A Phase II Study of LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Phase: PHASE2
Conditions: Lung Cancer, Non-Small Cell Lung Cancer, Adenocarcinoma of Lung
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: LMB-100 plus pembro in NSCLC 
Version Date: 12/3/2021
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Abbreviated Title: LMB-100 plus pembro in NSCLC
NIH Protocol #: 19C0127 
Version Date:  December 3, 2021
NCT Number: NCT04027946
Title: A Phase II Study of LMB-100 Followed by Pembrolizumab in the Treatment of Adults with 
Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC) 
NCI Principal Investigator:
Azam Ghafoor, MD
Thoracic & GI Malignancies Branch (TGMB)
Center for Cancer Research (CCR), NCI, NIH
Building 10, Room 4-5330
9000 Rockville Pike
Bethesda, MD 20892
Phone: 240-858-3289
E-mail: azam.ghafoor@nih.gov
Investigational Agents:
Drug Name:
LMB-100
Pembrolizumab 
(Keytruda®)
Mesothelin 
Expression 
Testing
TruSight 
Oncology 500
IND Number:
123332
123332
NSR device
NSR device
Sponsor:
CCR, NCI, NIH
CCR, NCI, NIH
CCR, NCI, NIH
CCR, NCI, NIH
Manufacturer:
Selecta 
Biosciences
Merck
NCI Laboratory 
of Pathology
NCI Laboratory 
of Pathology
Supplier:
CC Pharmacy
NIH CC 
Pharmacy
NCI Laboratory 
of Pathology
NCI Laboratory 
of Pathology

Abbreviated Title: LMB-100 plus pembro in NSCLC 
Version Date: 12/3/2021
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PRÉCIS 
Background:

Mesothelin is expressed in approximately half of all lung adenocarcinomas. 

LMB-100 has demonstrated anti-tumor efficacy against several mesothelin expressing 
tumor models including non-small cell lung cancer (NSCLC). 

Programmed death ligand 1 (PD-1) is an Ig superfamily member related to CD28 and 
CTLA-4 that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands.

Pembrolizumab, an IgG4 monoclonal antagonist antibody to PD-1, is FDA approved in the 
frontline for advanced non-squamous NSCLC as a single agent with high PD-L1 
expression [tumor proportion score (TPS) ≥50%] or in combination with platinum-based 
doublet chemotherapy (PD-L1 unselected). It also approved in the second-line for high PD-
L1 expressing tumors (TPS ≥ 1%).

Combination treatment with LMB-100 plus pembrolizumab results in greater anti-tumor 
efficacy in murine lung cancer model.
Objectives:

To determine the objective response rate of LMB-100 followed by pembrolizumab in the 
treatment of subjects with mesothelin-expressing non-squamous non-small cell lung cancer 
(NSCLC) previously treated with immune checkpoint inhibitors.
Eligibility:

Histologically confirmed locally advanced or metastatic non-squamous, non-small cell 
lung cancer lacking an EGFR sensitizing mutation, ALK or ROS1 gene rearrangement and 
not amenable to potentially curative surgical resection or chemoradiation. 

Tumor mesothelin expression of at least 25% of tumor cells as determined by the 
Laboratory of Pathology at the NCI.

Subjects must have at least progressed after one prior platinum-based doublet 
chemotherapy AND standard immune checkpoint inhibitor (ICI) with either frontline 
single-agent pembrolizumab, or in combination with platinum-based doublet 
chemotherapy, or second-line single-agent nivolumab, pembrolizumab, or atezolizumab.

Age ≥ 18 years.
Design:

This is an open-label, single center phase II study of LMB-100 followed by pembrolizumab 
in subjects with mesothelin expressing NSCLC who have progressed on standard therapies

Subjects will receive LMB-100 at the single agent MTD (140mg/kg) on days 1, 3 and 5 of 
a 21-day cycle for up to 2 cycles and pembrolizumab 200 mg on day 1 of cycle 3 of a 21-
day cycle (or cycle 2 if disease progression is observed after 1 cycle) onwards until disease 
progression (on or after pembrolizumab) or intolerable toxicity for a maximum of 2 years 
(unless second course initiated). 

Abbreviated Title: LMB-100 plus pembro in NSCLC 
Version Date: 12/3/2021
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
The total accrual ceiling for the screening will be set at 100 total patients in order to treat 
23 subjects.

Abbreviated Title: LMB-100 plus pembro in NSCLC 
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TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ................................................................................................7
1
INTRODUCTION....................................................................................................................7
1.1
Study Objectives ..........................................................................................................7
1.2
Background and Rationale ...........................................................................................8
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT........................................................28
2.1
Eligibility Criteria ......................................................................................................28
2.2
Screening Evaluation..................................................................................................32
2.3
Participant Registration and Status Update Procedures.............................................35
2.4
Treatment Assignment Procedures.............................................................................35
3
STUDY IMPLEMENTATION..............................................................................................35
3.1
Study Design ..............................................................................................................35
3.2
Drug Administration ..................................................................................................37
3.3
Dose Modifications/Delays........................................................................................41
3.4
Study Calendar...........................................................................................................49
3.5
Cost and Compensation..............................................................................................53
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria........................53
4
CONCOMITANT MEDICATIONS/MEASURES ...............................................................54
5
Correlative Studies for Research............................................................................................55
5.1
Biospecimen Collection .............................................................................................55
5.2
Sample Collection schedule .......................................................................................62
5.3
Sample Storage, Tracking and Disposition................................................................63
5.4
Samples for Genetic/Genomic Analysis .....................................................................65
6
DATA COLLECTION AND EVALUATION......................................................................66
6.1
Data Collection...........................................................................................................66
6.2
Data Sharing Plans .....................................................................................................67
6.3
Response Criteria .......................................................................................................67
6.4
Toxicity Criteria.........................................................................................................76
7
NIH REPORTING REQUIREMENTS/DATA SAFETY MONITORING PLAN...............76
7.1
Definitions..................................................................................................................76

Abbreviated Title: LMB-100 plus pembro in NSCLC 
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7.2
OHSRP Office of Compliance and Training / IRB Reporting...................................77
7.3
NIH Required Data and Safety Monitoring Plan .......................................................77
8
SPONSOR SAFETY REPORTING ......................................................................................78
8.1
Definitions..................................................................................................................78
8.2
Assessment of Safety Events......................................................................................79
8.3
Reporting of Serious Adverse Events ........................................................................79
8.4
Waiver of expedited reporting to CCR ......................................................................80
8.5
Reporting Pregnancy..................................................................................................80
8.6
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND..............80
9
CLINICAL MONITORING ..................................................................................................81
10
STATISTICAL CONSIDERATIONS...................................................................................81
10.1
Statistical Hypothesis.................................................................................................81
10.2
Populations for Analyses............................................................................................82
10.3
Statistical Analyses ....................................................................................................82
11
HUMAN SUBJECTS PROTECTIONS.................................................................................84
11.1
Rationale For Subject Selection.................................................................................84
11.2
Participation of Children............................................................................................84
11.3
Participation of Subjects Unable to Give Consent.....................................................84
11.4
Evaluation of Benefits and Risks/Discomforts ..........................................................85
11.5
Risks/Benefits Analysis .............................................................................................86
11.6
Consent Process and Documentation.........................................................................86
12
REGULATORY AND OPERATIONAL CONSIDERATIONS ..........................................87
12.1
Study Discontinuation and Closure............................................................................87
12.2
Quality Assurance and Quality Control .....................................................................87
12.3
Conflict of Interest Policy ..........................................................................................88
12.4
Confidentiality and Privacy........................................................................................88
13
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION ...............89
13.1
Mesothelin testing (NSR device) ...............................................................................89
13.2
TruSight Oncology 500 Assay (NSR device) ............................................................89
13.3
LMB-100 (IND #123332)..........................................................................................90
13.4
Pembrolizumab (Keytruda®).....................................................................................96
14
REFERENCES.....................................................................................................................104

Abbreviated Title: LMB-100 plus pembro in NSCLC 
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15
Appendices...........................................................................................................................108
15.1
Appendix A: Performance Status Criteria................................................................108
15.2
Appendix B: Contraception Requirements ..............................................................109
15.3
Appendix C: Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease on Pembrolizumab......................................................................................................111
15.4
Appendix D: Second Course (Retreatment) Imaging ..............................................112

Abbreviated Title: LMB-100 plus pembro in NSCLC 
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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
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INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective

Determine the objective response rate of LMB-100 followed by pembrolizumab in 
the treatment of subjects with mesothelin-expressing non-squamous non-small cell 
lung cancer (NSCLC) previously treated with immune checkpoint inhibitors.
1.1.2
Secondary Objectives

Determine duration of overall response, progression free survival and overall survival.

Determine the safety and tolerability of LMB-100 followed by pembrolizumab in the 
treatment of subjects with mesothelin-expressing non-squamous non-small cell lung cancer 
(NSCLC) previously treated with immune checkpoint inhibitors.
1.1.3
Exploratory Objectives

Establish the correlation of response with tumor mesothelin expression.

Evaluate correlation of tumor response with tumor PD-L1 expression.

Evaluate changes in the tumor microenvironment following treatment with LMB-100 
followed by pembrolizumab.

Evaluate the utility of serum mesothelin and megakaryocyte potentiating factor (MPF) as 
a biomarkers of tumor response.

Define the pharmacokinetics characteristics of LMB-100 to correlate responses with LMB-
100 blood levels.

Determine the incidence of antibody development at the end of cycles 1 and 2 with this 
combination.

Abbreviated Title: LMB-100 plus pembro in NSCLC 
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
Correlation of incidence of KRAS mutation with mesothelin immunohistochemical 
expression in tumor samples. 

Determine the utility of circulating tumor DNA (ctDNA) and characteristic mutations for 
biomarkers analysis of response in blood, and overall tumor genome evolution over the 
course of treatment.

Establish cell lines and cytology studies

To assess changes in circulating immune cell and cytokine levels caused by the treatment
1.2
BACKGROUND AND RATIONALE
1.2.1
Study Disease
234,000 new lung cancer cases are diagnosed every year in the US alone and the leading cause of 
cancer mortality worldwide. Approximately 80% of lung cancers are classified as NSCLC; a 
collection of histologically heterogeneous neoplasms including adenocarcinomas and squamous 
cell carcinoma subtypes(1). 
Patients with stage I-III NSCLC are generally treated with curative surgery, chemotherapy, 
radiation therapy, or a combined modality. Although patients with an early stage disease will 
benefit from these modalities, most patients (~40-45%) will present with more advanced stage IV 
disease at diagnosis or will progress after failing definitive treatment. For patients with advanced 
disease, the 5- year survival rate is less than 10% (2). Current standard systemic treatment involves 
an integration of platinum-based chemotherapy, targeted agents, and immunotherapy depending 
on histology (squamous versus non-squamous) and presence or absence of EGFR sensitizing 
mutations, ALK or ROS1 gene rearrangements, and expression of programmed death ligand 1 
(PD-L1) by immunohistochemistry (IHC). Frontline treatment for advanced or stage IV non-
squamous NSCLC without an EGFR-sensitizing mutation of ALK or ROS1 gene rearrangement 
and performance status (PS) 0 or 1(3): 

High PD-L1 expression [tumor proportion score (TPS) >= 50%] single 
agent pembrolizumab

Low 
PD-L1 
expression 
(TPS<50%) 
pemetrexed 
and 
platinum 
chemotherapy with pembrolizumab
Second-line treatment (initial cytotoxic therapy) for advanced tumors lacking sensitizing EGFR 
mutation or ALK or ROS1 translocation and PS 0 or 1(3):

High PD-L1 expression (TPS >=1%) and have not received prior immune 
therapy single agent nivolumab, pembrolizumab, or atezolizumab

Low or unknown PD-L1 (TPS <1%) and have not received prior immune 
therapy: nivolumab or atezolizumab

Systemic therapy with docetaxel or pemetrexed

Platinum combination chemotherapy with pemetrexed if received immune 
checkpoint inhibitor initially. 
1.2.2
Mesothelin as a target for Lung Adenocarcinoma
Mesothelin is a 40kDa glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein, 
which is present in a restricted set of normal adult tissues, such as the mesothelial lining of the 

Abbreviated Title: LMB-100 plus pembro in NSCLC 
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pleura, peritoneum and pericardium.(4) Immunohistochemistry has shown that mesothelin is 
highly expressed in nearly all epithelioid mesotheliomas as well as epithelial components of 
biphasic mesothelioma in addition to pancreatic ductal adenocarcinomas and in a high percentage 
of epithelial ovarian cancers and lung adenocarcinomas.(5) Although the normal biological 
function of mesothelin is unknown, growing evidence suggests that it may play a role in 
tumorigenesis and metastasis. Its limited expression in normal human tissue and high expression 
in tumor makes mesothelin an excellent target antigen for antibody-based immunotherapy.(6)
Ho et al, initially reported that in a cohort of lung adenocarcinomas (n=12), 10/12 patients or 86% 
showed expression of mesothelin mRNA. (7) In addition, 82% of the patients showed expression 
of the mesothelin precursor protein and half with mature form. Lung adenocarcinomas showed 
strong and diffuse staining for mesothelin versus weak-modest staining in squamous. Thomas et 
al further observed MSLN expression in 53% of advanced (stages IIIB to IV) lung 
adenocarcinomas, with high expression (>25% of mesothelin positive cells) found in 
approximately 24% of patients.(8) Importantly, high mesothelin expression was associated with 
inferior survival (median 18.2 months vs. 32.9 months; P = 0.014). Another study from Memorial 
Sloan Kettering Cancer Center demonstrated that mesothelin was expressed around 70% by IHC 
in stage I-III lung adenocarcinomas. (8)
Interestingly, increased expression was correlated with reduced overall survival (OS) through a 
multivariate analysis (HR 1.78, p<0.01). In unpublished data collected at the NCI by Thomas et 
al, it was demonstrated that 10% of patients with lung adenocarcinoma co-express PD-L1 and 
mesothelin expression (>25% of cells). (Table 1; Unpublished NCI data).
Because of the high expression of mesothelin in many malignancies, a variety of agents are being 
developed to target mesothelin. Results of several ongoing clinical trials of immunotherapy agents 
directed against mesothelin have shown that targeting mesothelin is safe and does not result in 
toxicity to essential normal tissues. Both antibody-based therapies, as well as mesothelin vaccines, 
are being investigated.(9) The Laboratory of Molecular Biology (LMB) and the Thoracic and GI 
Malignancies Branch (TGMB), CCR, NCI have pioneered the use of mesothelin-targeted agents 
and clinical trials over the last decade. Given that mesothelin is expressed in half of lung 
adenocarcinomas (co-expressed in 28% of cells with PD-L1) and is associated with a worse 
prognosis, there is an unmet need to utilize mesothelin directed therapies in the setting of 
mesothelin expressing NSCLC which may enhance overall responses to immunotherapy. 
Table 1: Co-expression of PD-L1 and Mesothelin. Patients with advanced (stage III/IV) lung adenocarcinoma 
enrolled in a prospective trial of molecular profiling at the National Cancer Institute with IHC performed for 
mesothelin and PD-L1 (n= 71) (unpublished NCI data).

Abbreviated Title: LMB-100 plus pembro in NSCLC 
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1.2.3
LMB-100 
Recombinant immunotoxins (RIT) are therapeutic agents composed of an antibody fragment 
attached to a protein toxin derived from bacteria or plants. After entering the cell by endocytosis, 
the immunotoxin reaches the cytosol, where it inactivates elongation factor 2, arrests protein 
synthesis and induces apoptotic cell death. LMB-100 is a recombinant immunotoxin consisting of 
a humanized anti-mesothelin Fab fused to a 24kDa truncated Pseudomonas exotoxin A (PE) 
fragment with mutations that suppress B and T cell epitopes.(10) It has anti-tumor efficacy against 
several mesothelin expressing tumor models including mesothelioma PDX models.(11) Also, the 
debut of mesothelin-targeting chimeric antigen receptor (CAR-T) cells has led to Phase I/II clinical 
trials of targeting mesothelin expressing lung cancers by administering autologous-engineered T 
cells systemically or intra-pleurally (NCT02414269). A phase I clinical trial of LMB-100 in 
patients with mesothelioma with or without nab-paclitaxel chemotherapy has been completed at 
NCI where the maximum tolerated dose (MTD) has been established and will be used in 
combination studies with pembrolizumab. Single agent activity was also evaluated, however, there 
is no single agent activity of LMB-100 in mesothelin expressing non-small cell lung cancers. 
LMB-100 is also currently being evaluated in other mesothelin expressing cancers such as 
pancreatic cancer.
1.2.3.1
Development of LMB-100 
LMB-100 (previously RO6927005 and RG7787) is a next generation anti-mesothelin RIT 
developed in NCI’s Laboratory of Molecular Biology in collaboration with Roche (Figure 1). 
LMB-100 contains a newly engineered PE fragment that has improved activity against most 
mesothelin-expressing cancer cell lines in-vitro and is also much less toxic than SS1P in pre-
clinical models. This improved therapeutic window allows administration of three to eight times 
the dose of RIT to mice, rats and monkeys compared to SS1P. The new PE contains modifications 
specifically designed to reduce immunogenicity of the molecule. This includes deletion of a 14 
kDa sequence that precedes the catalytic domain and seven-point mutations within the catalytic 
domain itself. These changes ablate the major human B cell epitopes within the molecule and also 
the most antigenic T cell epitope.(12, 13) The anti-mesothelin targeting region of LMB-100 uses 
a humanized Fab fragment instead of the smaller dsFv fragment used in SS1P. This increases 
molecular weight of the RIT above the threshold required to prevent filtration by the kidney and 
increases half-life.

Abbreviated Title: LMB-100 plus pembro in NSCLC 
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Figure 1. Structural models of SS1P and its de-immunized variants SS1P-LR and LMB-100. The 
targeting domain consists of VL (cyan) and VH (magenta). The linker between the targeting domain and PE contains 
the furin cleavage site (green), which is required for toxin cytotoxic activity. The furin cleavage site is part of PE 
Domain II. The remainder of Domain II (gray) is unnecessary for cytotoxicity and has been deleted in the PE24-based 
toxins, SS1-LR and LMB-100. Domain III (yellow) is the catalytic domain of PE. In LMB-100, alanine point 
mutations were introduced at seven bulky hydrophilic residues (red) to silence human B cell epitopes within this 
domain. Deletion of Domain II reduces the size of the molecule into the range where it can be easily filtered by the 
kidneys, reducing serum half-life. LMB-100 contains a larger humanized Fab for targeting which raises its molecular 
weight above this threshold. 
1.2.3.2
Nonclinical Studies of LMB-100 
1.2.3.2.1
Nonclinical Pharmacology
In vitro LMB-100 inhibited viability of a variety of mesothelin-positive cancer cell lines, including 
NSCLC cell line, at effective concentrations typically around 14 pM (~1 ng/mL). The cytotoxic 
potency of LMB-100 varied between 0.35 ng/mL in primary mesothelioma cells (RH21) and 15.7 
ng/mL in an adenosquamous lung carcinoma cell line (H596). Binding studies showed that while 
the Fab fragment did not bind to mouse or rat mesothelin, the binding affinities to cynomolgus and 
human mesothelin were identical. In agreement with this, LMB-100 induced apoptosis in 
mesothelin-positive primary cynomolgus pericardial cells and significantly impaired viability of 
HEK293 cells transfected with human mesothelin, but not of rat mesothelin transfected or un-
transfected HEK293 cells. In addition, control experiments showed that free PE24 was 1001000 
fold less potent on mesothelin-positive target cell lines, confirming low cytotoxic potential of PE24 
lacking a targeting moiety. LMB-100 showed broad activity against different mesothelin-
expressing cancer cell lines and patient derived xenograft models.(10, 14) 
Animal studies demonstrated that a single cycle of LMB-100 treatment given at an optimal dose 
of approximately 2 mg/kg, 3  per week, every other day (QOD) achieved tumor regressions in 
subcutaneous xenografts of adenosquamous lung carcinoma (H596) in severe combined 
immunodeficient (SCID) beige mice. Three consecutive treatment cycles, given with 1 week 
breaks in between, led to massive shrinkage of large tumors with an average initial volume of 600 
mm3. Tumor regressions in monotherapy were also achieved when treating subcutaneous 
xenografts of mesothelioma (NCI-H226), gastric (MKN-28), and triple negative breast (HCC70) 
cancer cell lines in athymic nude mice. Highly synergistic antitumor efficacy was observed in 
combination therapy with paclitaxel when treating subcutaneous xenografts of the recombinant 
LMB-100

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high mesothelin expressing A431/H9 cell line or the pancreatic cancer cell line KLM1. Synergy 
was also observed in the HCC70 and MKN-28 cell lines. These results support evidence that LMB-
100 in monotherapy or in combination with standard chemotherapies may provide clinical benefit 
to patients with cancer.
1.2.3.2.2
Pharmacokinetics in Animals
The pharmacokinetics (PK) of LMB-100 were tested in cynomolgus monkeys following a single 
IV administration at doses ranging from 0.03 mg/kg to 0.3 mg/kg. Two different enzyme-linked 
immunosorbent-based formats were used for analyzing plasma levels of LMB-100; free and total 
drug assay (where the total drug assay was the sum of free LMB-100 and LMB-100 complexed 
with binding molecules). LMB-100 showed a relatively rapid plasma clearance and a volume of 
distribution at steady-state similar to the plasma volume. Within the dose range tested, non-linear 
PK was observed for free drug with an extended half-life at higher doses (mean terminal half-life 
approximately 0.6 hours at 0.3 mg/kg compared to 0.3 hours at 0.03 mg/kg) suggesting saturation 
of MSLN-mediated clearance pathways. Clearance of total drug was consistently lower than that 
for free drug implying the presence of soluble binding partners such as soluble mesothelin and 
ADAs. Induction of anti-drug antibodies (ADA) responses was frequently detectable in all dose 
groups tested. Overall, given the limited predictive value of immunogenicity reactions in animals 
to human, a risk for immunogenicity in humans cannot be excluded. Toxicokinetics after repeated 
IV dosing in cynomolgus monkeys demonstrated an increase in total exposure in a dose 
proportional manner between 0.1 mg/kg and 3.0 mg/kg. No accumulation was observed over 5 
consecutive days of treatment or over two dosing cycles with 3  per week dosing. Almost all 
monkeys developed ADAs upon treatment, while induction of high ADA levels impaired the 
exposure of free drug. In some cases, the induction of ADAs may have induced a slight increase 
in exposure
The relationship between systemic drug exposure and anti-tumor activity of LMB-100 was 
investigated on human lung cancer NCI-H596 xenograft growth in female SCID beige mice. Free 
and total drug profiles were similar in mice. Modeling estimated a plasma concentration of 6800 
ng/mL ( 36%) to trigger a half maximal rate of tumor regression. Concentrations of LMB-100 
above this level resulted in potent tumor regression after dosing. Normalized for exposure, SS1P 
was found to be ~3-fold more potent than LMB-100 in terms of tumor growth inhibition.
1.2.3.2.3
Toxicology and Safety Pharmacology
The toxicological profile of LMB-100 was assessed after repeated intravenous administration to 
cynomolgus monkeys, the only relevant species, for a maximum of 5 daily doses for one week or 
2 cycles with QOD  3 dosing, separated by a 9-day dosing free period. Four daily doses of 3 
mg/kg exceeded the maximum tolerated dose with animals being found in moribund condition, 
indicated by clinical signs of hypoactivity, hunched posture, ataxia, and tremors. There were no 
histopathological changes to account specifically for the deteriorating physical condition of these 
animals.
Histopathological findings such as kidney tubular degeneration/regeneration and changes at 
serosal-lining tissues were observed at lower doses as well. In general, administration of LMB-
100 resulted in both on- and off-target toxicities.
On-target effects were observed on serosal-lining tissues, consistent with high expression of 
mesothelin. Mesothelium hypertrophy accompanied by subpleural cellular hypertrophy and 

