator suspects the event may reasonably be related to the study 
treatment. 
 
Preexisting Condition/General Physical Examination Findings 
A preexisting condition is one that is present prior to the start of the Adverse Event Reporting 
Period.  All clinically significant abnormalities should be recorded as a preexisting condition on 
the medical history eCRF. During the course of the study, a preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens.  
Preexisting conditions that improve should also be recorded appropriately. 
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met:  
• 
The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• 
The abnormality suggests a disease and/or organ toxicity 
• 
The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
 
Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they 
have returned to normal or an adequate explanation of the abnormality is found. When an 
abnormal laboratory or test result corresponds to a sign/symptom of an already reported adverse 


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event, it is not necessary to separately record the lab/test result as an additional event. Laboratory 
abnormalities that do not meet the definition of an adverse event, should not be reported as 
adverse events.  A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a 
SAE unless it meets the definition of serious defined above and/or as per investigator’s discretion.  
Whenever possible, a diagnosis, rather than a symptom should be provided (i.e. anemia instead 
of low hemoglobin).   
 
10.2 Recording of Adverse Events 
Safety will be assessed by monitoring and recording potential adverse effects of the treatment 
using the Common Terminology Criteria version 5.0 at each study visit. Patients will be monitored 
by medical histories, physical examinations, and blood studies to detect potential toxicities from 
the treatment.  If CTCAE grading does not exist for an adverse event, the severity of mild, 
moderate, severe, life-threatening, and death, corresponding to Grades 1-5, will be used whenever 
possible. Subjects will be monitored by medical histories, physical examinations, and blood studies 
to detect potential toxicities from the treatment. 
 
At each contact with the subject, the investigator must seek information on adverse events by non-
directive questioning and, as appropriate, by examination. Adverse events also may be detected 
when they are volunteered by the subject during the screening process or between visits, or 
through physical examination, laboratory test, or other assessments. Information on all adverse 
events should be recorded in the source documentation.  All clearly related signs, symptoms, and 
abnormal diagnostic procedures results should be recorded in the source document, though 
should be grouped under one diagnosis. To the extent possible, adverse events should be 
recorded as a diagnosis and symptoms used to make the diagnosis recorded within the diagnosis 
event.  Do not list symptoms separately if a diagnosis can be assigned. The safety team may 
require events be reported separately if they occur as SAEs (or in the context of a SAE) even if 
they can also be considered a constituent of another AE. 
 
All adverse events occurring during the adverse event reporting period (defined in Section 10.1 
above) must be recorded.  Adverse events that begin during the study treatment phase, and are 
ongoing at the time the subject enters the survival follow-up phase of the study, will continue to 
be followed in survival follow-up until: a) the adverse event resolves; b) the subject discontinues 
participation (i.e. End of Study); or c) there is a change in the adverse event that would normally 
require the event be captured as a new event (i.e. change in attribution).   Please refer to the CRF 
Completion Guidelines (CCG) for specific instructions on data entry. 
 
As much as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-5) 
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment- [Reasonable possibility that AE is related: No 
(unrelated/ not suspected) or Yes (a suspected adverse reaction)].  If yes (suspected)- is 
the event possibly, probably or definitely related to the investigational treatment?  
4. Expectedness to study treatment- [Unexpected- if the event severity and/or frequency is 
not described in the investigator brochure (if applicable) or protocol]. 
5. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
6. Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 


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7. Whether it is serious, where a serious adverse event (SAE) is defined as in  
Section 10.1. 
 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded.  Once an adverse event is detected, it should be 
followed until its resolution or until it is judged to be permanent, and assessment should be made 
at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the study treatment, the interventions required to treat it, and the outcome.   
 
Progression of malignancy, documented appropriately in the medical records, should not be 
reported as a serious adverse event.  Adverse events that occur concurrently with the progression 
of malignancy but that are not related to disease progression (i.e. deep vein thrombosis or 
hemoptysis) will be reported as an adverse event as described above.  Progression of malignancy 
resulting in death that occurs during the study treatment phase should not be reported as a serious 
adverse event.  
Serious adverse events that are still ongoing at the end of the adverse event reporting period 
must be followed to determine the final outcome.  Any serious adverse event that occurs after the 
adverse event reporting period and is considered to be possibly related to the study treatment or 
study participation, should be recorded and reported. 
 
10.3 Reporting of Serious Adverse Events  
Every SAE, regardless of suspected causality, occurring during the adverse event reporting 
period defined in Section 10.1 must be reported to the sponsor within 24 hours of learning of its 
occurrence. The original SAE notification may take place by email to meet the 24 hour reporting 
window.  However within 3 business days of knowledge of the event, the investigator must 
submit a complete SAE form to the Sponsor along with any other diagnostic information that will 
assist the understanding of the event.  The Investigator will keep a copy of this SAE Form on file 
at the study site.   
 
Follow-up information on SAEs should be reported when updates are available, as a follow-up to 
the initial SAE form, and should include both the follow-up number and report date.  New 
information on ongoing serious adverse events should be provided promptly to the sponsor. The 
follow-up information should describe whether the event has resolved or continues, if there are 
any changes in assessment, if and how it was treated, and whether the subject continued or 
withdrew from study participation.    
 
