Conditions: Mesothelioma
Keywords: Checkpoint Inhibitor Immunotherapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
Background:

Treatment outcomes for people with pleural or peritoneal mesothelioma are often poor. The drug LMB-100 can attack and kill cancer cells. The drug pembrolizumab helps the immune system fight cancer. Together, these drugs might help people with these cancers.

Objective:

To test if pembrolizumab given after LMB-100 shrinks tumors in people with pleural or peritoneal mesothelioma.

Eligibility:

People ages 18 and older with pleural or peritoneal mesothelioma that has not responded to platinum-based therapy

Design:

Participants will be screened with:

Tumor sample. Participants will have a biopsy if one is needed.

Medical history

Physical exam

Blood, heart, and urine tests

X-rays and scans: Participants will lie on a table. A machine will take pictures of the body.

Participants will receive LMB-100 by intravenous (IV) on days 1, 3, and 5 of two 21-day cycles. They will be observed for up to 2 hours after each infusion. They will receive drugs like Benadryl, Tylenol, and Zantac to help with side effects.

Starting with the 3rd cycle, participants will receive pembrolizumab by IV on day 1 of each 21-day cycle for up to 2 years.

Participants will have blood and urine tests, heart tests, and chest x-rays at least once per cycle. They will have scans every 6 weeks.

Participants may opt to provide tumor biopsies before starting the first cycle, after 2 cycles of LMB-100, and after 2 cycles of pembrolizumab.

Participants will a follow-up visit 4-6 weeks after their last drug dose of the study drug. This includes blood and heart tests and scans. They may then have scans every 6 weeks.

Participants will be contacted once a year for follow-up.

Detailed description:
Background:

* LMB-100, and a closely related immunotoxin, SS1P, also targeting mesothelin, have been studied in previous Phase 1 clinical studies for mesothelioma and pancreatic cancer.
* LMB-100 has demonstrated anti-tumor efficacy against several mesothelin expressing tumor models including mesothelioma patient-derived xenografts (PDX) models
* Programmed cell death protein 1 (PD-1) (encoded by the gene Pdcd1) is an Ig superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands
* 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.
* In immune-competent mice bearing human mesothelin expressing tumors local administration of LMB-100 with CTLA-4 blockade eradicates murine tumors by promoting anti-cancer immunity.
* LMB-100 treatment increase cluster of differentiation 8 (CD8)+ T cell infiltration in murine lung adenocarcinoma tumors that express human mesothelin.
* Combination treatment with LMB-100 plus anti-PD1 results in greater anti-tumor efficacy in murine lung cancer model
* Pembrolizumab is an anti PD-1 antibody that has demonstrated responses of long duration in clinical trials and has generally been well-tolerated
* It is hypothesized that the anti-mesothelin immunotoxin LMB-100 followed by pembrolizumab will result in greater anti-tumor efficacy in patients with mesothelioma.

Objectives:

\- To determine the objective response rate of sequential therapy with LMB-100 followed by pembrolizumab in subjects with pleural and peritoneal mesothelioma.

Eligibility:

* Histologically confirmed epithelial or biphasic pleural or peritoneal mesothelioma (with \<50% sarcomatoid component) not amenable to potentially curative surgical resection.
* Subjects must have at least one prior chemotherapy regimen that includes pemetrexed and cisplatin or carboplatin.
* Age greater than or equal to 18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Adequate organ and bone marrow function
* Prior PD1/Programmed death-ligand 1 (PD-L1) inhibitor treatment is prohibited
* Chemotherapy within 4 weeks or radiotherapy within 2 weeks prior to start of study therapy is prohibited.
* Subjects with active central nervous system (CNS) metastasis are excluded
* Subjects with active autoimmune disease for which they had received systemic treatment during the previous 2 years receiving systemic glucocorticoids (excluding daily glucocorticoid-replacement therapy for conditions such as adrenal or pituitary insufficiency) are excluded
* Subjects with active interstitial lung disease, or a history of pneumonitis for which they had received glucocorticoids are excluded