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13
serosal fibrin exudate was observed in the lung at doses  1 mg/kg. Mesothelium hypertrophy also 
occurred in heart (epicardium), spleen, and stomach. Off-target or non-specific toxicity included 
degeneration/regeneration of kidney tubular epithelium after repeated doses of  0.3 mg/kg. Local 
inflammatory findings at the injection sites were observed after administration of LMB-100 in 
several studies. Clinically, reddening of the skin, swelling, and skin being warm to touch, or flaky 
injection sites were reported. In the 2-cycle GLP study (3 intermittent doses over a 5-day period, 
9-days apart), impaired movement of animals from all dose groups was likely related to injection 
site findings and an overall inflammatory profile. One female at 1 mg/kg was sacrificed early on 
Day 4 after 2 doses due to severe clinical signs most likely attributed to inflammatory changes at 
injection sites resulting in moribundity of the animal. Clinically observed inflammatory changes 
correlated with histopathological changes such as hemorrhages and/or acute inflammation at the 
injection sites and clinical pathology changes consistent with an overall inflammatory profile 
(increases in monocytes, neutrophils, CRP, and haptoglobin). Microscopic changes reversed 
completely after the 4-week recovery period in the 2-cycle GLP study. The highest non-severely 
Toxic Dose in this study was 0.3 mg/kg, which resulted in a mean AUC for total drug of 16.0 
mcg/h/mL (study day 1, preliminary data). In a subsequent 1 cycle GLP study (QOD  3 dosing), 
markedly reduced Injection site findings were observed after administration of a batch with 
reduced levels of product related modifications of LMB-100. In this study, the HNSTD was 1 
mg/kg, resulting in an AUC for total drug of 27.4 and 23.6 mcg/h/mL after the first and third dose 
(preliminary data).
The potential of LMB-100 to induce off-target vascular leak in lungs was assessed in female Wistar 
rats. Mild perivascular edema was reported microscopically but did not correlate with macroscopic 
or serum chemistry findings consistent with CLS. Ultrasound evaluation in the NHP GLP study 
revealed minimal accumulation of pericardial fluid with limited biological significance at the 
highest dose of 1 mg/kg. No appreciable accumulation of pleural fluid was observed at necropsy.
In vitro evaluation of LMB-100 in human whole blood assay indicated a low risk for cytokine-
mediated infusion related reaction (IRR)/cytokine release syndrome (CRS) upon first 
administrations. LMB-100 caused no hemolysis when added to human peripheral blood up to the 
highest concentrations of 0.5 mg/L.
1.2.3.3
Clinical testing of single agent LMB-100 (Roche Study)
Initial clinical testing of LMB-100 was performed by Roche in a multi-center international first in 
human trial (NCT02317419). The primary objective of the Phase I study was to define the safety 
and tolerability (including the MTD) and pharmacokinetics of the drug in participants with MSLN-
expressing metastatic or locally advanced solid tumors for whom no standard therapy was 
available. Secondary objectives included determination of the RP2D and schedule, exploration of 
preliminary anti-tumor activity by assessing objective response rate (ORR) and disease control 
rate (DCR), and assessment of pharmacodynamic effects. 
A total of 15 participants were enrolled onto the study before termination. Median age of 
participants was 60.8 years and 53.3% were female. All participants had received prior anti-cancer 
therapy for their tumors. Enrolled participants had advanced mesothelioma (7), ovarian cancer (3), 
pancreatic cancer (3), and gastroesophageal cancer (2). Tumors from 13 of the 15 participants 
treated had moderately to strongly positive MSLN expression as measured by central IHC analysis. 

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LMB-100 was administered intravenously on Days 1, 3 and 5 of a 21-day treatment cycle. No pre-
medications were given. Treatment was initiated at the MTD of SS1P, 45 mcg/ kg. Five different 
dose levels were tested (see Table 2). Dose limiting toxicity (DLT) was reached at 250 mcg/kg, 
with 2 of 4 participants treated at this dose level experiencing capillary leak syndrome (grade 2 
and grade 4). Additional toxicities were associated with this dose level. At this point, a sixth cohort 
receiving 200 mcg/kg of study drug was enrolled, however, the study was terminated by the 
company before the two accrued participants completed cycle 1 of therapy. Therefore, the single 
agent MTD was not determined.
Table 2. LMB-100 Dose escalation study- NCT02317419
Dose (mcg/kg)
No. of patients
Pts with DLT
45
1
0
65
1
0
100
3
0
170
4
0
200
2
NE
250
4
2
DLTs were capillary leak syndrome and proteinuria
NE, Study terminated before DLT assessment period was complete and 
patients only received single dose of LMB-100
1.2.3.3.1
LMB-100 Adverse Events
Overall, 14 participants (93.3%) experienced at least one AE. The most common AEs were 
hypoalbuminemia (60.0%), fatigue (53.3%), peripheral edema (53.3%), nausea (46.7%), pyrexia 
(40.0%), decreased appetite (33.3%), dyspnea (33.3%), and myalgia (33.3%). SAEs included 
capillary leak syndrome, pyrexia, atrial flutter/fibrillation, infusion related reaction, arthritis, 
glomerulonephritis minimal lesion and dyspnea. No participants experienced an AE that led to 
withdrawal of study treatment. Four participants experienced a total of 8 infusion-related reactions 
that were independent of drug dose level. These AEs were non-serious and resolved within 
approximately 1 hour of onset. Pre-medication for infusion reaction was administered to these 
participants prior to subsequent doses of LMB-100. Two suspected Type III hypersensitivity 
reactions were observed. These consisted of arthritis (1 patient) and rash with fever (1 patient), 
both of which were fully reversible. When other AEs attributed to the study drug are presented by 
dose level of drug, it becomes clear that toxicity was strongly associated with the 250 mcg/kg dose 
level at which DLT was reached. Two of four patients treated at 250 mcg/kg experienced serious 
CLS which manifested with hypotension, respiratory compromise, serosal membrane reaction and 
hyponatremia as well as the hypoalbuminemia and edema that can be seen with mild CLS. Other 
symptoms associated with the DLT dose were fatigue, nausea, vomiting, decreased appetite and 
mild elevation of transaminases. 
1.2.3.4
Clinical testing of single agent LMB-100 at NCI (Study 16C0127-ongoing)
As of September 24, 2018, twenty-one patients were enrolled on the study. Ten patients were 
treated with single agent LMB-100; 11 with a combination of LMB-100 plus nab-paclitaxel.  Of 

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these 21 patients 12 had peritoneal mesothelioma and 9 pleural mesotheliomas; 12 female and 9 
male. The first 3 patients were treated at dose level 1 i.e. 170 mcg/kg with patient #1 initiating 
treatment on July 28, 2016. All three patients at this dose level during cycle 1 had grade 1 or 2 
increase in serum creatinine). Since increase in serum creatinine was a common toxicity pattern at 
this dose level it was defined as DLT per protocol established criteria. The protocol was 
subsequently amended to allow the treating these three patients at dose level -1 (140 mcg/kg) 
during cycle 2-4 though the protocol prior to the amendment would have allowed retreatment at 
170 mcg/kg as long as they met inclusion criteria for the study especially adequate renal function, 
defined in the protocol as creatinine clearance (by Cockcroft Gault formula) >50 mL/min. 
However, we felt it would be safer to re-treat these patients at dose level-1 instead of dose level 1 
and adjusted the dose modification section of the protocol accordingly. 
All subsequent patients have been treated at 140 mcg/kg.  Of the 21 patients; 9 patients were taken 
off treatment due to disease progression; 8 completed the study with stable disease. Out of the 21 
patients who received treatment on this study, 9 are still alive. The single agent MTD of LMB-100 
was established as 140 mcg/kg given on days 1, 3 and 5 of a 21-day cycle.
Grade 2 infusion reactions were seen in 6 patients at some point during the treatment with LMB-
100. In 3 patients it was seen during cycle 2, and in the remaining patients t during cycle 3 or cycle 
4. In most case the infusion reaction was managed by administration of dexamethasone and 
increasing infusion duration as per protocol. However, in two patients who had infusion reaction 
during cycle 4 of LMB-100 the treatment was discontinued. In one patient under Arm B who 
received 2 cycles of LMB-100 and 6 cycles of nab-paclitaxel, LMB-100 was held for cycle 2 day 
5 after a reaction in cycle 2 day 3.
The most frequently occurring events were hypoalbuminemia (22% of 278 events) anemia (14%) 
lymphocyte count decreased (13%), hypophosphatemia (5%) Most of the events were grade 2. 
There was one serious grade 3 thromboembolic event; however, it was not attributed to the IND.
1.2.3.5
Infusion-Related Reactions and Hypersensitivity Including Anaphylaxis
LMB-100 administration may cause infusion-associated symptoms such as fever, chills, 
hypotension, shortness of breath, skin rash, headache, nausea, and/or vomiting. Such reactions 
typically occur during or shortly after an infusion, predominantly the first infusion. Patients may 
also develop IgE-mediated hypersensitivity reactions to LMB-100. IRRs may be indistinguishable 
from an anaphylactic reaction. Patients should receive full supportive care to treat IRRs or 
anaphylaxis according to institutional practice. If infusion-associated signs or symptoms occur, 
patients should be monitored until complete resolution.
In vitro data suggest that the risk for the release of pro-inflammatory cytokines upon first 
administration of LMB-100 to humans is low (human whole blood assay, see section 1.2.3.2.3). 
Past experience with monoclonal antibodies that demonstrated a risk in the whole blood assay has 
shown that this risk could be effectively managed in the clinic with appropriate risk-minimization 
measures. The release of pro-inflammatory cytokines is believed to be partially responsible for the 
occurrence of IRRs.
1.2.3.5.1
Pharmacokinetics of LMB-100

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Free LMB-100 plasma concentrations were measured with a validated ELISA with a lower limit 
of quantification of 2.1 ng/mL. Doses ranged from 140 mcg/kg – 170 mcg/kg. Samples for 
pharmacokinetic (PK) analysis were obtained from patients at pre-dose, end of infusion (EOI; 30-
min post start), and 1 hour, 2 hours, 3 hours, 4 hours and 6 hours post EOI. Concentration data for 
each dose was plotted over time to assess the impact of increasing anti-drug antibodies (ADAs) 
that are generated in response to LMB-100 exposure. Measured LMB-100 plasma concentrations 
were consistent during the first week of treatment, with a near dose-proportional increase in CMAX 
from 140 mcg/kg to 170 mcg/kg. However, the suspected generation of ADAs greatly reduced 
LMB-100 exposure by cycle 2.
These results show that all patients can have good blood levels during cycle 1 and half had 
detectable blood levels during cycle 2. These results are in agreement with the Roche phase I 
clinical trial. It is also clear that administration of LMB-100 beyond cycle 2 is unlikely to result in 
meaningful clinical benefit since there are no detectable blood levels during cycle 3 and 4. 
1.2.3.5.2
Anti-Drug Antibodies (ADAs) and LMB-100 Drug Levels 
Twelve participants were evaluable for efficacy. The best confirmed overall response was stable 
disease in 3 participants. A Roche-developed ELISA test was used to retrospectively assess anti-
drug antibody (ADA) titers. 5 of 15 participants had detectable ADAs at study enrollment while 
the remaining participants did not, however, the remaining participants developed detectable 
ADAs by the end of Cycle 2. Immunogenicity of LMB-100 did affect serum drug levels. All 
evaluable participants achieved expected serum drug levels during the first cycle of treatment. Six 
of 7 participants without pre-existing ADAs achieved effective drug levels during the second 
cycle, while 0 of 2 participants with pre-existing ADAs did. One of 3 participants that received a 
third cycle of treatment also achieved effective drug levels during this cycle. A positive test for 
ADAs did not definitively predict poor blood levels in the subsequent cycle (see patient 1101 in 
Table 3). In summary these data show that the presence of ADAs is not predictive of ability to 
achieve measurable LMB-100 concentration in the serum, which is the most important parameter 
for drug efficacy.
Table 3: Effect of ADA on LMB-100 blood levels in patients without pre-existing ADA. The table 
shows patients treated at different dose levels of LMB-100; ADA prior to start of each cycle and LMB-100 blood 
levels as Cmax (ng/ml). In addition, the change in LMB-100 Cmax concentration (as percent increase or percent decrease) 
during cycle 2 and 3 is shown as dC1/dC2 and dC1/dC3 respectively. Please note that – means the PK assay was not 
performed.
 
 
Cycle 1
Cycle 2
Cycle 3
Patient 
Dose 
(mcg/kg)
ADA 
(Day1)
Cmax 
(ng/ml)
ADA 
(Day1)
Cmax 
(ng/ml)
dC1/dC 
(%)
ADA 
(Day1)
Cmax 
(ng/ml)
dC1/dC 
(%)
1002
65
0
1150
8100
711
-38
-
-
-
1401*
100
0
1790
0
1610
-10
24300
267
-85
1402
100
0
1650
0
1360
-18
8100
0
-100
1101*
170
0
2760
300
3950
43
900
3490
26
1202
170
0
3040
0
1940
-36
-
-
-
1301
170
0
3430
72900
527
-85
-
-
-
1403
170
0
1930
900
1550
-20
-
-
-

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Cycle 1
Cycle 2
Cycle 3
Patient 
Dose 
(mcg/kg)
ADA 
(Day1)
Cmax 
(ng/ml)
ADA 
(Day1)
Cmax 
(ng/ml)
dC1/dC 
(%)
ADA 
(Day1)
Cmax 
(ng/ml)
dC1/dC 
(%)
1102*
250
0
5480
0
4770
-13
-
-
-
1302
250
0
4340
-
-
-
-
-
-
* Patient’s treatment stopped due to study closure
ADA data are from Roche "Bioanalytical Report (ADA) for Clinical Study BP29387“with ADA 
time point codes translated as specified in the BP29837 Lab Manual Version 1.0. Cmax data were 
taken from the Roche final study report.
1.2.4
Pembrolizumab
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-
L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies. 
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
malignancies because of its mechanism of action to bind the PD-1 receptor on the T cell. 
1.2.4.1
Pharmaceutical and Therapeutic Information 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades.(15) Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as NSCLC, ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor responses 
in cancers such as melanoma.(16, 17)
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2).(18, 19)
The structure of murine PD-1 has been resolved.(20) PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-
based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following T-cell 

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stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor 
tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-
associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade.(19, 
21-23) The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct 
from, that of CTLA-4, because both molecules regulate an overlapping set of signaling 
proteins.(24, 25) As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in NSCLC. 
1.2.4.2
Preclinical and Clinical Trial Data
1.2.4.2.1
Preclinical Studies
1.2.4.2.1.1 Safety
The nonclinical toxicity studies consisted of pivotal 1-month and a 6-month repeat-dose chronic 
toxicity studies with 4-month recovery periods in cynomolgus monkeys. These studies were 
supported by toxicokinetic evaluation of pembrolizumab. Additional evaluation included 2 in vitro 
tissue cross-reactivity studies with pembrolizumab in normal human and cynomolgus monkey 
tissues, respectively, and immunotoxicology testing using surrogate antimurine PD-1 mAb in a 
TDAR study in mice to address whether treatment with anti-PD-1 would result in potential 
immune-mediated toxicity following vaccination and recall responses. There were no findings of 
toxicological significance in any of the conducted studies.
1.2.4.2.1.2 Pharmacology
No traditional metabolism studies were conducted with pembrolizumab per current ICH S6 (R1) 
guidance on preclinical safety evaluation of biotechnology-derived pharmaceuticals. However, in 
vivo studies were conducted in C.B-17 SCID mice to demonstrate the lack of Fab-arm or half 
molecule exchange for pembrolizumab. IgG4 wild-type molecules can undergo in vitro and in vivo 
molecular rearrangement called Fab-arm (or half molecule) exchange by swapping their half 
molecule with other IgG4 half molecules, thereby generating bispecific or hybrid antibodies.(26, 
27) A point mutation (S228P) in the core hinge region in IgG4 has been shown to be sufficient to 
prevent the Fab-arm exchange.(26, 27) The results supported that pembrolizumab, which has a 
hinge mutation from S to P at position 228, did not form detectable hybrid antibodies with co-
administered wild type IgG4 molecules in vivo in SCID mice (PK007). This observation is 
consistent with the results of extensive in vitro characterization of pembrolizumab (PK007) and 
indicates that pembrolizumab is not likely to engage in Fab-arm exchange in humans.
1.2.4.2.1.3 Assessment of Effects of PD-1 Blockade as Monotherapy and in Combination with 
Chemotherapy in Mouse Syngeneic Tumor Models
Anti-mouse PD-1 J43 was tested as a monotherapy in the MC38 (colon adenocarcinoma in 
C57Bl/6 mice), C1498 (acute myeloid leukemia in C57Bl/6 mice), PDV6 (squamous cell 
carcinoma in C57Bl/6 mice), and A20 (B cell lymphoma in BALB/c mice) syngeneic mouse tumor 
models. In all monotherapy experiments, tumor cells were implanted subcutaneously in syngeneic 
hosts and were staged at 50 to 80 mm3 before dosing was initiated. Anti-mouse PD-1 or isotype 
control antibody was administered intraperitoneally every 3 to 4 days for a total of 5 treatments. 
Efficacy was determined by monitoring tumor volumes and long-term survival for each 

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experimental group. PD-1 blockade demonstrated antitumor efficacy in each of these syngeneic 
tumor models.
Anti-PD-1 therapy also enhanced the effect of chemotherapeutic agents such as gemcitabine and 
5-FU with combination therapy resulting in increased efficacy and increased complete regression 
rates in vivo. 
In this study, MC38 colon adenocarcinomas were staged to approximately 100 to 120 mm3 before 
initiation of concurrent treatment with 5-FU (40 mg/kg) and anti-mouse PD-1 (10 mg/kg), both 
administered intraperitoneally once every 3 days for a total of 5 injections.
The combined treatment of MC38 colon adenocarcinomas with 5-FU and anti-mouse PD-1 
showed a significant increase in antitumor efficacy over the individual monotherapy groups.
This increased efficacy was reflected in a 60% complete regression rate in the combined treatment 
protocol. In the monotherapy groups, anti–PD-1 alone induced 20% (2 out of 10) complete 
responses, whereas none of the mice treated with control antibody or 5-FU plus control antibody 
demonstrated complete regression. PD-1 blockade using the anti-mouse PD-1 J43 surrogate 
antibody in combination with gemcitabine also showed enhanced efficacy in the mouse MC38 
colon adenocarcinoma tumor model.
1.2.4.2.2
Clinical Investigations
1.2.4.2.2.1 Pharmacokinetics
Pembrolizumab PK samples have been obtained from multiple trials for various tumor types 
including melanoma, NSCLC, HNSCC, UC and microsatellite instability high (MSI-H) tumors. 
The doses tested in these tumor types include one or more of the following doses: 2 mg/kg Q3W, 
10 mg/kg Q3W, 10 mg/kg every 2 weeks (Q2W), and 200 mg Q3W.
The PK profile of pembrolizumab is consistent with that of other humanized mAbs, which 
typically have a low CL and a limited central volume of distribution (Vc).(28-30) The estimates 
of between subject variability are low-to-moderate and are within the range of historically reported 
variability levels for mAbs. A recent review of mAbs reported the between subject variability 
range of 15% to 65% for CL and a median (range) of 26% (12%– 84%) for Vc.(28)
Steady-state concentrations of pembrolizumab are reached by 16 weeks of repeated dosing with a 
Q3W regimen and the systemic accumulation is 2.1-fold. The peak concentration, trough 
concentration, and area under the plasma concentration versus time curve at steady state of 
pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg Q3W.
As pembrolizumab is an IgG4 antibody that is administered parentally and cleared by catabolism, 
food and drug-drug interactions (DDI) are not anticipated to affect exposure. Therefore, no 
dedicated DDI studies have been performed. However, as systemic corticosteroids may be used to 
treat immune-mediated adverse reactions concomitant with pembrolizumab, the potential for a PK 
DDI with pembrolizumab as a victim was assessed. No relationship was observed between 
prolonged use of systemic corticosteroids and pembrolizumab exposure.
1.2.4.2.2.2 Safety
Pembrolizumab has been granted approval in a number of markets and indications and has an 
established safety profile. The overall safety profile of pembrolizumab is derived primarily from 