Report serious adverse events by email to: 
Attention:  Clinical Safety Manager or designee 
University of Pennsylvania 
 


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At the time of the initial report, the following information should be provided: 
• 
Study identifier 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• Whether study treatment was 
discontinued 
• The reason the event is classified as 
serious 
• Investigator assessment of the 
association between the event and study 
treatment 
• Expectedness relative to investigational 
product(s) 
 
The Sponsor Team will communicate all SAEs to Incyte per the terms of the research agreement.  
 
10.3.1 
Investigator Reporting:  Local Regulatory Review Committees 
Report events to local regulatory review committees per institutional policy. 
 
10.3.2 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to protocol sponsor within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the protocol sponsor Pregnancy follow-up should be recorded on the same form 
and should include an assessment of the possible relationship to the study drug for any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
 
10.4 Protocol Exceptions and Deviations 
Exception 
A one time, intentional action or process that departs from the approved study protocol, intended 
for one occurrence. If the action disrupts the study progress, such that the study design or 
outcome (endpoints) may be compromised, or the action compromises the safety and welfare of 
study subjects, advance documented approval from the Regulatory Sponsor and local regulatory 
review committees per institutional guidelines is required. Approval from the Regulatory Sponsor 
must be received prior to submission to local regulatory review committees for approval. However, 
the departure is intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately provided the Sponsor is subsequently notified immediately. 
 
Deviation 
A one time, unintentional action or process that departs from the approved study protocol, 
involving one incident and identified retrospectively, after the event occurred. If the impact on 
the protocol disrupts the study design, may affect the outcome (endpoints) or compromises the 
safety and welfare of the subjects, the deviation must be reported to the Regulatory Sponsor 


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within 10 business days of PI knowledge, and to local regulatory review committees per 
institutional guidelines. Acknowledgement from the Regulatory Sponsor must be received prior to 
submission to local regulatory review committees. 
 
Other deviations should be appropriately documented per site policies/procedures (such as a 
subject missing a visit is not an issue unless a critical/important treatment or procedure was 
missed and must have been done at that specific time).  
 
Include the following information on the Sponsor supplied exception/deviation form:  protocol 
number, subject study number, comprehensive description of the exception/deviation from the 
protocol, rationale and corrective and preventative action plan (deviations only).  Ensure all 
completed exception/deviation forms are signed by the Principal Investigator (or physician sub-
investigator) and submitted to the Sponsor Project Manager for review.    
 
Attention: Sponsor Project Manager  
University of Pennsylvania 
 
Once approval of the exception request or acknowledgement of the deviation has been granted 
by the Regulatory Sponsor, the exception or deviation will be submitted to all applicable 
committees for review and approval. 
11.0 DATA HANDLING AND RECORDKEEPING 
11.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA) of 1996.  Those 
regulations require a signed subject authorization informing the subject of the following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI  
 
In the event that the subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the 
end of their scheduled study period. 
 
11.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents   Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at 
the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
trial. 
 


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11.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study. All 
data requested on the CRF must be recorded. All entries will be entered into an electronic 
data capture system (EDC) via PennCTMS/VELOS. The Principal Investigator is responsible for 
assuring that the data entered into eCRF is complete, accurate, and that entry and updates are 
performed in a timely manner. 
 
11.4 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period if required by an agreement with the sponsor.  In such an 
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained.  
12.0 STUDY MONITORING, AUDITING, AND INSPECTING 
12.1 Study Monitoring Plan 
This study will be monitored according to the Sponsor Data and Safety Monitoring Plan.   
 
Interim Monitoring Visits will be conducted during the course of the study. The Monitors will assure 
that submitted data are accurate and in agreement with source documentation; verify that 
investigational products are properly stored and accounted for, verify that subjects’ consent for 
study participation has been properly obtained and documented, confirm that research subjects 
entered into the study meet inclusion and exclusion criteria, and assure that all essential 
documentation required by Good Clinical Practices (GCP) guidelines are appropriately filed. 
 
At the end of the study, Monitors will conduct a close-out visit and will advise on storage of study 
records and disposition of unused study drug. 
 
The investigator will allocate adequate time for such monitoring activities. The Investigator will 
also ensure that the monitor or other compliance reviewer is given access to all the above noted 
study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), 
and has adequate space to conduct the monitoring visit. 
 
12.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, government regulatory bodies, and University compliance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study 
data etc.).  The investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.).  
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance offices. 
 
The Principal Investigator must notify the Sponsor in real-time if an audit/inspection notification is 
received. 


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13.0 ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval 
of the study conduct.  The decision of the IRB concerning the conduct of the study will be made 
in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.   
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study. The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure. 
 
The protocol is listed under clinicaltrials.gov. 
14.0 STUDY FINANCES 
14.1 Funding Source 
This study will be funded by the Parker Institute for Cancer Immunotherapy (PICI). 
 
14.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on 
Conflicts of Interest Related to Research.   
 
14.3 Subject Stipends or Payments 
There is no subject stipend/payment for participation in this protocol. 
 
14.4 Study Discontinuation 
The study may be discontinued at any time by the IRB, the Sponsor, the FDA, or other government 
agencies as part of their duties that research subjects are protected. 
15.0 PUBLICATION PLAN 
Publication of the results of this trial will be governed by University of Pennsylvania policies. 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test results 
and all data derived from the study. 


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16.0 APPENDICES 
16.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
16.2 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1- Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, 
S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, 
J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
 
 


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