Design:

* This is an open-label, single center phase II study of LMB-100 followed by pembrolizumab in subjects with advanced pleural or peritoneal mesothelioma who have progressed on standard therapies.
* Subjects will receive LMB-100 at the single agent maximum tolerated dose (MTD) on days 1, 3 and 5 of a 21-day cycle for 2 cycles and pembrolizumab 200 mg on day 1 of each subsequent 21-day cycle until disease progression (on or after pembrolizumab) or intolerable toxicity for a maximum of 2 years (unless second course initiated).
* Tumor biopsies will be performed at baseline, at the end of cycle 2 and at the end of cycle 4 to evaluate changes in the tumor immune microenvironment following treatment with LMB-100 and pembrolizumab.
* Up to 35 evaluable subjects will be enrolled

Arms:
arm 1: LMB-100 administered in cycles 1 and 2 + pembrolizumab administered in subsequent cycles.

LMB-100 140mcg/kg Intravenous infusion (IVI), Days 1, 3, 5 in cycles 1, 2. Pembrolizumab 200mg IVI, every (Q) subsequent cycle on Day 1.

Interventions: intervention 1: LMB-100 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Given intravenous (IV) at recommended phase 2 dose (RP2D) on days 1, 3 and 5 of two (2) 21 day cycles. intervention 2: Given intravenous (IV) at approved dose on day 1 of each 21 day cycle, starting with cycle 3, for up to 2 years with the option of a second course for patients meeting criteria.

Protocol document:
Prot_SAP_000.pdf: 
1
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
NIH Protocol #: 18C0136
Version Date: February 16, 2021
NCT Number: NCT03644550
Title: Phase II Study of the Anti-Mesothelin Immunotoxin LMB-100 Followed by 
Pembrolizumab in Malignant Mesothelioma 
NCI Principal Investigator:
Raffit Hassan, M.D.
Thoracic and GI Malignancies Branch (TGMB), CCR, NCI
Building 10, Room 4-5330
9000 Rockville Pike
Bethesda, MD 20892
Telephone: 240-760-6232
E-mail: hassanr@mail.nih.gov
Investigational Agents: 
Drug Name:
LMB-100
Pembrolizumab (Keytruda®)
IND Number:
152907
152907
Sponsor:
Center for Cancer Research
Center for Cancer Research
Manufacturer:
Selecta Biosciences
Merck
Commercial Agents: None


2
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
PRÉCIS 
Background:

LMB-100, and a closely related immunotoxin, SS1P, also targeting mesothelin, have 
been studied in previous Phase 1 clinical studies for mesothelioma and pancreatic cancer. 

LMB-100 has demonstrated anti-tumor efficacy against several mesothelin expressing 
tumor models including mesothelioma PDX models

PD-1 (encoded by the gene Pdcd1) 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

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. 

In immune-competent mice bearing human mesothelin expressing tumors local 
administration of LMB-100 with CTLA-4 blockade eradicates murine tumors by 
promoting anti-cancer immunity.

LMB-100 treatment increase CD8+ T cell infiltration in murine lung adenocarcinoma 
tumors that express human mesothelin.

Combination treatment with LMB-100 plus anti-PD1 results in greater anti-tumor 
efficacy in murine lung cancer model

Pembrolizumab is an anti PD-1 antibody that has demonstrated responses of long 
duration in clinical trials and has generally been well-tolerated

It is hypothesized that the anti-mesothelin immunotoxin LMB-100 followed by 
pembrolizumab will result in greater anti-tumor efficacy in patients with mesothelioma.
Objectives:

To determine the objective response rate of sequential therapy with LMB-100 followed 
by pembrolizumab in subjects with pleural and peritoneal mesothelioma.
Eligibility:

Histologically confirmed epithelial or biphasic pleural or peritoneal mesothelioma (with 
<50% sarcomatoid component) not amenable to potentially curative surgical resection.