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a locked and verified dataset with pooled data from monotherapy clinical trials (n-2799) in 
melanoma and NSCLC, as part of the product development of pembrolizumab. 
In addition, the manufacturer continues to analyze data from other ongoing and completed clinical 
trials, as well as from the post marketing environment. The mechanism of action of pembrolizumab 
involves the interruption of the binding of PD-1 to its ligands, thereby interrupting the down-
modulation of T-cell immune response. It is therefore anticipated that ARs associated with 
pembrolizumab would include immune-mediated AEs. Based upon the mechanism of action, the 
Manufacturer Merck developed a broad list of immune-mediated adverse events of special interest 
(AEOSI) to evaluate and monitor. Additionally, though not immune-mediated, infusion-related 
reactions are also included in the AEOSI list. Based on ongoing monitoring, the manufacturer 
Merck has identified those AEOSIs that have been observed and assessed as related to 
pembrolizumab. These events form the basis of the current safety profile for the product.
In addition, several AEOSIs (encephalitis, myocarditis, myasthenic syndrome, sarcoidosis, as well 
as the further characterization of severe skin reactions to include fatal Stevens Johnson Syndrome 
[SJS] and toxic epidermal necrolysis [TEN]) have been identified from data sources primarily 
outside the verified dataset.
The majority of participants, 2727 or 97.4%, experienced 1 or more AEs, and 2062 (73.7%) 
experienced 1 or more AEs reported as drug-related by the investigator. The percentage of 
participants who experienced SAEs was lower; 1042 (37.2%) of participants experienced 1 or 
more SAEs; 334 (11.9%) participants discontinued due to an AE, and 282 (10.1%) participants 
experienced a drug-related SAE, as determined by the investigator. The 5 most frequently reported 
AEs were: fatigue (37.3%), nausea (24.5%), decreased appetite (22.5%), diarrhea (22.3%), and 
cough (22%). The 5 most frequently reported SAEs were pneumonia (3.0%), pleural effusion 
(1.7%), pneumonitis (1.6%), dyspnea (1.6%) and pulmonary embolism (1.5%).
The 5 most frequently reported AEs considered drug related by the investigator were fatigue 
(24.2%), pruritus (16.7%), rash (13.8%), diarrhea (12.3%), and nausea (10.9%). The 5 most 
frequently reported SAEs considered drug-related by the investigator were pneumonitis (1.6%), 
colitis (0.9%), diarrhea (0.6%), pyrexia (0.4%), and autoimmune hepatitis (0.3%).
The core risk profile of pembrolizumab was updated in IB v. 15 based on post-marketing data 
through 31-MAR-2017 to add a new potential risk of graft versus host disease (GVHD) after 
pembrolizumab in patients with a history of allogeneic hematopoietic stem cell transplant (HSCT).  
A further update was made based on data through 03-SEP-2018 to add Vogt-Koyanagi-Harada 
syndrome and hemophagocytic lymphohistiocytosis as adverse drug reactions.  
Pembrolizumab has a positive benefit-risk profile and is well tolerated in the approved indications, 
as evidenced by a low rate of toxicity Grade 3 to 5 drug-related AEs (13.8%), discontinuations due 
to AEs (11.9%), and deaths due to drug-related AEs (0.4%). Furthermore, the frequency of 
immune-mediated AEOSIs is low, and these events are readily managed in the clinical setting.
1.2.4.2.2.3 Efficacy
Pembrolizumab monotherapy and combination therapies have been administered to participants 
with hematologic malignancies and solid tumors in Merck-sponsored trials. Approved indications 
include: melanoma, NSCLC, HNSCC, cHL, UC, gastric/gastroesophageal junction cancer MSI-H 
tumors. Efficacy was not shown in multiple myeloma in combination with lenalidomide or 

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21
pomalidomide and low-dose dexamethasone. Pembrolizumab as monotherapy or in combinations 
is being studied in various indications.
For the treatment of unresectable or metastatic melanoma, pembrolizumab demonstrated superior 
efficacy over available treatment options (IPI, Investigator’s choice chemotherapy) in participants 
with advanced melanoma who were treatment-naïve, as well as those who progressed on prior 
therapy, including ipilimumab.
Pembrolizumab provided substantial, clinically meaningful benefits in OS, PFS, and ORR in 
participants with NSCLC who progressed after platinum-containing chemotherapy and whose 
tumor cells expressed PD-L1 and do not have any sensitizing EGFR mutations or ALK 
rearrangements. In the KEYNOTE-010 phase II/III trial, previously treated participants with PD-
L1 TPS ≥1% and disease progression following platinum-containing chemotherapy, 
pembrolizumab (2mg/kg and 10mg/kg) provided a statistically significant and clinically 
meaningful median OS benefit compared to standard docetaxel chemotherapy (10.4 and 12.7 
months vs 8.5 months respectively) (31, 32). There was also a higher ORR (18% and 18% 
(pembro) vs 9% for docetaxel). For participants with previously untreated metastatic NSCLC 
whose tumors express high levels of PD-L1 (TPS ≥50%) and EGFR/ALKWT, the phase III 
KEYNOTE-024, pembrolizumab (200mg intravenous every 3 weeks) demonstrated significant 
improvements in the primary endpoint of PFS (10.3 vs 6 months) and OS (30 vs 14.2 months, 
preliminary results at 25-month follow up) over standard of care platinum-doublet chemotherapy. 
ORR was also significantly different for pembrolizumab vs platinum-doublet chemotherapy (45% 
vs 28%) as well as median duration of response (33). They phase III KEYNOTE-042 comparing 
pembrolizumab monotherapy with chemotherapy (TPS ≥1%) for untreated advanced NSCLC is 
currently ongoing. 
Pembrolizumab (200mg ever 3 weeks) in combination with pemetrexed/platinum agent for the 
frontline treatment of metastatic non-squamous NSCLC (EGFR/ALKWT) demonstrated both a 
statistically significant and clinically meaningful difference in OS, PFS, and ORR compared with 
chemotherapy alone in PD-L1 unselected patients. In the phase III KEYNOTE-189 OS (primary 
endpoint) was 69% vs 49% at 12 months for chemotherapy + pembrolizumab vs chemotherapy 
alone (34). Median PFS (co-primary endpoint) was 8.8 vs 4.9 months respectively as was ORR 
48% vs 19%, respectively. The phase II (KEYNOTE-021) study led to the accelerated approval of 
chemotherapy (carboplatin, pemetrexed, and pembrolizumab) for metastatic, non-squamous 
NSCLC without activating EGFR mutations or ALK alterations in the frontline setting. 
For the treatment of advanced HNSCC in a heavily pretreated population, pembrolizumab 
demonstrated a clinically meaningful response rate and a prolonged duration of response that is 
substantially distinct from what is expected with standard of care in previously treated participants 
with HNSCC, and points to the meaningful clinical benefit of pembrolizumab.
Pembrolizumab for the treatment of relapsed or refractory classical Hodgkin lymphoma (cHL), 
has demonstrated durable, robust, clinically meaningful responses in this heavily pretreated 
population that generally included standard front-line therapies, salvage therapies, auto-SCT if 
eligible with chemosensitive disease, other single agent or combination chemotherapy regimens 
as needed, and with or without brentuximab vedotin (BV). For the treatment of urothelial 
carcinoma (UC) in participants who have not received prior chemotherapy and are cisplatin-
ineligible, pembrolizumab demonstrated a clinically meaningful ORR in participants with locally 
advanced or metastatic UC. In participants with locally advanced or metastatic UC who have 

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received platinum-containing chemotherapy, treatment with pembrolizumab demonstrated a 
significant improvement in OS and a clinically meaningful benefit in durable responses compared 
with standard of care therapies. 
In participants with MSI-H tumors, pembrolizumab provided evidence of clinically meaningful 
benefit over standard treatments, regardless of tumor histology. Data from early phase trials 
indicate that pembrolizumab has efficacy in mesothelioma with disease control rates of 72-77% 
and objective response rates of 20-21%. Likewise, the responses have been found to be durable, 
with the median duration of response being 12 months.(35, 36)
1.2.5
Rationale for Combination Therapy
Resistance to immunotherapy in NSCLC is a challenge and eventually results in disease 
progression. In an attempt to increase responses and overcome resistance to immune checkpoint 
inhibitors, combination therapy using an immunotoxin targeted to mesothelin expressing tumors 
may expand antigen spread and present new targets for immune recognition. Pre-clinical data show 
that combining immunotoxin with immune checkpoint blockade increases infiltration of CD8+ T 
cells and enhances anti-tumor immune response. We anticipate that LMB-100 will induce 
infiltration of CD8+ T cells and enhance anti-tumor immune response by expanding new tumor 
antigen targets for immune recognition. 
Primary resistance to immune checkpoint therapy in NSCLC is another challenge and can be tumor 
cell intrinsic driven from the absence of tumor specific antigenic proteins leading to ineffective T-
cell rejection (37). LMB-100 immunotoxin combined with checkpoint blockade may overcome 
primary refractoriness to checkpoint inhibitors by initiating apoptotic cell death and releasing a 
broader repertoire of tumor specific proteins required to mount an anti-tumor response.
1.2.5.1
Combining local immunotoxin targeting mesothelin with CTLA-4 blockade 
synergistically eradicates murine cancer by promoting anti-cancer immunity.
The Pastan lab has constructed a murine breast cancer cell line expressing human mesothelin 
(66C14-M) which grows in BALB/c transgenic mice expressing human mesothelin. The 
immunotoxins SS1P (first generation anti-mesothelin immunotoxin) or RG7787 (also called LMB-
100) were injected directly into established tumors and anti-CTLA-4 administered intra-
peritoneally. No cures occurred with CTLA-4 or immunotoxin SS1P/RG7787 alone. Combining 
anti-CTLA-4 with PBS, transient tumor shrinkage was observed in 1 of 6 mice and no complete 
remissions were obtained. However, combining anti–CTLA-4 and LMB-100 resulted in tumor size 
reduction in 11 of 13 mice, and complete tumor elimination in 8 of 13 mice (61%). Combining 
anti-CTLA-4 with SS1P resulted in the similar enhanced anti-tumor effects compared to single 
drug administration. LMB-100-I, an inactive mutant form of LMB-100. was tested as control. Only 
1 of 13 mice achieved a complete remission when treated with LMB-100-I and anti–CTLA-4, 
suggesting cell killing by the immunotoxin is required for the antitumor effect (Figure 2). 
Mechanistic studies showed that combination treatment induced tumor regression was associated 
with increased numbers of tumor infiltrating CD8+ cells (38). Surviving mice were protected from 
tumor re-challenge by 66C14 cells not expressing mesothelin, indicating the development of anti-
tumor immunity directed to non-mesothelin tumor antigens. Although the mechanism is unknown, 
LMB-100 may be inducing antigen spread through apoptosis and priming immune cells to various 
other tumor specific antigens.

Abbreviated Title: LMB-100 plus pembro in NSCLC 
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23
Figure 2:. LMB-100 and anti-CTLA-4 produces complete remissions but inactive LMB-100 (LMB-
100-I) does not.
1.2.5.2
Systemic LMB-100 administration plus anti-PD1 blocking antibody shows increased 
anti-tumor efficacy. 
The Hassan lab has established a mouse syngeneic lung adenocarcinoma model expressing human 
mesothelin for studies of anti-mesothelin agents with immune-checkpoint inhibitors. Using this 
model, we observed increased anti-tumor efficacy of LMB-100 given systemically with anti-PD-
1 antibody. As shown in Figure 3, LMB-100 was intravenously administered for 2 cycles (at a 
dose of 2.5mg/kg dose every other day for 3 times with cycle interval of 3 days). Anti-PD-1 
antibody 10 mg/kg was administered intra peritoneally. twice with interval of 4 days between first 
and second dose. All the drug treatments were started when tumor size reached 100-120mm3. 
Combination therapy with LMB-100 and anti-PD-1 antibody resulted in greater tumor regression 
compared to treatment with LMB-100 or anti-PD-1 alone. Furthermore, treatment with LMB-100 
plus anti-PD-1 antibody significantly prolonged overall survival (74 days) compared to no drug 
treatment (38 days) or treatment with LMB-100 or anti-PD-1 antibody alone (52 days) (Figure 4). 
The precise mechanism of synergy is not understood at this time but could be due to an abscopal 
effect from LMB-100.

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24
Figure 3. Combination therapy with LMB-100 plus anti-PD-1 antibody results in synergistic anti-
tumor efficacy in hMSLN expressing mouse syngeneic lung cancer model 
Figure 4. Treatment with LMB-100 plus anti-PD-1 antibody improves overall survival in hMSLN 
expressing mouse syngeneic lung cancer model 

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25
1.2.5.3
Anti-tumor responses in patients receiving pembrolizumab after LMB-100.
Table 4: A total of n= 9 patients with mesothelin expressing pleural or peritoneal mesothelioma were enrolled on 
trial at the NCI from August 2016- June 2018 and received immune-toxin LMB-100 with or without abraxane, 
followed by off-label pembrolizumab at progression. Results: two patients expired within 1-2 weeks of receiving 
pembrolizumab and were non-evaluable. The other seven patients were evaluable for response by RECIST. Prior 
treatments included cytoreductive surgery with HIPEC, chemotherapy with platinum-based combination with 
pemetrexed, navelbine, and anti-angiogenesis agent bevacizumab. Five of the seven patients received LMB-100 with 
abraxane, whereas two received LMB-100 alone. Overall responses to LMB-100 included three patients with stable 
disease (43%) and four patients (57%) with progressive disease. Progression free interval ranged from approximately 
1-10 months. At progression, each patient went on to receive pembrolizumab off -label, each starting immunotherapy 
within one month upon progressing post LMB-100. Overall responses to pembrolizumab included four (57%) partial 
responders (range: 29.3%-67% decrease) and three progressive disease (43%). Progression free interval for responders 
ranged from 8 months to ongoing (>2 years), whereas for non-responders the interval was shorter, 2-4 months. A 
majority of non-responders (2/3) lacked PD-L1 IHC expression (unpublished data) 
1.2.6
Justification for Study Doses
1.2.6.1
LMB-100
The planned LMB-100 dose is the recommended single agent dose from the phase 1 study of LMB-
100 (NCT02798536) established at 140 mcg/kg, on days 1, 3 and 5 of a 21-day cycle. Only two 
Patient
Prior Treatments
#LMB Cycles
Progression Free
Interval on LMB-100
Best Overall
Response to LMB-
100
Time to Starting
Pembrolizumab after
progression on LMB-100
Progression Free
Interval on
Pembrolizumab
Best Overall CT
Response to
Pembrolizumab
PDL1 Expression
Mesothelin Expression
1
HIPEC, Cisplatin +
Alimta x 6
4
10 months 17 days
SD
1 month (33 days)
11 months, 14 days
PR (-40%)
15%
3+ (100% )
2
Carbo + Alimta x 9
cycles (2 w/
Avastin) ,
Maintenance
Alimta x 4,
Navelbine x 4
2
1 months, 17 days
PD
< 1 month (19 days)
Ongoing (>24 months)
PR (-64%)
N/A
3+ (95-100%)
3
Cisplatin + Alimta
x 2, Carboplatin +
Alimta x 2, HIPEC,
Carboplatin +
Alimta x 2, HIPEC 2 (w/ Abraxane) 5 months, 15 days
SD
<1 month (22 days)
11 months, 10 days
PR (-29.3%)
5-7%
2-3+ (100%)
4
Cisplatin + Alimta
x 4, Maintenance
Alimta x 5
2 (w/ Abraxane)
1 months, 9 days
PD
<1 month (18 days)
8 months, 21 days
PR (-66.7%)
1%
3+ (100%)
5
Carbo + Alimta x 6
cycles
6 (w/ Abraxane) 5 months, 14 days
SD
< 1 month (14 days)
2 months, 3 days
PD
0%
3+ (100%)
6
Pleurectomy/Dec
ort, Carbo + Pem x
4
4 (w/ Abraxane)
3 months, 5 days
PD
< 1 month (14 days)
2 months, 30 days
PD
0%
epitheliod: 3+ (50-70% )
sarcomatoid: 0
7
Carbo + Alimta x 4
cycles, Carbo +
Alimta + Bev x 4
cycles,
Maintenance Bev
3 (w/ Abraxane
on D1)
1 month, 27 days
Clinical
Progression
< 1 month
4 months, 8 days
PD
20%
N/A

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26
cycles of LMB100 will be administered as it is anticipated that most patients will develop 
neutralizing antibodies after 2 cycles of treatment. 
1.2.6.2
Pembrolizumab
For patients with metastatic non-squamous NSCLC, pembrolizumab at a dose of 200mg 
intravenously in combination with pemetrexed and carboplatin chemotherapy is FDA approved as 
a front-line therapy irrespective of (PD-L1) expression. In the phase III KEYNOTE- Gandhi et al 
(34) demonstrated that overall responses was improved with the addition of pembrolizumab 48% 
versus 19%. Pembrolizumab combined with chemotherapy also improved 12-month OS rates 
relative to chemotherapy alone 69 versus 49%, and median PFS 8.8 vs 4.9 months across all PD-
L1 categories. 
Pembrolizumab is also approved in the frontline setting whose tumors have ≥50% PD-L 
expression. Reck et al demonstrated that in the phase III KEYNOTE-024 trial that untreated 
patients with metastatic NSCLC having at least 50% tumor cell PD-L1 expression, ORR was 
improved with pembrolizumab compared to platinum-doublet chemotherapy 45 vs 28% (33). 
Median PFS (the primary endpoint), was also increased 10.3 versus 6 months. 25-month follow-
up demonstrate improved median OS with pembrolizumab 30 versus 14.2 months (39).
Finally, pembrolizumab 200mg IV every three weeks demonstrates activity and survival benefit 
in patients who have been treated with platinum-based chemotherapy and is approved for tumors 
with at least 1% PD-L1 expression. Herbst et al randomized patients with metastatic NSCLC and 
at least 1% PD-L1 TPS to pembrolizumab or chemotherapy with docetaxel in the phase II/III 
KEYNOTE-10 trial (31). Median OS was improved with pembrolizumab of 12.7 months (higher 
dose) vs 8.5 months for docetaxel. ORRs were better in the pembrolizumab versus chemotherapy, 
18 vs 9%. 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type. As outlined 
below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W
Among the 8-randomized dose-comparison studies, a total of 2262 participant were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment 
naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg Q3W 
versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 
3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 
and KN006). All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 

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27
mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-exposure-response relationships were also observed in other tumor types 
including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumor type. These findings 
are consistent with the mechanism of action of pembrolizumab, which acts by interaction with 
immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a PBPK 
analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor penetration 
and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg Q3W achieves 
full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by 
these PK characteristics and given that fixed-dose has advantages of reduced dosing complexity 
and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation 
across all pembrolizumab protocols.
1.2.6.3
Combination treatment 
There is no phase I data of this combination of LMB-100 and pembrolizumab. However, the 
combination will be given sequentially with LMB-100 for two cycles followed by pembrolizumab 
rather than concurrently. We do not anticipate overlapping toxicities as the side effects profiles of 
LMB-100 (capillary leak syndrome, weight gain, atrial fibrillation) and pembrolizumab (immune 
related events) are different. In addition, treatment with pembrolizumab will not be initiated until 
LMB-100 related toxicities have resolved to grade 1 or better. Currently, we have a study in 
mesothelioma of LMB-100 followed by pembrolizumab (18C0136C). Of the 5 patients who 
completed two cycles of LMB-100, four have received two doses of pembrolizumab without any 
unanticipated toxicities.
We do have experience with patients who received LMB100 who received prior checkpoint 
therapy. In a prior study of LMB-100 in mesothelioma patients (16-C-0127), five patients received 
pembrolizumab prior to receiving LMB-100. None of these five patients unanticipated toxicities 
from receiving LMB-100 following immune checkpoint inhibitor. 
1.2.7
Hypotheses and Summary

We believe that anti-mesothelin immunotoxin LMB-100 followed by pembrolizumab will 
result in anti-tumor efficacy in subjects with non-squamous, NSCLC by augmenting anti-
tumor immunity. 

We hypothesize that LMB-100 will induce tumor direct inflammation that leads to 
recruitment of CD8+ cells in the tumor and administration of pembrolizumab will increase 
the efficacy of these cytotoxic T cells.

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28
In summary, our laboratory studies show remarkable synergy between LMB-100 and immune 
checkpoint inhibitors using local or systemic administration with anti-CTLA4 or anti-PD1 
blocking antibodies (38). Based on clinical trials of pembrolizumab therapy in subjects with 
refractory NSCLC which typically demonstrate responses of 18-20%, we propose a clinical trial 
of this combination to determine if administration of LMB-100 followed by pembrolizumab can 
induce anti-tumor immunity and achieve a desired response rate of 10% or greater in subjects who 
have previously failed a checkpoint inhibitor. 
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply.
2.1.1.1
Male and female participants who are at least 18 years of age on the day of signing the 
informed consent will be enrolled in the study.
2.1.1.2
Subjects must have histologically confirmed diagnosis of non-squamous non-small cell 
lung cancer not amenable to potentially curative treatments (surgical resection, definitive radiation 
therapy or a combined modality approach) or targeted agents to actionable EGFR mutations or 
ALK or ROS1 gene rearrangement and excluding neuroendocrine tumors. Activating KRAS 
mutations are allowed. The diagnosis must be confirmed by the Laboratory of Pathology, CCR, 
NCI.  Mutation confirmation may be done by referring institutions or by one of the assays in 
section 2.2.2. 
2.1.1.3
Have provided archival tumor tissue sample or newly obtained fresh core or excisional 
biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) 
tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. 
2.1.1.4
Histologically confirmed 25% of tumor cells expressing mesothelin as determined by 
NCI Laboratory of Pathology. Determination can be made using archival tumor tissue or fresh 
biopsy. 
2.1.1.5
Have measurable disease based on RECIST 1.1 (see section 6.3). Lesions in a previously 
irradiated area are considered measurable if progression has been demonstrated in such lesions. 
2.1.1.6
Subjects must have received prior standard of care treatments for locally advanced or 
metastatic NSCLC. 
2.1.1.7
Patients must be more than 3 weeks out of systemic treatments, such as chemotherapy. 
2.1.1.8
All acute toxic effects of any prior radiotherapy, chemotherapy, immunotherapy, or 
surgical procedure must have resolved to Grade less than or equal to 1, except alopecia (any grade) 
and Grade 2 peripheral neuropathy.
2.1.1.9
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. See 
Appendix A. Evaluation of ECOG is to be performed within 7 days prior to start of study therapy. 
2.1.1.10 Have adequate organ and marrow function as defined below: 

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System
Laboratory Value
Hematological
–
hemoglobin
≥ 9 g/dL or ≥5.6 mmol/La
–
absolute neutrophil count
≥ 1,500/mcL
–
platelets
≥ 100,000/mcL
Hepatic
–
total bilirubin
≤ 2.5 X institutional ULN OR direct bilirubin ≤ ULN 
for participants with total bilirubin levels >1.5 X ULN
–
AST and ALT
≤ 2.5 X institutional ULN (≤ 5 X ULN for participants 
with liver metastases)
Renal
–
Creatinine OR
–
Measured 
or 
calculatedb 
creatinine clearance (GFR 
can also be used in place of 
creatinine or CrCl)
≤1.5 × ULN OR
≥ 50 mL/min for participant with creatinine levels > 
1.5 X institutional ULN
Coagulation
–
International 
normalized 
ratio 
(INR) 
OR 
prothrombin time (PT)
–
Activated 
partial 
thromboplastin time (aPTT)
≤1.5 × ULN 
unless 
participant 
is 
receiving 
anticoagulant therapy as long as PT or aPTT is within 
therapeutic range of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR=glomerular filtration rate; ULN=upper limit of normal.
a.
Criteria must be met without erythropoietin dependency and without packed red 
blood cell (pRBC) transfusion within last 2 weeks. 
b.
Creatinine clearance (CrCl) or eGFR should be calculated per institutional 
standard.
2.1.1.11 Must have left ventricular ejection fraction >50%.
2.1.1.12 The effects of LMB-100 on the developing human fetus are unknown. For this reason 
and because anti-PD-1 antibodies such as pembrolizumab are assumed to be teratogenic:

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2.1.1.12.1
A male participant must agree to use contraception as detailed in see Appendix B 
of this protocol during the treatment period and for at least 180 days after the last 
dose of study treatment and refrain from donating sperm
2.1.1.12.2
A female participant is eligible to participate if she is not pregnant (see Appendix 
B), not breastfeeding, and at least one of the following conditions applies: 
a.
Not a woman of childbearing potential (WOCBP) as defined in Appendix B
OR
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix B 
during the treatment period and for at least 180 days after the last dose of study 
treatment.
2.1.1.12.3
Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician 
immediately.
2.1.1.13 Ability of subject to understand and the willingness to sign a written informed consent 
document.
2.1.1.14 Subjects with non-life-threatening immune-related endocrinopathies or AEs reduced to 
Grade 1 or 0 after withholding ICI or medical intervention are eligible as long as the AE resolved 
within 12 weeks of last dose and not requiring corticosteroids. 
2.1.2
Exclusion Criteria
2.1.2.1
Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: 
Participants who have entered the follow-up phase of an investigational study may participate as 
long as it has been 4 weeks after the last dose of the previous investigational agent.
2.1.2.2
Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically stable, i.e. 
without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat 
imaging should be performed during study screening), clinically stable and without requirement 
of steroid treatment for at least 14 days prior to first dose of study treatment.
2.1.2.3
Subjects who have received prior therapy with LMB-100.
Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks 
prior to start of study therapy. 
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
Note: If participant received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting study treatment.
2.1.2.4
Has received prior radiotherapy within 2 weeks of start of study treatment. Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and not have 
had radiation pneumonitis. A 2-week washout is permitted for palliative radiation (≤2 weeks of 
radiotherapy) to non-CNS disease.

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2.1.2.5
Has received a live vaccine within 30 days prior to the first dose of study drug. Examples 
of live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and 
are not allowed.
2.1.2.6
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive 
therapy within 7 days prior to start of study therapy. 
2.1.2.7
Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g.., thyroxine, insulin, or physiologic corticosteroid replacement therapy 
for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
2.1.2.8
Has a history of (non-infectious) pneumonitis/interstitial lung disease (ILD) that required 
steroids or has current pneumonitis/ILD
2.1.2.9
Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation for the full 
duration of the study, or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
2.1.2.10 Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
2.1.2.11 A WOCBP who has a positive urine pregnancy test within 72 hours prior to start of study 
therapy (see Appendix B). If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. Note: In the event that 72 hours have elapsed between the 
screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or 
serum) must be performed and must be negative in order for subject to start receiving study 
medication.
2.1.2.12 Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 180 days after the last 
dose of trial treatment. Pregnant women are excluded from this study because LMB-100 + 
pembrolizumab are agents with the potential for teratogenic or abortifacient effects. Because there 
is an unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with LMB-100 + pembrolizumab, breastfeeding should be discontinued if the mother 
is treated with LMB-100 + pembrolizumab. These potential risks may also apply to other agents 
used in this study.
2.1.2.13 Has a known history of Human Immunodeficiency Virus (HIV). HIV positive patients 
will be excluded due to a theoretical concern that the degree of immune suppression associated 
with the treatment may result in progression of HIV infection. (Note: No HIV testing is required)
2.1.2.14 Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) 
infection. or active HBV or HCV infection. (Note: No testing for Hepatitis B and Hepatitis C is 
required.)

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2.1.2.15 Has a known additional malignancy that is progressing or has required active treatment 
within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
2.1.2.16 Has an active infection requiring systemic therapy.
2.1.2.17
Participants with contra-indication and/or history of severe hypersensitivity 
reactions to any components related to LMB-100 or pembrolizumab (or any other immune 
checkpoint inhibitor such as PD1, PDL-1 and CTLA4). 
2.1.2.18Active or uncontrolled infections.
2.1.2.19 Subjects who experienced severe or life-threatening immune-related AEs with prior 
immune checkpoint therapy requiring medical intervention (steroid or immunosuppressant drugs) 
and permanent discontinuation of therapy, will be excluded. These include, but not limited to 
colitis, autoimmune hepatitis, hypophysitis, hyperthyroidism, nephritis, myocarditis, GBS, 
encephalitis.
2.1.2.20  Subjects with a history of pneumonitis that required steroids will be excluded. 
2.1.3
Recruitment Strategies
Information about the study will be posted on sites such as clinicaltrials.gov and the CCR 
recruitment website. Subjects will also be drawn from patients seen at the thoracic clinic at the 
NIH Clinical Center as well as from referrals from outside providers. Social media platforms 
managed by NIH/NCI may also be used to publicize the study. There is no plan to advertise this 
study at this time. 
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects 

Review of existing medical records to include H&P, laboratory studies, etc.  

Review of existing MRI, x-ray, or CT images

Review of existing photographs or videos

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes.
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent for this 
study for screening. Assessments performed at outside facilities or on another NIH protocol within 
the timeframes below may also be used to determine eligibility once a patient has signed the 
consent.
Performed at any time prior to start of study therapy Archival tumor sample for NCI LP 
confirmation of diagnosis: The mesothelin expression analysis will be performed by the NCI 
Laboratory of Pathology at the time of histological confirmation of non-squamous non-small cell 

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33
lung cancer. This must be done prior to subject enrollment to trial and treatment. A block of 
primary tissue (or 5-10 unstained sections on charged slides) from the time of diagnosis will be 
required from each patient. Tissue blocks from a known recurrence will be accepted if original 
tumor samples are unavailable. Referring institutions will send the tumor block or 5-10 unstained 
sections on charged slides to CCR/NCI for correlative studies and confirmation of diagnosis. A 
fresh biopsy or tumor effusion sample will be collected if archival tumor tissue is not available.

Confirmation of EGFR, ALK1, ROS1 and KRAS mutation status in patients with NSCLC
In cases where archival tumor tissue is unavailable, a fresh biopsy sample will be taken 
and sent to the NCI Laboratory of Pathology to screen for EGFR, ALK1, ROS1 and KRAS 
genes using the following assays:
Assay
Mutation Being 
Tested
Assay Description
FDA Cleared for 
This Use?
1
FISH ALK
ALK
LSI ALK (anaplastic 
lymphoma kinase) Break 
Apart (BA) DNA FISH test 
(in-house):  This is an FDA 
approved companion 
diagnostic test designed to 
detect rearrangement of ALK 
gene via FISH in FFPE tumor 
samples from patients with 
NSCLC and other tumor 
types. The Dual Color, Break 
Apart Rearrangement Probe 
from Abbott is designed to 
detect the known 2p23 
rearrangements of ALK due to 
pericentric inversion or 
translocation events in lung 
cancer. It will detect most of 
the ALK gene rearrangements 
regardless of fusion partner.
Yes
2
TruSight 
Oncology 500 
Assay 
(TSO500)
EGFR, ALK and 
ROS1
TSO500 gene panel is 
designed to provide full gene 
coverage for 523 genes. This 
assay is intended to detect 
pathogenic or potentially 
pathogenic variants relevant to 
cancer and does not 
distinguish somatic variants 
from germline variants. It will 
be able to detect most of the 
ROS1 rearrangements with 
No

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34
known and unknown fusion 
partners.
The limit of detection (LOD) 
for SNVs and indels is 5% 
variant allele frequency as 
determined by analytical 
sensitivity testing using 
reference samples containing 
approximately 200 known 
common variants. However, it 
is important to note that the 
LOD for this assay, at any 
particular nucleotide, is 
correlated with the sequencing 
coverage obtained at that 
locus. The limit of detection 
of the fusions covered by this 
assay is undetermined but 
requires a minimum 10% 
tumor cells.
Performed within 28 days prior to start of study therapy or, if applicable, second course

History and physical exam

Vital signs including pulse oximetry

ECG

Echocardiogram 

CT scan of chest, abdomen and/or pelvis and areas of known or suspected disease 
involvement; MRI* may also be performed when appropriate. Additional imaging may be 
done as clinically indicated. (If patient being assessed for Second Course, please see 
Appendix D)

18F FDG-PET/CT scan

Urinalysis
*NOTE:  MRIs done in this study will involve the use of the contrast agent gadolinium, unless 
contraindicated.  The risks associated with MRIs and contrast are discussed in the consent 
form.
Performed within 10 days prior to start of study therapy or, if applicable, second course

CBC with differential, Acute Care Panel (sodium, potassium, chloride, bicarbonate, 
creatinine, glucose, BUN), Hepatic Panel (alkaline phosphatase, AST, ALT, total bilirubin, 
direct bilirubin), Mineral Panel (albumin, calcium, magnesium, phosphorus), creatine 

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kinase, C-reactive protein, Coagulation (PT, PTT, fibrin degradation products), lactate 
dehydrogenase, Thyroid (TSH, free T4, total T3)
Performed within 7 days prior to start of study therapy or, if applicable, second course

ECOG performance status (within 7 days)
Performed within 72 hours prior to start of study therapy or, if applicable, second course

Urine or serum hCG in women of childbearing potential (must be repeated on C1D1 (pre-
treatment) if more than 72 hours have passed since screening assessment)
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here.
2.3.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details and eligibility criteria.
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
laboratory abnormality (except for negative mesothelin) may be rescreened.
2.4
TREATMENT ASSIGNMENT PROCEDURES
2.4.1
Cohorts:
Number
Name
Description
1
Mesothelin expressing 
NSCLC subjects
Up to 21 evaluable NSCLC subjects previously treated 
with standard therapies
2.4.1.1
Arms
Number
Name
Description
1
LMB-100 + 
Pembrolizumab
LMB-100 administered in first two cycles + pembrolizumab 
administered in subsequent cycles 
2.4.2
Arm Assignment
Patients in cohort 1 will be directly assigned to arm 1. 
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN

This is an open-label, single center phase II study of LMB-100 followed by pembrolizumab 
in patients with advanced non-squamous non-small cell lung cancer who must have 
progressed on standard therapies including an immune checkpoint inhibitor. 

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
Patients will receive LMB-100, 140 mcg/kg, on days 1, 3 and 5 of a 21-day cycle for the 
first two cycles.

Subjects will receive pembrolizumab monotherapy (200 mg) on day 1 of each subsequent 
21-day cycle for up to 2 years or until disease progression on pembrolizumab, or intolerable 
toxicity, whichever occurs first.

Patients who are progressing after cycle 1 of LMB-100, will be allowed to undergo early 
restaging scans to evaluate tumor response. If there is either radiological (RECIST) or 
clinical progression after cycle 1, patients will be treated antecedently with pembrolizumab 
starting cycle 2. In this case LMB-100 will be discontinued and will not be given at cycle 
2.

Pembrolizumab dosing will not be initiated until LMB-100 related toxicities have resolved 
to grade 1 or better; however, if the initiation of pembrolizumab is delayed for more than 
4 weeks, the patient will be removed from study therapy.

All participants who stop study treatment with stable disease or better may be eligible for 
an additional 17 cycles of pembrolizumab if they progress after stopping study treatment 
from the initial phase.

Response evaluation will be done every 6 weeks

Optional tumor biopsies for research will be performed at baseline, at the end of cycle 2 of 
LMB-100, after second cycle of pembrolizumab, to evaluate changes in the tumor immune 
microenvironment following treatment with LMB-100 and pembrolizumab. These biopsies 
are optional, and a fresh biopsy or tumor effusion sample will be collected if archival tumor 
tissue is not available. In the event that patients get one cycle of LMB-100, optional tumor 
biopsies for research will be performed at baseline, at the end of cycle 1 of LMB-100 and 
after second cycle of pembrolizumab.
* Note: A weight-based dose cap will be applied. LMB-100 dose for patients weighing more 
than 100 kg will be calculated as if they weigh 100 kg.
3.1.1
Schema and dose schedule
LMB-100 140 mcg/kg -> pembrolizumab (200 mg)
 

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3.1.2
Second Course of Treatment
All participants who stop study treatment with stable disease or better may be eligible for up to 
an additional 17 cycles (approximately 1 year) of pembrolizumab treatment if they progress after 
stopping study treatment from the initial treatment phase. This retreatment is termed the second 
course phase of this study and is only available if the study remains open and the participant 
meets the following conditions:
Either

Stopped initial treatment with study treatment after attaining an investigator-determined 
confirmed CR based on RECIST 1.1, and
o
Was treated with at least 8 cycles of study treatment before discontinuing treatment, 
and
o
Received at least 2 treatments with pembrolizumab beyond the date when the initial 
CR was declared
OR

Had SD, PR, or CR and stopped study treatment after completion of 35 administrations 
(approximately 2 years) of study treatment for reasons other than disease progression or 
intolerability
AND

Experienced an investigator-determined radiographic disease progression by RECIST 1.1 
after stopping initial treatment, and
o
No new anticancer treatment was administered after the last dose of study treatment, 
and
o
The participant meets all of the safety parameters listed in the inclusion criteria and 
none of the safety parameters listed in the exclusion criteria, and
o
The study is ongoing
An objective response or disease progression that occurs during the second course phase for a 
participant will not be counted as an event for the safety and efficacy endpoints of the study.
3.2
DRUG ADMINISTRATION
3.2.1
LMB-100
The qualified health care professional responsible for dispensing the study drug will prepare the 
correct dose according to the cohort allocation of each patient. 
LMB-100 (see section 3.1 for dose) will be given as an IV solution on Days 1, 3, and 5 (every 
other day) of a 21-day cycle for two cycles. 
LMB-100 must be administered in a hospital or clinic equipped for IV chemotherapy. Full 
emergency resuscitation facilities should be immediately available, and patients should always be 
under close supervision of the investigator or delegate. 

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The compatibility and stability of the active ingredient was tested under simulated 
preparation/administration conditions.
3.2.1.1
Instructions
1. Visually inspect the LMB-100 drug product prior to dose preparation. The solution should 
be colorless to brownish and may contain a small amount of translucent-to white 
amorphous LMB-100 particulates. Do not use if other particulate matter is seen or if the 
study drug is discolored. Do not shake the vial to mix.
2. Use an appropriately sized syringe and needle to draw up the required volume of LMB-
100 (undiluted drug) plus an additional 3 mL (overfill for priming the syringe extension 
line) from the vial.
3. Attach a Smiths Medical Ultra™ Small Bore Extension Set (REF #MX448HL60) to the 
syringe and a Smith medical 0.2-micron filter set (MX448HF) to the end of the extension 
set, then prime close to the distal end. Purge all air from the syringe and line. Cap with a 
sterile Spiro cap before dispensing.
3.2.1.2
Administration Instructions 
1. Intravenous (IV). Do not administer as IV push or bolus.
2. LMB-100 is administered either peripherally or centrally through a patient’s vascular 
access device. If there is no pre-existing central vascular access device (VAD) and 
peripheral access is inadequate, a central access device will be installed.
3. Undiluted LMB-100 (1 mg/mL) will be transferred to a disposable syringe and 
administered by IV infusion using a syringe pump. LMB-100 will be diluted in-line 1:10 
with 0.9% Sodium Chloride Injection, USP immediately prior to administration.
4. To accomplish this, a side flow with 0.9% Sodium Chloride Injection, USP, must be 
applied. A 4-way stopcock (alternatively two 3-way stopcocks joined end-to-end, or an 
alternative manifold with at least two inlets and one outlet ports that can be opened 
simultaneously) should be positioned at the patient’s VAD to allow simultaneous infusion 
of LMB-100 and 0.9% Sodium Chloride Injection, USP. The infusion rate of the 0.9% 
Sodium Chloride Injection will be 9-times the hourly rate of LMB-100.
5. LMB-100 will be filtered inline during administration with a 0.2-0.22micron filter.

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The LMB-100 drug product should be filtered using an in-line 
filter as depicted. 
For the first infusion, venous access (via peripheral IV or central line) should remain accessible 
for 2 hours after the end of infusion or longer, if necessary, during the remainder of the hospital 
stay.  Duration of use of venous access will comply with CC Nursing policies and procedures. If 
no infusion related symptoms occur during this time, the infusion line may be removed or de-
accessed. For subsequent infusions and if no IRR has been reported, venous access should remain 
in place for at least 30 minutes from the end of the infusion. If no adverse events occur during the 
30 minutes, the infusion line may be removed. 
During the infusion, vital signs (including, if possible, supine diastolic and systolic blood pressure, 
pulse rate, and temperature) must be monitored pre-infusion and every 15 minutes (± 5 minutes) 
until the end of the infusion. Following the completion of the infusion, vital signs should be 
checked every 30 minutes (± 10 minutes) for the first 2 hours and once at 4 hours after infusion 
completion. Vital signs during the infusion are not required to be captured in the eCRF unless 
abnormalities are observed.
LMB-100 drug product (DP) should be administered diluted using a side flow set-up at 1:10 (0.1 
mg/mL DP). In order to not compromise drug product physico-chemical stability, the dilution with 
0.9% NaCl should be done in line, immediately prior to administration of the DP. The infusion 

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duration should be 30 minutes (- 5 minutes, +10 minutes); however, the duration can be 
increased at the discretion of the investigator based on the total dose and volume to be 
administered and the patient’s physical condition. Syringe preparation and infusion duration 
should not exceed a maximum of 4 hours. In case of any adverse events related to the infusion, 
please refer to the specific recommendation described in section 3.3.1.
3.2.2
Pre-medications for Patients Receiving LMB-100
Due to the prevalence of infusion related reactions (IRRs) seen in the previous study of LMB-100, 
all patients will be predicated 30-60 minutes (+ 30 minutes) prior to each LMB-100 administration 
with the following medications (Table 5):
o
Diphenhydramine 25-50 mg PO or IV
o
Famotidine 20 mg PO 
o
Acetaminophen 650 mg PO
(See section 3.3.1 for complete instructions on response to IRRs)
Note: An alternative histamine H2 antagonist may be substituted for famotidine, if the preferred 
pre-medication is unavailable.
 Table 5. Premedication for LMB-100
Dose (mg)
Route
acetaminophen
650
Orally
famotidinea
20
Orally
diphenhydramineb
25-50
Orally or IV
a An alternate histamine H2 antagonist or famotidine IV are allowed if the preferred pre-medication 
is unavailable
b or alternative antihistamine at an adequate dose
3.2.3
Pembrolizumab
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks = 1 cycle. 
Pembrolizumab will be administered on day 1 (± 3 days) of each cycle starting with cycle 3 (if 
conditions in section 3.3.2 are met) for up to 2 years unless criteria for removal from therapy 
(3.6.1) are met. Patients who are progressing after cycle 1 of LMB-100, will be allowed to start 
pembrolizumab from cycle 2 onwards. Note: As indicated in section 3.1, in certain circumstances 
the total duration of pembrolizumab treatment may exceed the 2-year limit.
Every effort will be made to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps, a window of -5 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Vital signs (blood pressure, pulse, respiratory rate, temperature) will be measured pre and post 
infusion.
Pembrolizumab may be administered on an outpatient basis.
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution.

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Only if medically warranted in response to an AE will the Investigator modify the infusion 
parameters (decrease the rate of infusion, interrupt the infusion, or reduce the dose volume 
infused). 
3.3
DOSE MODIFICATIONS/DELAYS
3.3.1
LMB-100
LMB-100 infusion may be held for up to 72 hours due to drug-associated toxicity or adverse events 
from other intercurrent medical conditional (such as a primary cancer diagnosis) that resolve with 
or without medical intervention to grade 2 or less within this time frame.  Toxicities for which 
further LMB-100 treatment should NOT be given or which are exceptions to the above guidelines 
are stated below in Table 6.  The table also provides guidelines on how to manage some toxicities 
anticipated with LMB-100 
Table 6. Guidelines for Managing Specific LMB-100 Adverse Events
Event
Action to Be Taken
IRR/hypersensitivity reaction
If an IRR/hypersensitivity develops, the infusion of LMB-100 should 
be temporarily slowed down or interrupted. The patient should be 
monitored until complete resolution of the symptoms and treated as 
clinically indicated. Treatment or concomitant medication may 
include 
acetaminophen, 
antihistamine, 
IV 
saline, 
oxygen, 
bronchodilators, corticosteroids, and vasopressors depending on the 
symptoms.
If the infusion is interrupted:
o
In the event of IRR CTCAE Grade1, upon resolution of 
symptoms, the infusion will resume at the same rate (the rate 
being used at the time that the IRR occurred).
o
In the event of IRR Grade 2 or 3, upon resolution of symptoms, 
the infusion will resume at one-half the previous rate. The 
infusion can be re-escalated to initial rate if considered well 
tolerated after 1 hour of infusion.
o
In the event of IRR CTCAE Grade 3, or CTCAE Grade 4 
(which may include pulmonary or cardiac events) or an 
anaphylactic reaction:
The infusion must be stopped and the patient should receive 
aggressive treatment
o
Patients experiencing IRR CTCAE Grade 4 or anaphylaxis 
must be permanently discontinued from LMB-100 treatment

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Event
Action to Be Taken
Capillary leak syndrome 
(CLS) 
In the event of Grade ≥2 CTCAE capillary leak syndrome (urgent 
intervention indicated):
o
Delay LMB-100 administration until complete resolution of the 
event
o
For hypotension minimize fluid resuscitation to avoid fluid 
overload Minimize crystalloid solutions (e.g., saline)
o
Vasopressor support (e.g., phenylephrine) if indicated to 
stabilize blood pressure
o
Administer colloidal solutions (e.g., albumin) if there is a 
clinically significant and persistent systolic blood pressure 
drop, and the patient is symptomatic, or urine output declines
o
For pulmonary congestion provide diuretic and/or albumin 
treatment in case of hypoalbuminemia as appropriate
o
Progressive shortness of breath may require in addition 
endotracheal intubation or drainage of a pleural effusion
o
For oliguria and /or rising serum creatinine level delay LMB-
100 if Grade C3 urine output (<10 mL/hr)
o
Use fluids judiciously if increase in urine output is required
o
Use dopamine if patient is unresponsive to or unable to tolerate 
fluids Monitor serum albumin levels prior to the LMB-100 
treatment cycle
o
In the event of Grade ≥2 CTCAE pericardial effusion 
(asymptomatic effusion small to moderate size), consider 
delaying LMB-100 administration. In the event of Grade ≥3 
CTCAE pericardial effusion (effusion with physiologic 
consequences) stop LMB-100 treatment until full resolution
Inflammatory reactions to 
serosal membranes 
o
Hydrocortisone (200 mg IV) or equivalent dose of another 
corticosteroid as clinically indicated
o
In the event of pleuritis resulting in mild to severe pleuritic 
pain, treat with analgesics or steroids as clinically indicated
o
For patients who have previously experienced pleuritis 
consider administration of a tapering course of prednisone for 
7 days starting with the next LMB-100 infusion
Renal Toxicity
In the event of Grade 1 or greater renal toxicity consider increasing 
oral or intravenous hydration, and consider delaying LMB-100 
administration by up to 72 hours.
In the event of Grade 2 or greater renal toxicity hold LMB-100 
administration until recovery to Grade 1 or better.  If this does not 
occur within 72 hours, no further LMB-100 should be given during 
the cycle.
IRR = infusion related reaction; IV = intravenous; CTCAE = Common Terminology Criteria for Adverse 
Events

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3.3.2
Pembrolizumab
3.3.2.1
Dose delays
3.3.2.2
Cycle 3 day 1 or Cycle 2 day 1 (in the event that LMB-100 discontinued after cycle 1) of 
pembrolizumab may be delayed for up to 4 weeks if LMB-100 related toxicity has not resolved to 
grade 1 or better. If the delay exceeds 4 weeks, the patient will be removed from study therapy. 
Dose Modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than on body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 7. 
Table 7. Dose modification and toxicity management guidelines for immune related AEs associated 
with pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to 
taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after 
AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should 
be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids.
Immune-
related AEs
Toxicity 
grade or 
conditions 
(CTCAEv5.0)
Action taken to 
pembrolizumab
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer 
corticosteroids 
(initial dose of 1-2 

Monitor participants for 
signs and symptoms of 

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Grade 3 or 4, 
or recurrent 
Grade 2
Permanently 
discontinue
mg/kg prednisone 
or equivalent) 
followed by taper
pneumonitis

Evaluate participants with 
suspected pneumonitis 
with radiographic imaging 
and initiate corticosteroid 
treatment

Add prophylactic 
antibiotics for 
opportunistic infections
Grade 2 or 3
Withhold
Diarrhea / 
Colitis 
Grade 4
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper

Monitor participants for 
signs and symptoms of 
enterocolitis (i.e., diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 
bowel perforation 
(i.e., peritoneal signs and 
ileus).