Subjects must have at least one prior chemotherapy regimen that includes pemetrexed 
and cisplatin or carboplatin.

Age ≥ 18 years.

ECOG performance status of 0 or 1.

Adequate organ and bone marrow function

Prior PD1/PD-L1 inhibitor treatment is prohibited

Chemotherapy within 4 weeks or radiotherapy within 2 weeks prior to start of study 
therapy is prohibited.


3
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21

Subjects with active CNS metastasis are excluded

Subjects with active autoimmune disease for which they had received systemic treatment 
during the previous 2 years receiving systemic glucocorticoids (excluding daily 
glucocorticoid-replacement therapy for conditions such as adrenal or pituitary 
insufficiency) are excluded

Subjects with active interstitial lung disease, or a history of pneumonitis for which they 
had received glucocorticoids are excluded
Design:

This is an open-label, single center phase II study of LMB-100 followed by 
pembrolizumab in subjects with advanced pleural or peritoneal mesothelioma who have 
progressed on standard therapies.

Subjects will receive LMB-100 at the single agent MTD on days 1, 3 and 5 of a 21-day 
cycle for 2 cycles and pembrolizumab 200 mg on day1 of each subsequent 21-day cycle 
until disease progression (on or after pembrolizumab) or intolerable toxicity for a 
maximum of 2 years (unless second course initiated). 

Tumor biopsies will be performed at baseline, at the end of cycle 2 and at the end of 
cycle 4 to evaluate changes in the tumor immune microenvironment following treatment 
with LMB-100 and pembrolizumab. 

Up to 35 evaluable subjects will be enrolled


4
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
TABLE OF CONTENTS 
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ..............................................................................................10
1
INTRODUCTION..................................................................................................................10
1.1
Study Objectives ........................................................................................................10
1.1.1
Primary Objective ......................................................................................................10
1.1.2
Secondary Objectives.................................................................................................10
1.1.3
Exploratory Objectives...............................................................................................10
1.2
Background and Rationale .........................................................................................11
1.2.1
Hypotheses .................................................................................................................11
1.2.2
Background on Mesothelioma ...................................................................................11
1.2.3
Mesothelin as a target for cancer therapy...................................................................11
1.2.4
LMB-100:...................................................................................................................12
1.2.5
Pembrolizumab...........................................................................................................18
1.2.6
Rationale for Combination Therapy...........................................................................23
1.2.7
Justification for Study Doses......................................................................................25
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT........................................................27
2.1
Eligibility Criteria ......................................................................................................27
2.1.1
Inclusion Criteria........................................................................................................27
2.1.2
Exclusion Criteria.......................................................................................................29
2.1.3
Recruitment Strategies ...............................................................................................31
2.2
Screening Evaluation..................................................................................................31
2.2.1
Screening activities performed prior to obtaining informed consent.........................31
2.2.2
Screening activities performed after a consent for screening has been signed ..........31
2.3
Participant Registration and Status Update Procedures.............................................32
2.3.1
Treatment Assignment Procedures.............................................................................32
3
STUDY IMPLEMENTATION..............................................................................................33
3.1
Study Design ..............................................................................................................33
3.1.1
Schema .......................................................................................................................33
3.1.2
Second Course............................................................................................................34
3.2
Drug Administration ..................................................................................................34


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Version Date:  02/16/21
3.2.1
LMB-100....................................................................................................................34
3.2.2
Pembrolizumab...........................................................................................................37
3.3
Dose Modifications/Delays........................................................................................37
3.3.1
LMB-100....................................................................................................................37
3.3.2
Pembrolizumab...........................................................................................................40
3.4
Study Calendar...........................................................................................................46
3.5
Criteria for Removal from Protocol Therapy and Off Study Criteria........................50
3.5.1
Criteria for removal from protocol therapy................................................................50
3.5.2
Off-Study Criteria ......................................................................................................50
3.6
Clinical Criteria for Early Trial Termination.............................................................50
4
CONCOMITANT MEDICATIONS/MEASURES ...............................................................51
4.1
Permitted Therapy......................................................................................................51
4.2
Prohibited Therapy.....................................................................................................51
5
BIOSPECIMEN COLLECTION ...........................................................................................52
5.1
Correlative Studies for Research/Pharmacokinetic Studies.......................................52
5.1.1
Pharmacokinetic Assessments....................................................................................52
5.1.2
Assessment of anti-drug antibodies (ADAs)..............................................................53
5.1.3
Retrospective Analysis of Mesothelin and PD-L1 Expression in tumor tissue .........54
5.1.4
Mesothelin and Megakaryocyte Potentiating Factor (MPF) Serum Samples............54
5.1.5
Gene expression-based characterization of the immune landscape before and after 
treatment with LMB-100 and pembrolizumab...........................................................55
5.1.6
Tumor Microenvironment Studies Using Multiplex Staining Technologies.............56
5.1.7
Retrospective analysis of MSI status .........................................................................56
5.1.8
Mechanism of Capillary Leak Syndrome (CLS)........................................................56
5.2
Sample Collection Schedule.......................................................................................58
5.3
Sample Storage, Tracking and Disposition................................................................60
5.3.1
Clinical Pharmacology Program ................................................................................60
5.3.2
Leidos Biomedical, Inc. Lab ......................................................................................60
5.3.3
NCI Laboratory of Pathology.....................................................................................61
5.3.4
Laboratory of Dr. Raffit Hassan.................................................................................61
5.3.5
CAT-I Laboratory ......................................................................................................61
5.3.6
Protocol Completion/Sample Destruction..................................................................62


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Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
6
DATA COLLECTION AND EVALUATION......................................................................62
6.1
Data Collection...........................................................................................................62
6.2
Data Sharing Plans .....................................................................................................63
6.2.1
Human Data Sharing Plan..........................................................................................63
6.2.2
Genomic Data Sharing Plan.......................................................................................63
6.3
Response Criteria .......................................................................................................63
6.3.1
Peritoneal Mesothelioma............................................................................................64
6.3.2
Pleural Mesothelioma.................................................................................................69
6.3.3
iRECIST.....................................................................................................................70
6.3.4
Duration of Response.................................................................................................74
6.3.5
Progression-Free Survival..........................................................................................74
6.3.6
Objective Response Rate............................................................................................74
6.4
Toxicity Criteria.........................................................................................................74
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .....74
7.1
Definitions..................................................................................................................74
7.2
OHSRP Office of Compliance and Training / IRB Reporting...................................74
7.2.1
Expedited Reporting...................................................................................................74
7.2.2
IRB Requirements for PI Reporting at Continuing Review.......................................74
7.3
NCI Clinical Director Reporting................................................................................75
7.4
Data and Safety Monitoring Plan...............................................................................75
7.4.1
Principal Investigator/Research Team .......................................................................75
7.4.2
Safety Monitoring Committee (SMC)........................................................................75
8
SPONSOR REPORTING CRITERIA...................................................................................75
8.1
Definitions..................................................................................................................75
8.1.1
Adverse Event ............................................................................................................75
8.1.2
Serious Adverse Event (SAE)....................................................................................76
8.1.3
Events to Be Treated as Adverse Events for Manufacturer Reporting ......................76
8.1.4
Life-threatening..........................................................................................................76
8.1.5
Severity.......................................................................................................................76
8.1.6
Relationship to Study Product....................................................................................77
8.1.7
Overdose.....................................................................................................................77
8.1.8
Events of clinical interest...........................................................................................77