Participants with ≥ Grade 
2 diarrhea suspecting 
colitis should consider GI 
consultation and 
performing endoscopy to 
rule out colitis. 

Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. 
If sufficient oral fluid 
intake is not feasible, fluid 
and electrolytes should be 
substituted via IV 
infusion.
Grade 2
Withhold

Administer 
corticosteroids 
(initial dose of 0.5- 
1 mg/kg prednisone 
or equivalent) 
followed by taper
Aspartate 
aminotransferase 
/ Alanine 
aminotransferase 
increased, or 
blood bilirubin 
increased
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper

Monitor with liver 
function tests (consider 
weekly or more frequently 
until liver enzyme value 
returned to baseline or is 
stable

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Type 1 diabetes 
mellitus 
(T1DM) or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure
Withhold

Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 

Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 

Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically 
indicated. 

Monitor for signs and 
symptoms of hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency) 
Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1

Treat with non-
selective beta-
blockers (e.g., 
propranolol) or 
thionamides as 
appropriate 

Monitor for signs and 
symptoms of thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid 
replacement 
hormones (e.g., 
levothyroxine or 
liothyroinine) per 
standard of care

Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 2
Withhold 
Nephritis and 
Renal 
dysfunction
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by taper.

Monitor changes of renal 
function
Grade 1 or 2
Withhold
Myocarditis
Grade 3 or 4
Permanently 
discontinue

Based on severity 
of AE administer 
corticosteroids

Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
All other 
immune-related 
AEs
Intolerable/ 
persistent 
Grade 2
Withhold

Based on type and 
severity of AE 
administer 

Ensure adequate 
evaluation to confirm 
etiology and/or exclude 

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Grade 3
Withhold or 
discontinue 
based on the 
type of event. 
Events that 
require 
discontinuation 
include and not 
limited to: 
Guillain-Barré 
Syndrome, 
encephalitis
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue
corticosteroids 
other causes
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. 
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement 
therapy or achieved metabolic control (in case of T1DM). 
3.3.2.3
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab associated infusion reaction 
are provided in Table 8. 
Table 8. Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).

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NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of 
the original infusion rate (e.g. from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment
Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Participant is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov
3.3.2.4
Other allowed dose interruptions for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as medical 
or surgical events or logistical reasons not related to study therapy. Participants should be placed 

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back on study therapy within 3 weeks of the scheduled interruption. The reason for interruption 
should be documented in the patient's study record.

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3.4
STUDY CALENDAR
1 cycle = 21 days
Screening assessments will occur within 28 days prior to enrollment unless otherwise indicated. If screening assessments are performed within 3 
days prior to enrollment, the assessments do not need to be repeated on C1D1 unless otherwise indicated.
Assessments after C1D1 may be performed up to 3 days prior to indicated time unless otherwise indicated.
LMB-100 dosing cycles after cycle 1 may be delayed for up to two weeks to accommodate schedule conflicts, federal holidays and inclement 
weather, etc. Pembrolizumab dosing cycles  may be delayed up to three weeks for the same reasons, however, cycle 3 day 1 (or Cycle 2 day 1 in the 
event that LMB-100 discontinued after cycle 1) may be delayed for longer as described in section 3.3.2.
LMB-100 Cycle(s) 
(cycle 1 +/- cycle 2) 
 (1 cycle=21days1)
Subsequent Cycles (starting 
at cycle 2 or cycle 3) 
(for a maximum of 2 years 
after initial pembrolizumab 
therapy and, if applicable, 
through second course)14
Procedure
Scree-
ning
Day 
1
Day 
3
Day 
4
Day 
5
Day 
8
Day 
1513
Day 1
Safety Follow-
Up Visit (_~30 
days and ~90 
days after 
completion of 
study therapy)15
Long-Term 
Follow Up (every 
6 – 12 weeks)16
LMB-100
X
X
X
Pembrolizumab
X
History and PE
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
Height
X
Vital signs2
X
X
X
X
X
X
X
X
Performance Score
X16
X
X
Labs3, 18
X4
X5
X
X
X
X
X
X
TSH, free T4, total T3
X
X
X
Urinalysis
X
X
X

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LMB-100 Cycle(s) 
(cycle 1 +/- cycle 2) 
 (1 cycle=21days1)
Subsequent Cycles (starting 
at cycle 2 or cycle 3) 
(for a maximum of 2 years 
after initial pembrolizumab 
therapy and, if applicable, 
through second course)14
Procedure
Scree-
ning
Day 
1
Day 
3
Day 
4
Day 
5
Day 
8
Day 
1513
Day 1
Safety Follow-
Up Visit (_~30 
days and ~90 
days after 
completion of 
study therapy)15
Long-Term 
Follow Up (every 
6 – 12 weeks)16
HLA Typing (Class 
I and Class II)
X6
Urine or serum hCG 
in women of 
childbearing 
potential7
X8
X8
X
X
Confirmation of dx9
X
NIH Advance 
Directives Form
X10
Biopsy (optional) 
X17
X6
Post-LMB-100 and after second 
cycle of pembrolizumab
Correlative 
Research Studies 
See section 5.2
CT CAP and/or 
MRI
X
Every 6 weeks ± 7 days
X11
X
FDG CT/-PET
X
Every 6 weeks ± 7 days
X11
X
ECG12
X
X
X
X
X
X
Echocardiogram
X
Adverse Events
Monitored continuously

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LMB-100 Cycle(s) 
(cycle 1 +/- cycle 2) 
 (1 cycle=21days1)
Subsequent Cycles (starting 
at cycle 2 or cycle 3) 
(for a maximum of 2 years 
after initial pembrolizumab 
therapy and, if applicable, 
through second course)14
Procedure
Scree-
ning
Day 
1
Day 
3
Day 
4
Day 
5
Day 
8
Day 
1513
Day 1
Safety Follow-
Up Visit (_~30 
days and ~90 
days after 
completion of 
study therapy)15
Long-Term 
Follow Up (every 
6 – 12 weeks)16
Concomitant 
Medications
Monitored continuously
Telephone/email 
follow-up q 3 
months
X
1
Most subjects are expected to complete 2 cycles of LMB-100; however, in the case of RECIST or clinical disease progression, LMB-100 may be discontinued after 1 cycle with 
pembrolizumab initiated in cycle 2 instead.
2
At screening: heart rate, blood pressure, body temperature, pulse oximetry. During the infusions of LMB-100 in Cycle 1, vital signs (including, if possible, supine diastolic 
and systolic blood pressure, pulse rate, and temperature) must be monitored pre-infusion and every 15 minutes (± 5 minutes) until the end of the infusion. Following the 
completion of the infusion, vital signs should be checked every 30 minutes (± 10 minutes) for the first 2 hours and once at 4 hours after infusion completion. On days when 
there is no infusion, vital signs should be monitored per standard of care. 
3
CBC with differential, Acute Care Panel (Na, K, Cl, CO2, creatinine, glucose, BUN), Hepatic Panel (ALP, AST, ALT, total & direct bilirubin), Mineral Panel (albumin, Ca, 
Mg, P), lactate dehydrogenase, creatine kinase, C-reactive protein, PT, PTT, fibrin degradation products.
4
Performed within 10 days prior to start of study therapy.
5
Only required if more than 10 days have passed since screening assessment. If eligibility criteria are not met at this timepoint, subject may not be treated.
6
May be performed after study consent is signed but prior to treatment initiation (baseline). 
7
Required in women of childbearing potential (see Appendix B for definition).
8
Performed within 3 days prior to enrollment. Must be repeated on C1D1 (pre-treatment) if more than 72 hours have passed since screening assessment and actual treatment 
initiation.
9
This includes confirmation of histology, mutation status as required and mesothelin expression.  Please see section 2.2 for tissue requirements
10
As indicated in section 11.3, all subjects will be offered the opportunity to complete an NIH advance directive form. This should be done preferably at baseline but can be done 
at any time during the study as long as the capacity to do so is retained. The completion of the form is strongly recommended but is not required.
11
PET is optional at this timepoint and may be performed if feasible.
12
Single 12-lead ECG will be recorded at screening, then pre- and end of LMB-100 infusion for first cycle and at the withdrawal and follow-up visit. Pre-infusion at all other 
study drug administrations. Additional unscheduled ECG assessments should be performed if cardiovascular symptoms or abnormalities occur.
13
Day 15 laboratory assessments should be performed -3/+1 day and may be performed outside of NIH. History may be performed remotely, and physical exam is only required 
in subjects seen at NIH.
14
Per section 3.1.2, some subjects may be eligible for up to an additional 17 cycles of therapy, called the second course. Surveillance during the second course will be the same 
as during the initial course unless otherwise indicated. See Appendix D for further details on second course imaging.

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15
Follow up visit will occur within +/- 1 week of indicated time (4- 6 weeks after the last dose of study drug (first course and second course). The assessments listed refer to 
those that will be performed if the patient is seen in clinic (first course and second course). If the patient is unable to return to the clinic for the follow up visit, adverse event 
and ECOG assessments will be performed by telephone or email, we will request that required labs, scans and ECG evaluations be performed locally and provided to us, and if 
the patient has visited a local oncologist in this timeframe, the progress notes will also be requested.. Scans performed only in patients who have not had progressive disease on 
pembrolizumab. Scans will continue every 6 weeks until disease progression or start of a new anti-cancer treatment. After disease progression on pembrolizumab or in those 
subjects who were removed from study therapy for reasons other than disease progression, subjects will be followed every 12 weeks by telephone/email for assessment of 
survival status, adverse events and initiation of new anti-cancer therapy.
16
Performed within 7 days prior to start of study therapy. 
17
Performed if no archival tumor tissue is available for diagnosis confirmation. Tissue samples will also be sent to Mr. Liqiang Xi in the Laboratory of Pathology for biomarker 
analysis.
18
In addition to the labs noted in the Study Calendar, clinical labs (mineral panel, hepatic panel, CBC with differential, CRP, UA) are to be drawn daily while patients are admitted 
for LMB-100 administration.

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3.5
COST AND COMPENSATION
3.5.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not covered 
by insurance company.  Medicines that are not part of the study treatment will not generally be 
provided or paid for by the NIH Clinical Center.    
3.5.2
Compensation
Participants will not be compensated on this study.
3.5.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.   
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 90 days following the last dose of study therapy.
3.6.1
Criteria for removal from protocol therapy

Completion of protocol therapy
o
Note: The number of treatments is calculated starting with the first dose of 
Pembrolizumab. Participants who stop Pembrolizumab after receiving 35 doses 
may be eligible for retreatment if they progress after stopping study treatment 
provided they meet the requirements detailed in section 3.1. Participants may be 
retreated in the Second Course Phase (Retreatment) for up to an additional 17 
cycles (approximately 1 year).

Progressive disease on pembrolizumab

Noncompliance with study treatment or procedure requirements

Requirement for use of prohibited medications/vaccines (see 4.1.2)

Recurrent Grade 2 pneumonitis

Participant (or LAR if one was designated when participant become incapacitated 
during study) requests to be withdrawn from active therapy

Unacceptable Toxicity as defined in section 3.3 

Investigator discretion

Positive pregnancy test 
3.6.2
Off-Study Criteria

Investigator decision to end the study

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
Participant requests to be withdrawn from study

Lost to follow up

Death

Screen failure
3.6.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:

The site will attempt to contact the participant and reschedule the missed visit within 3 
business days and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the 
study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, an IRB approved certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
All concomitant medications received within 28 days before the first dose of trial treatment and 
90 days after the last dose of trial treatment (first course and if applicable, second course) should 
be recorded. Concomitant medications administered after 90 days after the last dose of trial 
treatment (first course and if applicable, second course) should be recorded for SAEs and ECIs as 
defined in section 7.2.
4.1.1
Permitted Therapy
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) including 
all prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and date 
may also be included on the CRF.
Supportive care may be administered according to NIH CC Pharmacy Guidelines unless otherwise 
specified in section 3.3.
4.1.2
Prohibited Therapy
Patients should be treated for all concomitant conditions and adverse events according to accepted 
standards of medical care at the discretion of the investigator. The following treatments are not 
permitted while patient is receiving study therapy:

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
Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than the study agents 

Radiotherapy. Note: Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.

Live vaccines. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed. 

Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be considered per investigator discretion.

Strong inhibitors or inducers of CYP3A4 (as can be found here: Flockhart Table or in 
another frequently updated source)
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing study. If there is a clinical indication for any medication or vaccination specifically 
prohibited during the study, discontinuation from study therapy is required. The final decision on 
any supportive therapy or vaccination rests with the investigator and/or the participant's primary 
physician. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION
5.1.1
Pharmacokinetic Assessments
All blood samples for PK assessment will be collected from an IV line different to that receiving 
the infusion to measure free and total concentrations for LMB-100 for all patients. The date and 
time of each sample collection will be recorded. If multiple samples are drawn at a given time 
point, the PK sample should take precedence.
Free and total plasma concentrations of LMB-100 will be measured using validated ligand-binding 
assays.
5.1.1.1
Sample collection:
Blood for PK samples should be drawn from the opposite extremity as the one used for drug 
delivery. If feasible, a peripheral line used for this purpose should remain in place until the last 

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scheduled collection for a given day. Blood will be collected in 2 mL K2EDTA tubes (purple top) 
at the times defined in section 5.2. Samples should be inverted 8 to 10 times after collection. Store 
on wet ice or at 4°C. Processing within 60 minutes of blood collection is highly preferred. 
5.1.1.2
Sample processing
Samples will be processed in the Clinical Pharmacology Program. 
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact at NCIBloodcore@mail.nih.gov by e-mail or 
at 240-858-3191.
Upon arrival in the CPP the following procedures should be followed:
1. Store on wet ice until centrifugation. 
2. Centrifuge 1500xg for 10 minutes at 4°C within 60 minutes of blood collection. 
3. Transfer plasma specimen to 2mL cryovials and store at -70°C. 
The analyses will be performed retrospectively in batched samples or at the end of the trial.
5.1.1.3
Sample Shipping
Samples will be shipped by the CPP on dry ice to Ms. Yanyu Wang in Frederick for analysis.
Leidos Biomedical Research, Inc.
Attention: Ms. Yanyu Wang & Dr. Jon Inglefield
Building 469, Room 120
Miller Drive
Frederick, MD 21702
Phone: 301-846-6905/301-846-6865
5.1.1.4
Sample storage
Samples will be stored in the CPP until shipment to the Leidos Biomedical Inc. Lab in Frederick. 
5.1.2
Assessment of anti-drug antibodies (ADAs) 
5.1.2.1
Sample Collection 
Samples will be per the schedule in section 5.2.
Draw 2mL blood into K2EDTA tube (purple top). Samples should be inverted 8 to 10 times after 
collection. Store on wet ice or at 4°C. Processing within 60 minutes of blood collection is highly 
preferred.
5.1.2.2
Sample Processing 
Samples will be processed in the Clinical Pharmacology Program. 

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Please e-mail:NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov .
Upon arrival in the CPP, each sample should be processed in the following manner: 
1. Store on wet ice until centrifugation. 
2. Centrifuge 1500xg for 10 minutes at 4°C within 60 minutes of blood collection. 
3. Transfer plasma specimen to 2mL cryovials and store at -70°C. 
Autoantibody levels will be retrospectively assessed.
5.1.2.3
Sample Shipping
Samples will be shipped by the CPP on dry ice to Ms. Yanyu Wang in Frederick for analysis.
Leidos Biomedical Research, Inc.
Attention: Ms. Yanyu Wang, Dr. Jon Inglefield
Building 469, Room 120
Miller Drive
Frederick, MD 21702
Phone: 301-846-6905/301-846-6865
5.1.2.4
Sample Storage
Samples will be stored in the CPP until shipment to the Leidos Biomedical Inc. Lab in Frederick. 
5.1.3
Retrospective Analysis of Mesothelin, KRAS and PD-L1 Expression in tumor tissue
The mesothelin expression analysis and KRAS mutation status will be performed by the NCI Lab 
of Pathology at the time of histological confirmation of non-squamous non-small cell lung cancer. 
This must be done prior to subject enrollment to trial and treatment. Mesothelin expression can be 
analyzed on archival tumor tissue sample or newly obtained fresh core or excisional biopsy of a 
tumor lesion not previously irradiated. 
Leftover tissue from archival specimens or tumor biopsies obtained at baseline or from optional 
collections at postLMB-100 (either post cycle 1 or post cycle 2 depending upon progression), and 
post second cycle of pembrolizumab may be used for this purpose. Specimens will be used to 
correlate treatment response with mesothelin expression and with anti PD-L1 in exploratory 
analyses. Additionally, this tissue will undergo IHC staining to analyze CD4 and CD8 T-Cell 
subsets.
5.1.3.1
Specimen collection 
Collection of optional tumor biopsies should be guided by ultrasound, CT scan, or other method 
according to the location of the selected lesion using a ≤ 18-gauge needle to provide cores ideally 
of at least 20 mm in length or equivalent size. At least 3, ideally 4 core biopsies will be obtained 
at each time point (baseline, post cycle 2, and post pembrolizumab). Fine needle aspiration and 

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biopsy of bone lesions are not acceptable. All biopsies collected under this protocol will undergo 
review in the NCI Laboratory of Pathology.
5.1.4
Mesothelin and Megakaryocyte Potentiating Factor (MPF) Serum Samples 
The levels of serum mesothelin as well as megakaryocyte potentiating factor, which is released 
into serum from the processing of mesothelin precursor protein will be assessed in order to 
determine correlation with therapeutic response.
5.1.4.1
Sample Collection 
Samples will be obtained prior to the first LMB-100 dose in cycle 1 and at the end of treatment
All blood samples will be taken by either direct venipuncture or an indwelling venous access. At 
each sample collection time, blood (2mL) will be drawn in a 3.5 mL (red) serum separator tube 
labeled as follows:
- Subject ID Number 
- Study Number 
- Time and date of collection
5.1.4.2
Sample Processing
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
Upon arrival in the CPP, each sample should be processed in the following manner:
Allow blood to clot for 10 minutes and centrifuge to separate the serum within 30 minutes of 
collection. If unable to process within 30 minutes, then whole blood tubes may be stored upright 
in refrigerator (4-8C) for up to 48 hours prior to processing. Processing of samples within 30 
minutes is strongly preferred. Stability studies will establish if degradation of soluble mesothelin 
in whole blood during 0.5 to 48 hours is significant and therefore if the data from these samples 
should be included in the analysis. 
Transfer the serum into two pre-labeled cryotubes and immediately freeze by placing on dry ice. 
Transfer frozen serum samples into a – 80C freezer for storage.
5.1.4.3
Sample Storage
All serum samples will be stored by Dr. Figg’s Clinical Pharmacology Program.
5.1.5
Gene expression-based characterization of the immune landscape before and after 
treatment with LMB-100 and pembrolizumab
As referenced in section 5.1.3.1, optional tumor biopsies will be performed in consenting patients 
when deemed feasible at the following time points: before initiation of therapy at baseline (archival 
tissue may also be used), at the end of cycle 2, and after pembrolizumab. We will evaluate tumor 