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Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
8.2
Assessment of Safety Events......................................................................................77
8.3
Reporting of Serious Adverse Events ........................................................................78
8.4
Safety Reporting Criteria to the Pharmaceutical Collaborators.................................78
8.4.1
Reported by Sponsor to Manufacturer .......................................................................78
8.4.2
Reported by Study Team to Manufacturer.................................................................80
8.5
Reporting Pregnancy..................................................................................................81
8.5.1
Maternal exposure.....................................................................................................81
8.5.2
Paternal exposure .......................................................................................................81
8.6
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND..............81
9
CLINICAL MONITORING PLAN.......................................................................................81
10
STATISTICAL CONSIDERATIONS...................................................................................82
10.1
Statistical Hypothesis.................................................................................................82
10.2
Sample Size Determination........................................................................................82
10.3
Populations for Analyses............................................................................................83
10.3.1 Evaluable for toxicity.................................................................................................83
10.3.2 Evaluable for objective response: ..............................................................................83
10.4
Statistical Analyses ....................................................................................................83
10.4.1 General Approach ......................................................................................................83
10.4.2 Analysis of the Primary Endpoints.............................................................................83
10.4.3 Analysis of the Secondary Endpoints.........................................................................83
10.4.4 Safety Analyses..........................................................................................................84
10.4.5 Baseline Descriptive Statistics ...................................................................................84
10.4.6 Planned Interim Analyses...........................................................................................84
10.4.7 Sub-Group Analyses ..................................................................................................84
10.4.8 Tabulation of individual Participant Data..................................................................84
10.4.9 Exploratory Analyses.................................................................................................84
11
COLLABORATIVE AGREEMENTS ..................................................................................84
11.1
Clinical Trials Agreement (CTA) ..............................................................................84
12
HUMAN SUBJECTS PROTECTIONS.................................................................................84
12.1
Rationale For Subject Selection.................................................................................84
12.2
Participation of Children............................................................................................85
12.3
Participation of Subjects Unable to Give Consent.....................................................85


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Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
12.4
Evaluation of Benefits and Risks/Discomforts ..........................................................85
12.4.1 Risks from Study Drugs.............................................................................................85
12.4.2 Blood Collection ........................................................................................................85
12.4.3 CT Scans ....................................................................................................................85
12.4.4 Image Guided Biopsy Collection...............................................................................85
12.4.5 Radiation ....................................................................................................................85
12.5
Risks/Benefits Analysis .............................................................................................86
12.6
Consent Process and Documentation.........................................................................86
12.6.1 Request for Waiver of Consent for Screening Activities...........................................87
13
REGULATORY AND OPERATIONAL CONSIDERATIONS ..........................................87
13.1
Quality Assurance and Quality Control .....................................................................87
13.2
Conflict of Interest Policy ..........................................................................................87
13.3
Confidentiality and Privacy........................................................................................87
14
PHARMACEUTICAL INFORMATION..............................................................................88
14.1
LMB-100 (IND # 152907).........................................................................................88
14.1.1 Source.........................................................................................................................88
14.1.2 Toxicity ......................................................................................................................88
14.1.3 Handling.....................................................................................................................90
14.1.4 Formulation and preparation......................................................................................90
14.1.5 Stability and Storage ..................................................................................................90
14.1.6 Administration procedures.........................................................................................91
14.1.7 Incompatibilities.........................................................................................................91
14.2
Pembrolizumab...........................................................................................................93
14.2.1 Source.........................................................................................................................93
14.2.2 Clinical Supplies Disclosure ......................................................................................93
14.2.3 Toxicity ......................................................................................................................93
14.2.4 Formulation and preparation....................................................................................108
14.2.5 Stability and Storage ................................................................................................108
14.2.6 Administration procedures.......................................................................................108
14.2.7 Incompatibilities.......................................................................................................108
14.2.8 Returns and Reconciliation ......................................................................................109
15
REFERENCES.....................................................................................................................110


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Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
16
APPENDICES......................................................................................................................114
16.1
Appendix A: Performance Status Criteria................................................................114
16.2
Appendix B: Contraception Requirements ..............................................................115
16.3
Appendix C: Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease on Pembrolizumab......................................................................................117
16.4
Appendix D: Second Course (Retreatment) Imaging ..............................................118


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Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective

To determine the objective response rate of sequential therapy with LMB-100 followed 
by pembrolizumab in subjects with pleural and peritoneal mesothelioma.
1.1.2
Secondary Objectives

Safety of sequential administration of pembrolizumab following LMB-100

To determine the duration of response, progression free survival and overall survival.
1.1.3
Exploratory Objectives

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 
and pembrolizumab.

To evaluate the utility of serum mesothelin and megakaryocyte potentiating factor as a 
biomarkers of tumor response.

To define the pharmacokinetics characteristics of LMB-100 in order to correlate 
responses with LMB-100 blood levels

To determine the incidence of antibody development at the end of cycles 1 and 2 with 
this combination 

To evaluate MSI status in participants demonstrating objective response

To determine the mechanism of capillary leak syndrome (CLS)


11
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
1.2
BACKGROUND AND RATIONALE
1.2.1
Hypotheses 

Anti-mesothelin immunotoxin LMB-100 followed by pembrolizumab will result in 
greater anti-tumor efficacy in subjects with mesothelioma by augmenting anti-tumor 
immunity. 

LMB-100 will induce tumor inflammation that leads to recruitment of CD8+ cells in the 
tumor and administration of pembrolizumab will increase the efficacy of these cytotoxic 
T cells.
1.2.2
Background on Mesothelioma
Mesothelioma is a neoplasm originating from the mesothelial cells lining human body cavities. 
Mesothelioma may involve the pleura and less frequently, the peritoneum. Approximately 3000 
new cases are diagnosed every year in the US alone. The epithelioid variant is the most common, 
comprising about 60 percent of all mesotheliomas. Malignant pleural mesothelioma is an 
aggressive disease with poor prognosis. Although patients with a limited tumor burden may 
benefit from surgical resection, most patients have advanced disease at diagnosis and are not 
candidates for cytoreductive surgery.[1] For patients who are not eligible for curative surgery, the 
median survival with supportive care alone is 6 months whereas with the current standard 
treatment, a combination of cisplatin and pemetrexed, the median survival is 12 months.[2] 
Peritoneal mesothelioma represents about one-fifth to one-third of all forms of mesothelioma; 
there are approximately 400 new cases in the United States each year.[3] Cytoreductive surgery 
and hyperthermic perioperative chemotherapy is the accepted initial management for suitable 
patients with peritoneal mesothelioma.[4-7] Peritoneal mesothelioma patients with surgically 
unresectable disease or whose medical co-morbidities preclude surgery are considered for 
palliative systemic therapy. Due to its relatively low incidence and inherent difficulties of 
radiologic assessment, few studies of systemic therapy have been conducted. Treatment 
recommendations are often extrapolated from pleural mesothelioma and outcomes are poor. 
1.2.3
Mesothelin as a target for cancer therapy
Mesothelin is a glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein, which is 
present in a restricted set of normal adult tissues, such as the mesothelial lining of the pleura, 
peritoneum and pericardium.[8] 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 non-small cell lung cancer (NSCLC).[9] 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.[10]
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.[11] The Laboratory of Molecular Biology (LMB) and the 