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biopsies before and after treatment with LMB-100 and after treatment with pembrolizumab using 
a hybridization-based digital gene expression platform nCounter (NanoString Technologies). This 
platform allows for unbiased multiplexed quantification of RNA transcripts achieving sensitivity 
comparable to quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR), without 
any enzymatic reaction involved in the process. We have expertise in the use of this technology 
for the characterization of purified cell subsets and for the study of the changes that occur in human 
tumors, as a consequence of a given treatment, using tumor core biopsy tissues. This analysis can 
be performed on flash frozen biopsies without any further isolation or enrichment of specific cell 
types.
For the present study, we will screen pre- and post-treatment samples for the expression of markers 
of immune cell subsets (CD3, CD8, CD4, etc.), local production of cytokines (interferon-gamma, 
tumor necrosis factor-alpha, etc.) and chemokines (CXCL13, CCL5, etc.), adhesion molecules and 
others. The purpose of this study is to characterize the molecular changes that occur within the 
tumors following treatment with LMB-100 and pembrolizumab. The ultimate goal is to gain a 
better understanding of the mechanism of action of this treatment, and to identify molecular 
correlates of clinical outcomes such as objective responses and/or improved survival. 
 In order to achieve these goals, flash frozen samples will be subjected to total RNA isolation 
followed by hybridization with capture and detection probes specific for 620 transcripts, including 
genes involved in the regulation of the immune function and markers expressed by tumor cells and 
tumor stroma. To cover those target transcripts, a combination of a commercially available pre-
designed probe set (GX Human Immunology v2, NanoString Technologies) will be used in 
combination with a custom-designed code set of thirty additional targets (Panel Plus, NanoString 
Technologies). Hybridization complexes will be quantified using a NanoString nCounter Analysis 
System, at the Genomics Core Facility of the Center for Cancer Research, NCI. 
Results obtained by this approach will be correlated with data obtained from 
immunohistochemistry of tumor biopsies as well as with data from analysis of peripheral blood 
populations, for a comprehensive study of the mechanism of action of LMB-100 in mesothelioma 
patients. Samples will be stored in the Laboratory of Dr. Raffit Hassan, Building 10, Room 3B51.
5.1.6
Biomarker analysis
If not previously completed, every patient entering the trial will have tumor tissue analyzed with 
the the TruSight Oncology 500 Assay in the Molecular Diagnostics Section of the Laboratory of 
Pathology.  If previously completed, the existing results will be used to inform study results.  This 
is a clinical next-generation sequencing-based multiple-biomarker assays that targets the most 
relevant single nucleotide variants, small insertions and deletions, copy number variants, and gene 
fusions from 161 cancer genes. 
Tissue samples will be sent to Mr. Liqiang Xi at LP for analysis.
Phone: 301-480-8933 
Email:  xil2@mail.nih.gov 
5.1.7
Circulating tumor DNA (ctDNA) before and sequentially after treatment with LMB-100 
and pembrolizumab:
For post-treatment correlative study, based on comprehensive data analysis (as explained above) 
we will select 1-3 mutation targets per patient as circulating tumor DNA (ctDNA) markers to be 

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used for monitoring the treatment response. The customized digital droplet PCR (ddPCR) mutation 
detection assay will be performed on a QX200 ddPCR system (Bio-Rad Laboratories, Inc) with 
10-20 ng cell-free DNA extracted from about 4 mL plasma for each time point. Two time points 
before treatment and as many as time points during/after treatment will analyzed.
Specifically, blood samples will be collected at baseline, pre/post LMB-100 on days 1, 3, 5 
followed by day 8, 15 (-3/+1 day of C1D15 and C2D15) for each cycle and end of treatment using 
standard procedures and transferred to Figg’s lab on a patient by patient basis. Plasma preparation 
/storage will be done at Figg lab as described below. Once the plasma samples are collected for 
few patients in a batch, PI will request to Laboratory of Pathology for ddPCR mutation detection 
assay. 
Samples will be sent by the Figg lab on dry ice to Mr. Liqiang Xi at LP for analysis.
Phone: 301-480-8933 
Email:  xil2@mail.nih.gov 
There will also be blood drawn pre/post pembrolizumab on each subsequent cycle. The ultimate 
goal is to identify ctDNA correlates of clinical outcomes such as objective responses and/or 
improved survival to LMB-100 with pembrolizumab. 
Plasma preparation for cell free (cf)DNA extraction using Streck collection tubes: Streck 
tubes can be stored for processing when Figg’s lab is open. Collect 2- 10 ml brown/black Streck 
cell free DNA/ cf DNA (brown black tiger top). Samples are stable for up to 5 days at room 
temperature.
1. In hood: transfer blood to 15 mL conical tube
2. Centrifuge 15 mL conical tubes for 10 minutes at 1500 ± 150xg (=1500RCF) 4°
3. Transfer supernatant to a fresh 15 ml tube without disturbing the leukocyte layer
4. Centrifuge plasma a second time for 10 min at 3000 ± 150xg (=3000 RCF) 4°
5. Transfer supernatant to a fresh 15 ml centrifuge tube without disturbing the cellular layer. 
Leave a residual volume of about 0.3 ml (~7 mm) on the bottom of the 15 ml tube to avoid 
cellular contamination
6. After transferring the plasma to a new 15 ml centrifuge tube as described, gently mix 
plasma and record total plasma volume (typically ~ 4 ml plasma per 10 ml blood)
7. Make 1 mL aliquots into standard cryovials
8. Store plasma in freezer at -80°C
5.1.8
Pleural effusion to establish cell lines and cytology studies
In the case that patients present with or develops a pleural effusion who are symptomatic may 
proceed with therapeutic thoracentesis during any time point during the course of treatment at the 
IR suite or at bedside from a pigtail catheter. Fluid that is collected will be analyzed and used for 
research purposes including cytology and establishing cell-lines. All samples will be coded. 
5.1.9
Cytokines and circulating endothelial cells (CECs) for identification of a mechanism for 
Pseudomonas exotoxin A (PE)-mediated capillary leak syndrome (CLS)
PE-based RITs cause dose-limiting CLS. At low doses CLS manifests as mild and transient weight 
gain, hypoalbuminemia, and peripheral or facial edema. At higher doses it can cause life-
threatening cardiopulmonary compromise. Previous studies in rats have indicated that pathological 

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changes indicative of CLS onset occur within just two hours of toxin administration and even when 
the PE fragment lacks a targeting domain (40). In vitro studies with cultured endothelial cells have 
demonstrated that super-physiologic doses of PE-based RITs cannot induce endothelial cell 
toxicity unless the cells express the RIT target (41). Together these data suggest the hypothesis 
that PE-based RITs cause CLS by triggering release of vasoactive cytokines by specific 
immune cells rather than through direct damage to endothelial cells. To test this hypothesis, 
we will collect additional blood from participants. Levels of a panel of cytokines known to affect 
the vasculature will be assessed. Change in cytokine levels from baseline will be compared. 
In addition, circulating endothelial progenitor cells (CEP) and mature circulating endothelial cells 
(CEC) will be collected to assess endothelial cell dynamics (see Section 5.2 for specific time 
points). These cells will be assessed by multiparameter flow cytometry. Cells will be analyzed for 
forward and side scatter, and cells expressing hematopoietic markers will be excluded.  Endothelial 
cells will be identified using co-expression of markers, such as CD31 and CD146 for CEC, and 
CD31 and CD133 for CEP. The cell populations will also be analyzed for viability using scatter 
profiles and a vital stain, such as Hoechst 33258. Percentages of stained cells will be determined 
and compared with appropriate negative controls. Multiparameter flow cytometric analysis will be 
performed with a Miltenyi Quant equipped with FlowJo software, using a minimum of 100,000 
events per analysis.
5.1.9.1
Specimen collection- cytokine analysis
Two mL of plasma and serum will be collected in SST (red top) tubes from participants on the 
days and time points shown in Sections 5.2.
5.1.9.2
Sample processing- cytokine analysis
Samples will be processed in the Clinical Pharmacology Program as described in Section 5.1.1.2.
Upon arrival in the CPP, each plasma sample should be processed in the following manner: 
1. Store on wet ice until centrifugation.  
2. Centrifuge 1500xg for 10 minutes at 4°C within 60 minutes of blood collection. 
3. Immediately transfer plasma specimen (maintaining samples at 4°C throughout handling 
process) to 2mL cryovials and store at -70°C.  
Upon arrival in the CPP, each serum sample should be processed in the following manner: 
1. Store at room temperature for 15-30 minutes to allow blood to clot
2. Centrifuge at 1500xg for 10 minutes at 4°C to remove clot
3. Immediately transfer serum specimen (maintaining samples at 4°C throughout handling 
process) to 2mL cryovials and store at -70°C. 
5.1.9.3
Sample Storage- cytokine analysis
Samples will be stored in the CPP. Deidentified samples will be transferred to TGMB or NCI-
Frederick for analysis within 12 months of freezing.
5.1.9.4
Sample Collection- CECs
Draw blood into one 8-cc CPT citrate (BD) tube as specified in Section 5.2.

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5.1.9.5
Sample Processing-CECs
Contact the Trepel Lab, Developmental Therapeutics Branch, NCI by email (Jane Trepel- 
trepel@helix.nih.gov and Sunmin Lee- lees@pop.nci.nih.gov) when the patient is scheduled and 
by phone as soon as the blood is drawn at 240-760-6330 and a lab member will pick up the sample.  
5.2
SAMPLE COLLECTION SCHEDULE
PK
(5.1.1)
ADA
(5.1.2)
Tumor 
Sampl
e
(5.1.3, 
5.1.5, 
5.1.6)
Serum 
mesothelin 
and MPF
(5.1.4)
ctDNA 
Blood 
sample
(5.1.7)
Pleural 
effusion
(5.1.8)
Cytokines 
& CECs
(5.1.9)
Cycle
Daye
2 mL blood 
in K2EDTA 
tube (purple 
top)
2 mL 
blood in 
K2EDTA 
tube 
(purple 
top)
N/A
2 mL blood 
in 3.5 mL 
SST tube
 10 mL  
cfDNA in 
brown / 
black 
streck 
tiger top 
1 Liter 
(vacuum 
drainage 
container)
2 mL SST 
tube,
8 mL CPT 
tube
Screening
Screeni
ng 
period 
± 3 
days
Xa
Screening
1 
1
Pre-dose, 
EOI, 1, 2, 3, 
4, and 6 
hours after 
start of 
infusion
Pre-dose
Xb
X
Pre-
dose/EOI 
on days 1, 
3, 5. 
Day 8, 15d
Pre-dose on 
day 1, post-
dose on day 
5, day 8 & 
15
2 
1
Pre-dose, 
EOI, 1, 2, 3, 
4, and 6 
hours after 
start of 
LMB-100 
infusion if 
given
Pre-dose
Xb
Pre-
dose/EOI 
on days     
1, 3, 5
Day 8, 15 
d
Pre-dose on 
day 1, post-
dose on day 
5, day 8 & 
15
3 
1
X 
Xb
Pre-
dose/EOI
Pre-dose 
pembro
4 
1
X
Xb
Pre-
dose/EOI
Pre-dose 
pembro
5 and 
beyond
1
Xb
Pre-
dose/EOI
Any time 
during the 
course of 
treatment 
Pre-dose 
pembro 

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End of 
Treat
mentc
X
End of 
treatment
X
ADA =anti-drug antibody; EOI =End of infusion; PK =pharmacokinetic; MPF= 
Megakaryocyte Potentiating Factor; ctDNA=circulatory tumor DNA
a.
A fresh biopsy or tumor effusion sample will be collected if archival tumor tissue is not available. 
b.
Optional tumor biopsies for research will be performed at baseline (C1D1), at the end of cycle 2 of LMB-100, after 
second cycle of pembrolizumab.  In the event that patients get one cycle of LMB-100, optional tumor biopsies for research 
will be performed at baseline, at the end of cycle 1 of LMB-100 and after second cycle of pembrolizumab.
c.
Refers to the end of the first course. No additional research samples will be collected during the second course.
d.
If Day 15 assessments are performed at the NIH.  Blood collection may occur -3/+1 day of C1D15 and C2D15. 
e.
Samples may be collected 1 ± 3 days from indicated time.
Note: Timed samples above must be drawn within a +/- 5 minute window for draws up to 4 hours 
post dose and within a +/- 20 minute window for 8-10 hr and 12-16 hr post dose draws. 
5.3
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples 
will not be sent outside NIH without appropriate approvals and/or agreements, if required. 
5.3.1
Blood Processing Core (BPC)
Upon arrival in the Blood Processing Core (BPC), all samples are barcoded, with data entered and 
stored in Labmatrix, the system utilized by the CPP. This is a secure program, with access limited 
to defined Figg lab personnel, who are issued individual user accounts. Installation of Labmatrix 
is limited to computers specified by Dr. Figg. These computers have a password restricted login 
screen.
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix access. The data recorded for each sample includes the patient 
ID, name, trial name/protocol number, time drawn, cycle, time point, dose, material type, as well 
as box and freezer location. Patient demographics associated with the clinical center patient 
number are provided in the system. For each sample, there are notes associated with processing 
method (delay in sample processing, storage conditions on the ward, etc.).
Sample Storage and Destruction
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20°C or -80°C 
according to stability requirements. These freezers are located onsite in the CPP and offsite at NCI 
Frederick Central Repository Services in Frederick, MD.  Visitors to the laboratory are required 
to be accompanied by laboratory staff at all times.
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per IRB approved protocol) and that any unused samples 
must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that 
the samples requested are being used in a manner consistent with IRB approval.

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Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting the 
rights to use the material.
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed or returned to the patient, if so requested. The PI will record any loss or 
unanticipated destruction of samples as a deviation. Reporting will be per the requirements of 
section 7.2.
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables.
5.3.2
Leidos Biomedical Research, Inc. Lab
Blood and tissue collected during the course of this study will follow storage, handling and labeling 
procedures to ensure that security, confidentiality and sample integrity are maintained. All samples 
(blood or tissue) are tracked by distinct identification labels that include a unique patient identifier 
and date of specimen collection. Thus, samples will be coded, with access to the code key linking 
personal data restricted to the study investigators. 
All cryopreserved samples are tracked for freezer location and storage criteria. All Samples are 
stored in a locked freezer at -70C according to stability requirements. These freezers are located 
offsite at NCI-Frederick, at the Leidos Biomedical Research, Inc. Lab in Frederick, MD. Samples 
will be stored until requested by a researcher named on the protocol. All use and requests for use 
will be recorded by the Leidos Biomedical, Inc. Lab. Any unused samples must be returned.
Some samples as indicated below may be stored in monitored freezers/refrigerators in the 
investigator’s laboratory at specified temperatures with alarm systems in place. 
At the completion of this protocol, samples will remain in storage as detailed above. If additional 
studies are to be performed on any samples retaining patient identifiers, obtained during the 
conduct of this trial, access to these samples will only be granted following IRB approval of an 
additional protocol, granting the rights to use the material. If specimens are to be discarded at any 
point, they will be disposed of in accordance with the environmental protection laws, regulations 
and guidelines of the Federal Government and the State of Maryland.
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested). 
5.3.3
NCI Laboratory of Pathology
Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) 
where they are examined grossly, and relevant portions are fixed, embedded in paraffin and 
sectioned and stained for diagnostic interpretation. Unutilized excess tissue that is not placed in 
paraffin blocks is stored in formalin for up to three months, in accordance with College of 
American Pathologists/Joint Commission on Accreditation of Healthcare Organizations 
(CAP/JCAHO) guidelines, and then discarded. Following completion of the diagnostic workup, 

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the slides and tissue blocks are stored indefinitely in the LP’s clinical archives. All specimens are 
catalogued and retrieved utilizing the clinical laboratory information systems, in accordance with 
CAP/JCAHO regulations. The use of any stored specimens for research purposes is only allowed 
when the appropriate IRB approval has been obtained. In some cases, this approval has been 
obtained via the original protocol on which the patient was enrolled. 
5.3.4
Laboratory of Dr. Raffit Hassan
This study will follow storage, handling and labeling procedures to ensure that security, 
confidentiality and sample integrity are maintained. All samples (blood or tissue) are tracked by 
distinct identification labels generated by LabMatrix that include a unique patient identifier and 
date of specimen collection. Thus, samples will be coded, with access to the code key linking 
restricted to the study investigators. 
Depending on specimen type, samples are stored in liquid nitrogen, in monitored 
freezers/refrigerators at either -20 or -80C according to stability requirements or in a slide cabinet 
in the research Laboratory of Dr. Raffit Hassan (Building 10, Room 3B51)
5.3.5
Protocol Completion/Sample Destruction
All specimens obtained in the protocol are used as defined in the protocol. Any specimens 
remaining at the completion of the protocol will be stored in the conditions described above. The 
study will remain open as long as sample or data analysis continues. Samples from consenting 
subjects will be stored until they are no longer of scientific value or until a subject withdraws 
consent for their continued use, at which time they will be destroyed. Once primary research 
objectives for the protocol are achieved, intramural researchers can request access to remaining 
samples, provided they have an IRB-approved protocol and patient consent or an exemption from 
IRB review. 
The PI will report any unanticipated loss or destruction of samples per section 7.2.1. Freezer 
problems, lost samples, or other problems associated with samples that meet expedited reporting 
requirements (see section 7.2.1) will also be reported.
5.4
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.4.1
Description of the scope of genetic/genomic analysis
Using the tissue samples, we will perform the TruSight Oncology 500 Assay. This is a clinical 
next-generation sequencing-based multiple-biomarker assay developed by Thermo Fisher and 
targets most relevant single nucleotide variants, small insertions and deletions, copy number 
variants, and gene fusions from 161 cancer genes. 
5.4.2
Privacy and Confidentiality of medical information/biological specimens
Initially the samples of each patient will be barcoded. At no time will patient’s names be used on 
the tissue samples. Sometimes, because a group collaboration or journal policy requires it, a 
subject’s genetic data will be deposited in a database such as dbGaP. Although there is controlled 
access to such a database, such a submission carries theoretical risks of revealing the identity of 
the subject. This is discussed in the consent.

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5.4.3
Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
incidental findings that is current at the time of primary analysis. (A list of current guidelines is 
maintained on the CCR intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). Subjects 
will be contacted at this time with a request to provide a blood sample to be sent to a CLIA 
certified laboratory. 
The costs of CLIA testing will be paid for by the Center for Cancer Research, the Branch, or the 
Principal Investigator. If the health history, family history, or tumor diagnosis from the Laboratory 
of Pathology at the NIH Clinical Center suggests that the participant might benefit from genetic 
testing, we will discuss this with him/her.
5.4.4
Genetic counseling
If the research findings are verified in the CLIA certified lab, the subject will be offered the 
opportunity to come to NIH (at our expense) to have genetic education and counseling with the 
NCI Genetics Branch to explain this result. If the subject does not want to come to NIH, a referral 
to a local genetic healthcare provider will be provided (at their expense). This is the only time 
during the course of the study that incidental findings will be returned. No interrogations regarding 
clinically actionable findings will be made after the primary analysis.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. Primary and final analyzed data will have identifiers so that 
research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.  
Document AEs from the first study intervention, Study Day 1, through 90 days after the subject 
received the last product administration (first course and if applicable, second course). After 90 
days (first course, and if applicable second course) only adverse events which are serious and 
related to the study investigational agent/intervention need to be recorded. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

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
Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1. 
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:

Coded, linked data in an NIH-funded or approved public repository. 

Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
How and where will the data be shared? 

Data will be shared through:

An NIH-funded or approved public repository: clinicaltrials.gov, dbGaP

BTRIS (automatic for activities in the Clinical Center)

Publication and/or public presentations.
When will the data be shared?

Before publication.

At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.
6.3
RESPONSE CRITERIA
For the purposes of this study, patients should be re-evaluated for response every 6 weeks (2 
cycles). In addition to a baseline scan, confirmatory scans should also be obtained no less than 4 
weeks following initial documentation of objective response. Refer to Appendix C for 
confirmatory scan and continued treatment instructions.
Response and progression will be assessed by the investigator on the basis of physical 
examinations, computed tomography (CT) or Magnetic Resonance (MR) scans, and potentially 
other modalities according to standard of care.
When the Investigator identifies radiographic progression while on pembrolizumab per RECIST 
1.1 or mRECIST, efforts should be made to verify radiologic PD. Treatment should continue until 

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PD has been verified. Regardless of whether PD is verified, if the Investigator considers the 
participant has progressed, but elects to implement iRECIST, the Investigator will assess for 
confirmation of progression by iRECIST at subsequent time points. When clinically stable, 
participants should not be discontinued until progression is confirmed by the Investigator, working 
with local radiology, according to the rules below. This allowance to continue treatment despite 
initial radiologic PD takes into account the observation that some participants can have a transient 
tumor flare in the first few months after the start of immunotherapy, and then experience 
subsequent disease response.
6.3.1
Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as: 

By chest x-ray: >20 mm; 

By CT scan: 
o
Scan slice thickness 5 mm or under: >10 mm
o
Scan slice thickness >5 mm: double the slice thickness 

With calipers on clinical exam: >10 mm. 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 

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and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease.
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or 
in rare cases unequivocal progression of each should be noted throughout follow-up. 
6.3.1.1
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is 
also acceptable in certain situations (e.g. for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible.
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 

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measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data, which may bias an investigator if it is not routinely or serially performed. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances.
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, such techniques may be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published.(42-44) In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer.(45)
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
b.
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-
PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans 
are needed to determine if there is truly progression occurring at that site (if so, the date of PD will 
be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The 
use of FDG-PET in this circumstance should be prospectively described in the protocol and 

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supported by disease-specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET 
and biopsy resolution/sensitivity.
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
6.3.1.2
RECIST version 1.1 Response Criteria
6.3.1.2.1
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.
6.3.1.2.2
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator).
6.3.1.2.3
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient's best response assignment will depend on the 
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For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-
CR/Non-PD
No
PR
CR
Not 
evaluated
No
PR
PR
Non-
CR/Non-
PD/not 
evaluated
No
PR
>4 wks. Confirmation**
SD
Non-
CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks. from baseline**
PD
Any
Yes or 
No
PD
Any
PD***
Yes or 
No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
Only for non-randomized trials with response as primary endpoint.
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression.
Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort 
should be made to document the objective progression even after discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*

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Non-Target Lesions
New Lesions
Overall Response
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised
6.3.2
iRECIST
6.3.2.1
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment.
6.3.2.2
Assessment and Decision at RECIST 1.1 Progression
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will decide 
whether to continue a participant on study treatment until repeat imaging is obtained (using 
iRECIST for participant management (see Appendix C). This decision by the Investigator should 
be based on the participant’s overall clinical condition.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, radiation, 
or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at site-
assessed first radiologic evidence of PD and is not required to have repeat tumor imaging for 
confirmation of PD by iRECIST.
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir
o
Please note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)

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iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and 
iCPD (confirmed progressive disease). For purposes of iRECIST assessment, the first visit 
showing progression according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, 
regardless of which factors caused the progression.
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as 
usual.
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST 1.1. From measurable new lesions, up to 5 
lesions total (up to 2 per organ), may be selected as New Lesions – Target. The sum of diameters 
of these lesions will be calculated and kept distinct from the sum of diameters for target lesions at 
baseline. All other new lesions will be followed qualitatively as New Lesions – Non-target.
6.3.2.3
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
6.3.2.4
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the initial iUPD show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, 
compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, compared 
to a prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST 
1.1
o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD time point 

Visible growth of new non-target lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
6.3.2.5
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which 
iUPD is seen. This may correspond to the next visit in the original visit schedule. The assessment 
of the subsequent confirmation scan proceeds in an identical manner, with possible outcomes of 
iCPD, iUPD, and iSD/iPR/iCR.

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6.3.2.6
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), 
or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”. This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned.
6.3.2.6.1
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the regular 
imaging schedule. If PD is confirmed, participants will be discontinued from study treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study treatment 
may be considered. In this case, if study treatment is continued, tumor imaging should continue to 
be performed following the intervals as outlined in section 6.
6.3.2.6.2
Detection of Progression at Visits After Pseudo-Progression Resolves
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated by 
any of the following events:

Target lesions
o
Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir is 
always the smallest sum of diameters seen during the entire trial, either before or after an 
instance of pseudo-progression.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so 
for the first-time results in iUPD.
o
If non-target lesions had shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of non-target 
lesions, taken as a whole.

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥ 5 mm in the new 
lesion sum of diameters, from the nadir value of that sum

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o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. Progression 
must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, except in one 
respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan the 
burden of new lesions has increased from its smallest value (for new target lesions, their sum of 
diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will 
remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or 
until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication.(46)
6.3.3
Duration of Response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
6.3.4
Progression-Free Survival
Progression free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression (on or after pembrolizumab) or death, whichever occurs first.
6.3.5
Objective Response Rate
Objective response rate (ORR) is defined as the proportion of patients with partial response or 
complete response.
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy 
of 
the 
CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)
7
NIH REPORTING REQUIREMENTS/DATA SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found here.

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7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports 
that meet the definition of an unanticipated problem will need to be reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here. 
7.2.3
NCI Clinical Director Reporting 
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the Clinical 
Director.
In addition to those reports, deaths not reported to the OHSRP that occur within 30 days after 
receiving a research intervention should be reported via email to the Clinical Director unless they 
are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut 
at  NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.3
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.3.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis weekly when patients are being actively 
treated on the trial to discuss each patient. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator.  Events meeting requirements for expedited reporting as described in section 
7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
7.3.2
Safety Monitoring Committee (SMC)
This protocol will be periodically reviewed by an intramural Safety Monitoring Committee. Initial 
review will occur as soon as possible after the annual NIH Intramural IRB continuing review date. 
Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting 
schedule permits or more frequently as may be required by the SMC based on the risks presented 
in the study. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual 
within the review period. 
The SMC review will focus on unexpected protocol-specific safety issues that are identified during 
the conduct of the clinical trial.

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Written outcome letters will be generated in response to the monitoring activities and submitted to 
the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
8
SPONSOR SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:

Death,

A life-threatening adverse event (see 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.

Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions

A congenital anomaly/birth defect

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)

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8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  

Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in section 8.4.
All SAE reporting must include the elements described in 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 

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and instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
Following the assessment of the SAE by OSRO, other supporting documentation of the event may 
be requested by the OSRO Safety and should be provided as soon as possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR 
As death due to disease progression is a part of the study objectives (PFS and OS) and captured as 
an endpoint in this study, they will not be reported in expedited manner to the Sponsor. However, 
if there is evidence suggesting a causal relationship between the study drug and the event, report 
the event in an expedited manner according to section 8.3.
Hospitalization that is deemed to be due to disease progression, and not attributable to the 
intervention will not be reported as an SAE. The event, and the assessment that it was caused by 
disease progression will be documented in the medical records. The causality assessment of 
hospitalization will be re‐evaluated any time when new information is received. If the causality 
assessment changes from disease progression to related to the study intervention, SAE report will 
be sent to the Sponsor in an expedited manner according to Section 8.3. If there is any uncertainty 
whether the intervention is a contributing factor to the event, the event should be reported as AE 
or SAE as appropriate.
8.5
REPORTING PREGNANCY 
All 
required 
pregnancy 
reports/follow-up 
to 
OSRO 
will 
be 
submitted 
to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions can 
be found here: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
8.5.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy become known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (8.1.2) should be reported as SAEs. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented.
8.5.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 180 
days after the last dose of LMB-100 or pembrolizumab.
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 180 days after the last dose 
should, if possible, be followed up and documented.
8.6
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected adverse 

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reaction only if there is evidence to suggest a causal relationship between the study product and 
the adverse event.  CCR will notify FDA and all participating investigators (i.e., all investigators 
to whom the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND 
safety report of potential serious risks from clinical trials or any other source, as soon as possible, 
in accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
9
CLINICAL MONITORING 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6, and SOPs; and human subjects protection. This is done through 
independent verification of study data with source documentation focusing on:

Informed consent process

Eligibility confirmation

Drug administration and accountability

Adverse events monitoring

Response assessment
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center.
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.  
10
STATISTICAL CONSIDERATIONS 
10.1
STATISTICAL HYPOTHESIS
10.1.1 Primary Endpoint 

To determine the objective response rate for the combination of LMB-100 and 
Pembrolizumab in the treatment of patients with advanced, mesothelin-expressing non-
squamous non-small cell lung cancer (NSCLC) previously treated with immune checkpoint 
inhibitors.
10.1.2 Secondary Endpoints

To determine the overall survival (OS), duration of response and progression free survival 
(PFS) of LMB-100 and Pembrolizumab in the treatment of patients with advanced, non-
squamous non-small cell lung cancer (NSCLC). 

To determine the safety and tolerability of combination of LMB-100 and Pembrolizumab 
in the treatment of patients with advanced, mesothelin-expressing non-squamous non-
small cell lung cancer (NSCLC) previously treated with immune checkpoint inhibitors
10.1.3 Sample size determination:
Patients will be screened for adequate mesothelin expression. Patients eligible for treatment will 
directly enrolled without randomization or any stratification. 

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An observed response rate of 10% or greater would be considered desirable in this population of 
subjects who have previously failed a checkpoint inhibitor. In this arm, the trial will be conducted 
using a Simon minimax two-stage phase II trial design (47) to rule out an unacceptably low 
response rate of 5% (p0=0.05) in favor of an improved response rate of 20% (p1=0.20). With 
alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.20 (probability of 
rejecting a good treatment=0.20), the first stage will enroll 12 evaluable patients, and if 0 of the 
12 have a response, then no further patients will be accrued. If 1 or more of the first 12 patients 
have a response, then accrual would continue until a total of 21 evaluable patients have been treated 
on Arm A. As it may take up to several months to determine if a patient has experienced a response, 
a temporary pause in the accrual may be necessary to ensure that enrollment to the second stage is 
warranted. If there are 1-2 patients with a response out of 21 patients, this would be an 
uninterestingly low response rate. If there were 3 or more of 21 (14.3%) who experienced a 
response, this would be sufficiently interesting to warrant further study in later trials. Under the 
null hypothesis (5% response rate), the probability of early termination is 54.0%.
It is expected that 25% of patients who have NSCLC will have adequate (25%) mesothelin 
expression to receive treatment on this protocol and 10% of patient with lung adenocarcinoma co-
express PD-L1 and >25% mesothelin expression.
In order to enroll and treat up to 21 evaluable patients with adequate mesothelin expression, the 
trial will plan to enroll and screen up to 100 patients. With 100 patients, there would be 85.1% 
probability of enrolling 21 or more evaluable patients if the true probability of adequate expression 
for a given patient was 25%.
It is expected that up to 2 patients per month may be screened on this protocol, yielding 
approximately 5 to 6 treated patients per year. It is expected that up to 4 years may be required to 
enroll up to 100 patients for screening and 21 evaluable for response. To allow for a small number 
of unevaluable patients and screen failures 23 patients will be treated and the screening will be set 
at 100 total patients.
10.2
POPULATIONS FOR ANALYSES
10.2.1 Evaluable for toxicity
All patients will be evaluable for toxicity from the time of their first treatment with LMB-100. 
Events occurring after initiation of a second course of therapy will not be included in this analysis.
10.2.2 Evaluable for objective response
Only those patients who have measurable disease present at baseline, have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. 
Patients on the second course will not be included in this analysis
10.3
STATISTICAL ANALYSES
10.3.1 General Approach
Efficacy will be assessed as the fraction of patients who experience a response and will be reported 
along with confidence intervals. Safety and tolerability will be assessed in a descriptive fashion.
10.3.2 Analysis of Primary Endpoint (s)
The fraction of patients who experience a response will be reported along with 80% and 95% two-
sided confidence intervals.

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10.3.3 Analysis of the Secondary Endpoint (s)
Overall Survival, and progression free survival will be calculated from the on-study date using the 
Kaplan-Meier method. Duration of response will be calculated for responders only, beginning at 
the date a patient is noted to have at least a PR.
Safety and tolerability of LMB-100 + pembrolizumab will be assessed by reporting the grade of 
adverse events noted in each patient and reporting the proportion with grade 3 and grade 4 adverse 
events. The summary of the proportion with grade 3 and 4 adverse events will constitute the main 
analysis of the safety data. In addition, the number of patients who are treated who are unable to 
tolerate the treatment for other than development of adverse events will be reported.
10.3.4 Safety Analyses
Safety and tolerability of LMB-100 + pembrolizumab, will be assessed by reporting the grade of 
adverse events noted in each patient and reporting the proportion with grade 3 and grade 4 adverse 
events. The summary of the proportion with grade 3 and 4 adverse events will constitute the main 
analysis of the safety data. Safety data will be presented in individual listings. Summaries will also 
be prepared. The safety data will consist of the reporting of all adverse events, vital signs, physical 
examination data, and appropriate laboratory safety data.
10.3.5 Baseline Descriptive Statistics
Baseline demographic characteristics will be reported.
10.3.6 Planned Interim Analyses
As indicated in the two-stage design, the number of responses after 12 evaluable have been treated 
will be noted and will be used to determine if enrollment to the second stage of accrual may 
proceed.
10.3.7 Sub-Group Analyses
None
10.3.8 Tabulation of individual Participant Data
None.
10.3.9 Exploratory Analyses
The following are the exploratory analyses which may be undertaken:

To establish the correlation of response with tumor mesothelin expression.

To evaluate correlation of tumor response with tumor PD-L1 expression.

To evaluate changes in the tumor microenvironment following treatment with LMB-
100 followed by pembrolizumab.

To evaluate the utility of serum mesothelin and megakaryocyte potentiating factor 
(MPF) as a biomarkers of tumor response.

To define the pharmacokinetics characteristics of LMB-100 to correlate responses with 
LMB-100 blood levels.

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
To determine the incidence of antibody development at the end of cycles 1 and 2 with 
this combination.

Correlation of incidence of KRAS mutation with mesothelin immunohistochemical 
expression in tumor samples. 

To determine the utility of circulating tumor DNA (ctDNA) and characteristic 
mutations for biomarkers analysis of response in blood, and overall tumor genome 
evolution over the course of treatment. 

To determine if there is association between PD-L1 expression level or mesothelin 
expression level and response, patients will be divided into responders vs. non-
responders and these expression levels will be compared between the two groups using 
an exact Wilcoxon rank sum test. 

To assess changes in circulating immune cell and cytokine levels caused by the 
treatment
Any of the exploratory evaluations which generate quantitative measures will be done using 
descriptive statistics including confidence intervals when appropriate. Any statistical tests 
performed for evaluation of exploratory objectives will be done without formal adjustment for 
multiple comparisons, but in the context of the number of tests performed. 
11
HUMAN SUBJECTS PROTECTIONS 
11.1
RATIONALE FOR SUBJECT SELECTION
LMB-100 is a mesothelin-targeted cytolytic fusion protein (cFP) and has shown preclinical dose-
dependent activity in monotherapy and/or combination in xenografts representing MSLN-positive 
indications (NSCLC, mesothelioma, triple negative breast cancer, gastric cancer, pancreas, 
ovarian, potentially other tumor indications). LMB-100 has shown synergy in laboratory models 
with inhibitors of the PD1 axis. Pembrolizumab is an anit-PD1/PD-L1 inhibitor. The rationale to 
evaluate LMB-100 with pembrolizumab in mesothelin expressing NSCLC patients is to determine 
the effect of the addition of pembrolizumab to LMB-100 therapy. All patients meeting the criteria 
listed in section 2.1 are eligible for enrollment.
11.2
PARTICIPATION OF CHILDREN
There are no dosing or adverse event data are currently available on the use of LMB-100 with 
pembrolizumab in patients <18 years of age; therefore, children are excluded from this study.
11.3
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 11.5), all subjects ≥ age 18 will be offered the opportunity to fill in 
their wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or cognitively 
impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent 
Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment 
of whether an individual has the capacity to provide consent; assistance in identifying and 

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assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint 
a surrogate. 
Please see section 11.6.1 for consent procedure.
11.4
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
11.4.1 Risks from Study Drugs
Patient safety will be managed by careful proactive patient selection prior to study to exclude 
patients at risk from study treatment due to their pre-existing conditions. During the study, safety 
of patients will be proactively managed by protocol-mandated physical examinations, vital signs 
assessments, ECGs, clinical laboratory assessments, and collection of adverse events and their 
assessment. 
The risks of the study include those associated with the study agents as discussed in section 13. 
11.4.2 Blood Collection
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 
11.4.3 Biopsy Collection 
The risks of the research biopsies collected at baseline, Post-C2, and after Pembrolizumab include 
pain, bleeding and infection at the biopsy site. 
11.4.4 CT contrast
In addition to the radiation risks from the scans discussed above, patients may experience an 
allergic reaction to CT contrast dye.  
11.4.5 Radiation Risks
The biopsies referenced above will be collected under CT guidance and subjects will have up to 9 
CTs of the chest/abdomen/pelvis and 9 FDG PET/CT scans in a year. Subjects in this study may 
be exposed to approximately 23.9 rem total. 
11.4.6 Non-Physical Risks of Genetic Research
11.4.6.1 Risk of receiving unwanted information
Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will be 
clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with patients, family members or health care providers.
11.4.6.2 Risk related to possibility that information may be released
This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency 
or trait can be released to members of the public, insurers, employers, or law enforcement agencies. 
Although there are no plans to release results to the patients, family members or health care 
providers, this risk will be included in the informed consent document.
11.4.6.3 Risk to family or relatives
Family members or relatives may or may not want to be aware of familial tendencies or genetic 
risks of disease which may cause anxiety about possible future health problems. As previously 

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noted, patients will be notified of any medically significant and actionable incidental findings. 
Study results will not be shared with patients.
11.5
RISKS/BENEFITS ANALYSIS
Patients with advanced NSCLC are in continuous need of improved therapy options. This is 
especially true for patients where no standard therapy exists such as the patient population that will 
be eligible for this trial. Preclinical data has demonstrated promising anti-tumor efficacy of LMB-
100 in xenograft models in monotherapy and combination therapy. Laboratory studies have further 
demonstrated synergy with PD1/PD-L1 inhibitors. Therefore, LMB-100 + pembrolizumab may 
improve clinical outcome of patients with NSCLC. A number of clinically appropriate strategies 
to minimize risk to patients have been built into the protocol through the means of 
inclusion/exclusion criteria, monitoring strategies, and management guidelines. Overall, the 
potential benefits of mesothelin targeted cFP for NSCLC patients retaining the ability to consent 
and those who lose capacity to consent during the course of the trial outweigh the risks associated 
with the proposed entry-into-human trial with LMB-100 + pembrolizumab 
11.6
CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting.  A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s).  Whether in person or remote, the privacy of 
the subject will be maintained. Consenting investigators (and participant/consent designee, when 
in person) will be located in a private area (e.g., clinic consult room). When consent is conducted 
remotely, the participant/consent designee will be informed of the private nature of the discussion 
and will be encouraged to relocate to a more private setting if needed.  
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document.  When required, witness signature will be 
obtained similarly as described for the investigator and participant.
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures:

Adobe platform (which is not 21 CFR Part 11 compliant); or,  

iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location but is not required.  

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Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) found here.
11.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in section 11.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 11.6. 
12
REGULATORY AND OPERATIONAL CONSIDERATIONS 
12.1
STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, IND 
sponsor and regulatory authorities.  If the study is prematurely terminated or suspended, the 
Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board 
(IRB), and sponsor and will provide the reason(s) for the termination or suspension.  Study 
participants will be contacted, as applicable, and be informed of changes to study visit schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
12.2
QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.

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12.3
CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the National Cancer Institute has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest.
12.4
CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records.
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be stored at the NCI CCR. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by clinical 
sites and by NCI CCR research staff will be secured and password protected. At the end of the 
study, all study databases will be archived at the NCI CCR.
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.

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13
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION
13.1
MESOTHELIN TESTING (NSR DEVICE) 
In order to be eligible for the study, participants are required to have positive mesothelin expression 
in archival tumor tissue, defined as at least 25% of tumor cells expressing mesothelin. Mesothelin 
expression testing is not FDA approved for this purpose; however, it is being used as an in-vitro 
diagnostic device. Validation assays to support the use of the IVD assay have been submitted to 
IND. All of the documentation is in the IND files.
According to 21 CFR 812.3(m), a significant risk device presents a potential for serious risk to the 
health, safety and welfare of a subject and meets the significant risk criteria listed in the table 
below along with the sponsor’s conclusions with regard to the applicability of these criteria to the 
current study. The device has been assessed by the sponsor as non-significant risk per the below. 
Applicable 
to current 
study
Justification
Is an implant 
No 
The mesothelin test is not introduced into the subject 
Is used in supporting or 
sustaining human life 
No 
The device is diagnostic 
Is of substantial 
importance in diagnosing 
mitigating or treating 
disease or preventing 
impairment of human 
health 
No 
While the device is diagnostic, we do not believe it 
presents a potential for serious risk to the health and 
welfare of the subject. The assessment of mesothelin 
positivity is only used in tumors that may not have a 
ubiquitous mesothelin expression and is assessed to help 
to increase the possibility that all persons enrolling on 
the study might derive benefit from therapy. Persons 
that are deemed ineligible to enroll on the basis of this 
test are eligible for studies within TGMB that are not 
reliant on this test. 
Otherwise poses a risk 
No 
Testing will be performed on archival samples or on 
fresh tissue that is collected at screening for 
confirmation of diagnosis. No additional collection of 
tissue will occur for purposes of mesothelin testing. 
Source: Testing will be performed via an IHC assay developed by the NCI Laboratory of 
Pathology.  
13.2
TRUSIGHT ONCOLOGY 500 ASSAY (NSR DEVICE) 
In order to be eligible for the study, participants are required to have a cancer that is not amenable 
to treatment with targeted agents to an EGFR, ALK or ROS1 variant. TruSight Oncology 500 
(TSO 500) is not FDA approved for the purpose of testing for these mutations; however, it is being 
used in this study as a diagnostic device. Validation assays to support the use of the assay have 
been submitted to the IND. All documentation is in the IND files.
According to 21 CFR 812.3(m), a significant risk device presents a potential for serious risk to the 
health, safety and welfare of a subject and meets the significant risk criteria listed in the table 

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below along with the sponsor’s conclusions with regard to the applicability of these criteria to the 
current study. The device has been assessed by the sponsor as non-significant risk per the below. 
Applicable 
to current 
study
Justification
Is an implant 
No 
The TruSight Oncology 500 assay is not introduced into 
the subject 
Is used in supporting or 
sustaining human life 
No 
The device is diagnostic 
Is of substantial 
importance in diagnosing 
mitigating or treating 
disease or preventing 
impairment of human 
health 
No 
While the device is diagnostic, we do not believe it 
presents a potential for serious risk to the health and 
welfare of the subject. EGFR, ALK and ROS1 
variations are assessed to help to increase the possibility 
that all persons enrolling on the study may not be more 
likely to benefit from an alternative therapy outside of 
this study. Persons that are deemed ineligible to enroll 
on the basis of this test may be eligible for other 
standard of care or experimental therapies better suited 
for their tumor type. 
Otherwise poses a risk 
No 
Testing will be performed on archival samples or on 
fresh tissue that is collected at screening for 
confirmation of diagnosis. No additional collection of 
tissue will occur for purposes of mesothelin testing. 
Source: Testing will be performed via an assay developed by the NCI Laboratory of Pathology.  
13.3
LMB-100 (IND #123332)
13.3.1 Source: LMB-100 was transferred to the NIH CC Pharmacy by Selecta Biosciences, the 
drug manufacturer.  For this trial, the drug will be supplied by the NIH CC Pharmacy. 
13.3.2 Mechanism of action
LMB-100 is a novel recombinant anti-mesothelin targeted cytolytic fusion protein (cFP) 
developed for the treatment of patients with solid tumors that express the mesothelin protein. 
Mesothelin is a suitable candidate for targeted therapy due to its very limited expression in 
normal/non-malignant tissue and its high expression in several tumor entities including 
mesothelioma, ovarian cancer, pancreatic cancer, gastric cancer, breast cancer, and lung cancer. 
To target mesothelin, a humanized Fab fragment of the anti-mesothelin antibody SS1 is linked to 
a truncated and de-immunized recombinant 24 kDa fragment of Pseudomonas exotoxin (PE24). 
After binding to mesothelin, the complex is internalized by endocytosis and kills cells by inhibition 
of eukaryotic elongation factor 2 (eEF2), leading to arrest of protein synthesis and secondarily 
triggering cell death by apoptosis or necrosis.
13.3.2.1 Molecular Weight: approximately 73 kDa

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13.3.2.2 Chemical Structure
H1L1 polypeptide structure consisting of one variable heavy chain containing the Pseudomonas 
Exotoxin A moiety and one variable light change held together
13.3.3 Toxicity 
Information in this section is based on clinical studies of tLMB-100.
Toxicities Observed in Participants Receiving LMB-100 Alone or in Combination
System Organ Class
NCI Common Terminology 
Criteria for Adverse Events 
(CTCAE) Term
# of Subjects
% of Subjects
Blood and Lymphatic system 
Disorders
Anemia
36
29.03
Atrial fibrillation
7
5.65
Atrial flutter
1
0.81
Chest pain - cardiac
1
0.81
Myocarditis
1
0.81
Palpitations
4
3.23
Pericardial effusion
8
6.45
Pericardial tamponade
2
1.61
Pericarditis
3
2.42
Cardiac Disorders
Sinus tachycardia
24
19.35
Ear and Labyrinth Disorders
External ear pain
1
0.81
Endocrine Disorders
Hypothyroidism
1
0.81
Eye Disorders
Eye disorders - Other, 
specify
1
0.81
Abdominal distension
2
1.61
Abdominal pain
9
7.26
Gastrointestinal Disorders
Ascites
1
0.81

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System Organ Class
NCI Common Terminology 
Criteria for Adverse Events 
(CTCAE) Term
# of Subjects
% of Subjects
Constipation
5
4.03
Diarrhea
5
4.03
Dry mouth
1
0.81
Dyspepsia
4
3.23
Nausea
29
23.39
Upper gastrointestinal 
hemorrhage
1
0.81
Vomiting
14
11.29
Chills
5
4.03
Edema face
7
5.65
Edema limbs
38
30.65
Fatigue
54
43.55
Fever
25
20.16
General disorders and 
administration site conditions 
- Other, specify
1
0.81
Generalized edema
1
0.81
Irritability
1
0.81
Localized edema
22
17.74
Malaise
1
0.81
Non-cardiac chest pain
6
4.84
General Disorders and 
Administration Site 
Conditions
Pain
10
8.06
Immune System Disorders
Allergic reaction
1
0.81
Immune system disorders - 
Other, specify
1
0.81
Herpes simplex reactivation
1
0.81
Infections and infestations - 
Other, specify
1
0.81
Infections and Infestations
Lung infection
1
0.81
Fall
1
0.81
Injury, Poisoning and 
Procedural Complications
Infusion related reaction
14
11.29
Alanine aminotransferase 
increased
31
25
Alkaline phosphatase 
increased
11
8.87
Aspartate aminotransferase 
increased
47
37.9
Cardiac troponin I increased
5
4.03
CPK increased
5
4.03
Investigations
Creatinine increased
33
26.61

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System Organ Class
NCI Common Terminology 
Criteria for Adverse Events 
(CTCAE) Term
# of Subjects
% of Subjects
Ejection fraction decreased
1
0.81
Investigations - Other, 
specify
1
0.81
Lymphocyte count decreased
54
43.55
Neutrophil count decreased
9
7.26
Platelet count decreased
14
11.29
Thyroid stimulating hormone 
increased
3
2.42
Urine output decreased
1
0.81
Weight gain
42
33.87
Weight loss
3
2.42
White blood cell decreased
21
16.94
Anorexia
23
18.55
Dehydration
5
4.03
Hypercalcemia
1
0.81
Hyperglycemia
1
0.81
Hypernatremia
2
1.61
Hyperuricemia
2
1.61
Hypoalbuminemia
99
79.84
Hypocalcemia
7
5.65
Hypokalemia
8
6.45
Hypomagnesemia
2
1.61
Hyponatremia
49
39.52
Metabolism and Nutrition 
Disorders
Hypophosphatemia
5
4.03
Arthralgia
6
4.84
Arthralgia
6
4.84
Back pain
4
3.23
Flank pain
3
2.42
Generalized muscle 
weakness
3
2.42
Myalgia
33
26.61
Neck pain
1
0.81
Pain in extremity
2
1.61
Musculoskeletal and 
Connective Tissue Disorders
Rhabdomyolysis
1
0.81
Neoplasms Benign, 
Malignant and Unspecified 
(Incl Cysts And Polyps)
Tumor pain
3
2.42
Confusion
2
1.61
Dizziness
12
9.68
Nervous System Disorder
Dysgeusia
1
0.81

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System Organ Class
NCI Common Terminology 
Criteria for Adverse Events 
(CTCAE) Term
# of Subjects
% of Subjects
Headache
8
6.45
Lethargy
1
0.81
Peripheral motor neuropathy
1
0.81
Peripheral sensory 
neuropathy
8
6.45
Presyncope
1
0.81
Somnolence
1
0.81
Syncope
1
0.81
Tremor
1
0.81
Psychiatric Disorders
Insomnia
2
1.61
Acute kidney injury
5
4.03
Renal and Urinary Disorders
Proteinuria
9
7.26
Reproductive System and 
Breast Disorders
Pelvic pain
1
0.81
Allergic rhinitis
1
0.81
Cough
2
1.61
Dyspnea
27
21.77
Hypoxia
5
4.03
Pleural effusion
7
5.65
Pleuritic pain
5
4.03
Pneumonitis
1
0.81
Productive cough
1
0.81
Pulmonary edema
1
0.81
Respiratory failure
1
0.81
Sore throat
2
1.61
Respiratory, Thoracic and 
Mediastinal Disorders
Upper respiratory infection
1
0.81
Alopecia
10
8.06
Dry skin
1
0.81
Periorbital edema
2
1.61
Pruritus
3
2.42
Rash maculo-papular
4
3.23
Skin and Subcutaneous 
Tissue Disorders
Skin and subcutaneous tissue 
disorders - Other, specify
1
0.81
Capillary leak syndrome
11
8.87
Flushing
2
1.61
Hypertension
4
3.23
Hypotension
34
27.42
Vascular Disorders
Thromboembolic event
1
0.81

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13.3.3.1 Risk of Immunogenicity and Potential Safety Impact
LMB-100 may cause the formation of ADAs. These may trigger hypersensitivity reactions or 
immune complex-mediated responses. The development of ADAs to LMB-100, an improved 
cytolytic fusion protein with a humanized targeting moiety directed against mesothelin and a de-
humanized, truncated Pseudomonas exotoxin A is expected to be less likely than SS1P. Clinical 
trials with SS1P have led to the development of neutralizing ADAs in 75% and 88% of patients 
after 1 cycle of therapy, in the IV bolus and continuous infusion trials respectively.(48)
Patients will be monitored at regular intervals for the development of ADAs and cytokines. In 
particular, any clinical signs and symptoms suggestive of a hypersensitivity reaction and/or an 
immune complex-mediated reaction possibly due to ADA formation will be carefully investigated.
13.3.4 Handling
LMB-100 is to be handled following all hazardous precautions. There is no evidence currently 
available to determine the hazardous status of the product. The Clinical Center will exercise 
caution and categorize LMB-100 as a hazardous agent.
13.3.5 Formulation and preparation 
LMB-100 drug product (20 mg/20 mL) is provided for syringe infusion as a sterile, colorless to 
brownish, preservative-free liquid in single-use, 20 mL vials. The nominal fill volume is 20 mL 
and the approximate concentration of LMB-100 recombinant fusion protein in the vials is 1 mg/mL.
13.3.6 Stability and Storage 
13.3.6.1
Stability
Stability tests are ongoing for intact LMB-100 vials.
13.3.6.2
LMB-100 does not contain antimicrobial preservatives and should be used 
immediately after preparing into dosing syringes. If prepared dosing syringes are not used 
immediately, total in-use storage times of prepared syringes for infusion should not 
exceed 24 hours when stored under refrigeration (2°– 8°C).
13.3.6.3
Storage
Store intact vials in the refrigerator (2 – 8°C), protected from light. Do not shake and do not freeze 
drug vials.
LMB-100 should be protected from exposure to direct sunlight during preparation and 
administration.
13.3.7 Administration procedures
Please refer to section 3.2.1.
13.3.8 Incompatibilities 
Pharmacodynamic drug interaction studies have not been conducted. LMB-100 is contraindicated 
in subjects with a history of severe allergic anaphylactic reactions to humanized, chimeric or mouse 
peptides/antibodies or to any components of the product.
Other drugs that require parenteral co-administration (if applicable) should be delivered via 
separate infusion lines and at separate infusion sites and should not be mixed with the study drug.
LMB-100 is compatible with non-DEHP, latex-free, lipid resistant, non-PVC extension sets.

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13.4
PEMBROLIZUMAB (KEYTRUDA®)
13.4.1 Source 
Commercially available pembrolizumab will be supplied by NIH Clinical Center Pharmacy. 
13.4.2 Clinical Supplies Disclosure
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
13.4.3 Toxicity 
The most frequently reported adverse events that were considered by the investigator to be 
“possibly,” “probably,” or “definitely” related to pembrolizumab are displayed below in Table 9. 
The 5 most frequently reported AEs considered drug related by the investigator were fatigue 
(24.2%), pruritus (16.7%), rash (13.8%), diarrhea (12.3%), and nausea (10.9%). 
Table 9. Most Frequently Reported (≥5%) Adverse Events Presented by Decreasing Frequency and 
Considered Drug-Related by the Investigator in Subjects Treated with Pembrolizumab
Reference Safety Dataset for Pembrolizumaba
Preferred Term
N
(%)
Subjects in population 
2799
Fatigue
678
(24.2)
Pruritus
467
(16.7)
Rash 
386
(13.8)
Diarrhea
343
(12.3)
Nausea
304
(10.9)
Arthralgia
281
(10.0)
Decreased appetite
255
(9.1)
Asthenia
218
(7.8)
Hypothyroidism
213
(7.6)
Vitiligo
159
(5.7)
Myalgia
146
(5.2)
Every subject is counted a single time for each applicable row and column.
MedDRA version used is 18.1.

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Reference Safety Dataset for Pembrolizumaba
Preferred Term
N
(%)
Includes all subjects who received at least one dose of MK-3475 in KN001 Part B1, B2, B3, D, C, F1, 
F2, F3; KN002 (original phase), KN006, and KN010.
 Table 10. Serious Adverse Reactions Considered Expected for Pembrolizumab
System/Category
Adverse Reaction (MedDRA Preferred Terms)
NOTE: Adverse reaction term is considered expected for all 
indications unless otherwise noted. Those terms followed by 
parentheses with notations afterward, are expected only in the 
indications noted.
Blood and lymphatic system 
disorders
Anemia (NSCLC Combo Tx, UC)
Hemolytic anemia
Cardiac
Autoimmune myocarditis
Cardiac failure (MEL)
Myocarditis
Endocrine disorders
Adrenal insufficiency
Adrenocortical insufficiency acute
Autoimmune thyroiditis
Hyperthyroidism
Hypophysitis
Hypopituitarism
Hypothyroidism
Lymphocytic hypophysitis
Secondary adrenocortical insufficiency
Thyroid disorder
Thyroiditis
Eye disorders
Autoimmune uveitis
Iridocyclitis
Iritis
Ocular myasthenia
Uveitis

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System/Category
Adverse Reaction (MedDRA Preferred Terms)
NOTE: Adverse reaction term is considered expected for all 
indications unless otherwise noted. Those terms followed by 
parentheses with notations afterward, are expected only in the 
indications noted.
Gastrointestinal disorders
Abdominal discomfort (UC)
Abdominal pain (MEL, UC)
Abdominal pain lower (UC)
Abdominal pain upper (UC)
Autoimmune pancreatitis
Colitis
Colitis microscopic
Constipation (MEL, NSCLC, NSCLC Combo Tx, UC)
Diarrhea
Enterocolitis
Enterocolitis hemorrhagic
Frequent bowel movements (UC)
Gastroenteritis (cHL, UC)
Nausea (MEL, NSCLC, NSCLC Combo Tx, cHL, UC)
Oral lichen planus
Pancreatitis
Pancreatitis acute
Pancreatitis necrotizing
Vomiting (MEL, NSCLC, NSCLC Combo Tx, HNSCC, cHL, UC)
General disorders and administration 
site conditions
Asthenia (MEL, NSCLC, cHL, UC)
Face edema (HNSCC)
Fatigue (MEL, NSCLC, NSCLC Combo Tx, HNSCC, cHL, UC)
Generalized edema (MEL)
Generalized physical health deterioration (MEL)
Malaise (UC)
Edema peripheral (NSCLC Combo Tx, UC)
Pyrexia
Hepatobiliary disorders
Autoimmune hepatitis
Drug-induced liver injury
Hepatic pain (UC)
Hepatitis
Hepatitis acute
Hepatitis fulminant
Hepatitis toxic (UC)
Hyperbilirubinemia (UC)
Liver injury (UC)

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System/Category
Adverse Reaction (MedDRA Preferred Terms)
NOTE: Adverse reaction term is considered expected for all 
indications unless otherwise noted. Those terms followed by 
parentheses with notations afterward, are expected only in the 
indications noted.
Infections and infestations
Gastroenteritis (cHL, UC)
Herpes zoster (cHL)
Pneumonia (NSCLC, HNSCC, cHL, UC)
Rash pustular
Septic shock (cHL)
Sepsis (UC)
Upper respiratory tract infection (NSCLC Combo Tx, cHL)
Urinary tract infection (UC)
Urosepsis (UC)
Immune system disorders
Anaphylactic reaction
Anaphylactoid reaction
Cytokine release syndrome
Drug hypersensitivity
Graft versus host disease (cHL)
Hypersensitivity
Serum sickness
Injury, poisoning and procedural 
complications
Infusion related reaction
Investigations
Alanine aminotransferase increased (UC)
Aspartate aminotransferase increased (UC)
Blood bilirubin increased (UC)
Blood creatinine increased (UC)
Hepatic enzyme increased (NSCLC, UC)
Liver function test increased (UC)
Neutrophil count decreased (NSCLC Combo Tx)
Transaminases increased (UC)
Weight decreased (UC)
Metabolism and nutritional disorders
Decreased appetite (MEL, NSCLC, NSCLC Combo Tx,
HNSCC, UC)
Diabetic ketoacidosis
Fulminant type 1 diabetes mellitus
Hyponatremia (UC)
Latent autoimmune diabetes in adults
Type 1 diabetes mellitus

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System/Category
Adverse Reaction (MedDRA Preferred Terms)
NOTE: Adverse reaction term is considered expected for all 
indications unless otherwise noted. Those terms followed by 
parentheses with notations afterward, are expected only in the 
indications noted.
Musculoskeletal and connective 
tissue disorders
Arthralgia (MEL, NSCLC, NSCLC Combo Tx, cHL, UC)
Arthritis
Back pain (MEL, NSCLC, cHL, UC)
Bone pain (cHL, UC)
Flank pain (UC)
Immune-mediated necrotizing myopathy
Musculoskeletal chest pain (cHL, UC)
Musculoskeletal discomfort (cHL, UC)
Musculoskeletal pain (cHL, UC)
Myalgia (cHL, UC)
Myopathy
Myositis
Neck pain (cHL, UC)
Necrotizing myositis
Pain in extremity (cHL, UC)
Polymyositis
Psoriatic arthropathy
Rhabdomyolysis
Spinal pain (UC)
Neoplasms benign, malignant and 
unspecified (incl cysts and polyps)
Tumor pain (UC)
Nervous system disorders
Axonal neuropathy
Demyelinating polyneuropathy
Diabetic ketoacidotic hyperglycemic coma
Dizziness (NSCLC Combo Tx)
Dysesthesia (cHL)
Dysgeusia (NSCLC Combo Tx)
Guillain-Barré syndrome
Headache (MEL, NSCLC Combo Tx, cHL)
Hypoesthesia (cHL)
Lethargy (UC)
Miller Fisher syndrome
Myasthenia gravis
Myasthenia gravis crisis
Myasthenic syndrome
Myelitis
Neuropathy peripheral (MEL, cHL)
Paresthesia (cHL)
Peripheral sensory neuropathy (cHL)
Polyneuropathy (MEL, cHL)
Psychiatric
Confusional state (HNSCC)
Insomnia (NSCLC Combo Tx)

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System/Category
Adverse Reaction (MedDRA Preferred Terms)
NOTE: Adverse reaction term is considered expected for all 
indications unless otherwise noted. Those terms followed by 
parentheses with notations afterward, are expected only in the 
indications noted.
Renal and urinary disorders
Acute kidney injury (NSCLC Combo Tx, UC)
Autoimmune nephritis
Chromaturia (UC)
Glomerulonephritis
Glomerulonephritis membranous
Hematuria (UC)
Nephritis
Nephrotic syndrome
Tubulointerstitial nephritis
Reproductive system and breast 
disorders
Pelvic pain (UC)
Respiratory, thoracic and mediastinal 
disorders
Cough (MEL, NSCLC, NCSLC Combo Tx, cHL, UC)
Dyspnea (MEL, NSCLC, NSCLC Combo Tx, HNSCC, cHL, UC)
Dyspnea exertional (cHL, UC)
Interstitial lung disease*
Pleural effusion (HNSCC)
Pneumonitis*
Productive cough (cHL, UC)
Respiratory failure (HNSCC)
Wheezing (cHL, UC)

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System/Category
Adverse Reaction (MedDRA Preferred Terms)
NOTE: Adverse reaction term is considered expected for all 
indications unless otherwise noted. Those terms followed by 
parentheses with notations afterward, are expected only in the 
indications noted.
Skin and subcutaneous tissue 
disorders
Acute febrile neutrophilic dermatosis
Dermatitis
Dermatitis acneiform (cHL, UC)
Dermatitis bullous
Dermatitis contact (cHL, UC)
Dermatitis exfoliative
Dermatitis psoriasiform (cHL)
Drug eruption
Drug reaction with eosinophilia and systemic symptoms
Eczema
Eczema asteatotic (cHL, UC)
Erythema (UC)
Erythema multiforme
Lichen planus
Lichenoid keratosis (UC)
Palmar-plantar erythrodysesthesia syndrome
Pemphigoid
Perivascular dermatitis
Pruritus
Psoriasis
Rash
Rash erythematous
Rash generalized
Rash macular
Rash maculo-papular
Rash morbilliform
Rash papular
Rash pruritic
Skin disorder
Skin hypopigmentation (MEL)
Skin necrosis
Skin reaction (UC)
Skin toxicity
Stasis dermatitis
Stevens-Johnson syndrome*
Subacute cutaneous lupus erythematosus
Toxic epidermal necrolysis*
Vitiligo (MEL)
Vascular disorders
Vasculitis

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System/Category
Adverse Reaction (MedDRA Preferred Terms)
NOTE: Adverse reaction term is considered expected for all 
indications unless otherwise noted. Those terms followed by 
parentheses with notations afterward, are expected only in the 
indications noted.
cHL = Classical Hodgkin Lymphoma; MEL = Melanoma; HNSCC = Head and Neck Squamous Cell 
Carcinoma; NSCLC = Non-Small Cell Lung Cancer; NSCLC Combo Tx = Non-Small Cell Lung Cancer 
participants receiving KEYTRUDA in combination with chemotherapy (pemetrexed and carboplatin); and 
UC = Urothelial Carcinoma For the purpose of safety reporting in clinical trials only serious adverse 
reactions are considered expected
*Term also considered expected with fatal outcome
13.4.4 Formulation and preparation 
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg/ 4mL
Solution for Injection
13.4.5 Stability and Storage 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
13.4.6 Administration procedures
Please refer to section 3.2.3.
13.4.7 Incompatibilities 
None
13.4.8 Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the participants and the amount 
remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept.

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14
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15
APPENDICES
15.1
APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, 
no 
complaints, 
no 
evidence of disease.
0
Normal activity. Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
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).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance 
but is able to care for most of 
his/her needs.
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.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated. Death not imminent.
20
Very 
sick, 
hospitalization 
indicated. Death not imminent.
4
100% 
bedridden. 
Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair.
10
Moribund, 
fatal 
processes 
progressing rapidly.
5
Dead.
0
Dead.

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15.2
APPENDIX B: CONTRACEPTION REQUIREMENTS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below) 
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
o
Documented hysterectomy
o
Documented bilateral salpingectomy
o
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
o
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 

A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with two FSH measurements in the postmenopausal range is required. 
o
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
Male Participants:
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to one of the following during the protocol defined time frame in section 2.1.1.12: 

Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent

Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in Table 11 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant.
Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in 
Table 11 during the protocol-defined time frame in section 2.1.2.11. 

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110
Table 11: Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of < 1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing) hormonal contraception
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception
○
Oral 
○
Injectable 
Highly 
Effective 
Methods 
That 
Have 
Low 
User 
Dependency
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant 
●
Intrauterine hormone-releasing system (IUS) 
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for participants
of clinical studies. 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and correctly). 

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15.3
APPENDIX C: IMAGING AND TREATMENT AFTER FIRST RADIOLOGIC EVIDENCE OF 
PROGRESSIVE DISEASE ON PEMBROLIZUMAB
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First 
radiologic 
evidence of PD by 
RECIST 1.1 
Repeat imaging at 
4 to 8 weeks to 
confirm PD.
May continue study 
treatment 
at 
the 
Investigator’s 
discretion 
while 
awaiting confirmatory 
tumor imaging by site 
by iRECIST.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only.
Discontinue treatment
Repeat 
tumor 
imaging confirms 
PD 
(iCPD) 
by 
iRECIST 
per 
Investigator 
assessment
No 
additional 
imaging required.
Discontinue treatment 
(exception is possible 
upon 
consultation 
with Sponsor).
No 
additional 
imaging required.
Not applicable
Repeat 
tumor 
imaging 
shows 
iUPD by iRECIST 
per 
Investigator 
assessment
Repeat imaging at 
4 to 8 weeks to 
confirm PD. May 
occur 
at 
next 
regularly 
scheduled 
imaging visit.
Continue 
study 
treatment 
at 
the 
Investigator’s 
discretion.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only.
Discontinue treatment
Repeat 
tumor 
imaging 
shows 
iSD, iPR, or iCR by 
iRECIST 
per 
Investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue 
study 
treatment 
at 
the 
Investigator’s 
discretion.
Continue 
regularly 
scheduled 
imaging 
assessments.
May 
restart 
study 
treatment if condition 
has improved and/or 
clinically 
stable 
per 
Investigator’s 
discretion. Next tumor 
image 
should 
occur 
according to the regular 
imaging schedule.
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified 
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; 
iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation 
Criteria in Solid Tumors 1.1. 

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15.4
APPENDIX D: SECOND COURSE (RETREATMENT) IMAGING
Tumor imaging must be performed within 28 days prior to restarting treatment with 
pembrolizumab. Investigator assessment with site radiology reading will be used to determine 
eligibility.
The first on-study imaging assessment should be performed at 6 weeks ±7 days) after the restart 
of treatment. Subsequent tumor imaging should be performed every 6 weeks ±7 days or more 
frequently, if clinically indicated.
Per RECIST 1.1, if tumor imaging shows initial PD, tumor assessment should be repeated 4 to 8 
weeks later in order to confirm PD with the option of continuing treatment while awaiting 
radiologic confirmation of progression. Participants who obtain confirmatory imaging do not 
need to undergo scheduled tumor imaging if it is less than 4 weeks later and may wait until the 
next scheduled imaging time point, if clinically stable.
Imaging should continue to be performed until disease progression, the start of a new anticancer 
treatment, withdrawal of consent, death, or investigator discretion, whichever occurs first. Disease 
progression may be confirmed 4 to 8 weeks after the first tumor imaging indicating PD, by the 
Investigator using iRECIST, in clinically stable participants.
In participants who discontinue study treatment, tumor imaging should be performed at the time 
of treatment discontinuation (±4-week window). If previous imaging was obtained within 4 weeks 
prior to the date of discontinuation, then imaging at treatment discontinuation is not mandatory. In 
participants who discontinue study treatment due to documented disease progression, this is the 
final required tumor imaging.
In participants who discontinue study treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging every 6 
weeks ±7 days until either the start of a new anticancer treatment, disease progression, death, or 
the end of the study, whichever occurs first.