12
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute 
have pioneered the use of mesothelin- targeted agents and clinical trials over the last decade.
1.2.4
LMB-100: 
Recombinant immunotoxins 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.[12] It has anti-tumor efficacy against 
several mesothelin expressing tumor models including mesothelioma PDX models.[13] Phase I 
clinical trial of LMB-100 has been completed at NCI and we have established the MTD, which 
will be used in combination studies with pembrolizumab. 
1.2.4.1
Rationale for the development of LMB-100
The clinical use of SS1P, and of immunotoxins in general, has been hampered mainly by their 
high immunogenicity which limits the number of effective treatment cycles that patients can 
receive. LMB-100 (see Figure 1 for structure) is a next generation PE-fusion protein that has 
been protein-engineered to maximally reduce its immunogenicity by:
1. Using a fully humanized Fab fragment derived from the anti-mesothelin antibody SS1 for 
tumor targeting
2. Substituting the bulk of domain II (residues 251–273 and 284–394 of native PE) by an 
extended furin cleavable linker whose sequence is devoid of any T cell neo-epitopes
3. Deimmunizing domain III of PE, which has the catalytic activity for ADP-ribosylation by 
introducing 7 point mutations that silence B- and T-cell epitopes
Classical PE-based immunotoxins, such as SS1P, contain a 38 kD fragment of the exotoxin 
encompassing the so-called translocation domain II and the catalytic domain III. Omission of the 
domain II from LMB-100 has not only removed a highly immunogenic 14 kD portion of PE that 
contains the main T-cell epitopes,[14] but has also resulted in reduced incidents of CLS in animal 
models of CLS.[15]
1.2.4.2
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 kD 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.[15, 16] 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. 


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Abbreviated Title: LMB-100 plus pembrolizumab
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Figure 1. Structural models of SS1P and its de-immunized variants SS1P-LR and LMB-100 are shown. 
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. 
1.2.4.3
Nonclinical Studies
1.2.4.3.1 Nonclinical Pharmacology
In vitro LMB-100 inhibited viability of a variety of mesothelin-positive cancer cell lines 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 
untransfected 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.[12, 17] 
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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Abbreviated Title: LMB-100 plus pembrolizumab
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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.
1.2.4.3.2 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. Toxico-kinetics 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.
1.2.4.3.3 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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Abbreviated Title: LMB-100 plus pembrolizumab
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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 µg·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 
µg·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.
1.2.4.4
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 


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Abbreviated Title: LMB-100 plus pembrolizumab
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participants treated had moderately to strongly positive MSLN expression as measured by central 
IHC analysis. 
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 1). 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 1. 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
1.2.4.4.1 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. 


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Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
1.2.4.5
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 
these 21 patients 12 had peritoneal mesothelioma and 9 pleural mesothelioma; 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.
1.2.4.5.1 Pharmacokinetics of LMB-100:
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. PK analysis for the 10 patients 
treated with single agent LMB-100 is shown in Table 2 below. 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.
As shown in Table 2, all 10 patients had good LMB-100 blood levels during cycle 1. However, 
only 5 of 10 patients had good blood levels during cycle 2. None of the 8 patients who got cycle 
3 and 4 of LMB-100 had good LMB-100 blood levels during cycle 3 or 4.


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Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
Table 2. Decrease in LMB-100 Exposure Over Time
C1D1
C2D1
C3D1
C4D1
Patient
Dose 
(µg/kg)
Cmax 
(ng/mL)
Dose 
(µg/kg)
Cmax 
(ng/mL)
Dose 
(µg/kg)
Cmax 
(ng/mL) 
Dose 
(µg/kg)
Cmax 
(ng/mL)
1
170
1991
140
1091 
140
21
140
21
2
170
2286
140
297
140
70
140
21
3
170
2760
140
4.4
140
BQL
140
BQL
4
140
1054
140
681
140
BQL
140
BQL
5
140
1124
140
BQL
140
‒
140
‒
6
140
2584
140
1099
140
BQL
140
BQL
7
140
3118
140
2450
140
BQL
140
BQL
8
140
1721
140
BQL
140
BQL
140
BQL
9
140
1526
140
27.8
140
20
140
BQL
10
140
2689
140
5.1
140
N/A
140
N/A
* BQL: below assay’s quantifiable limit (2.1 ng/mL); ‒ Because of disease progression patient did not receive cycle 
3 and 4; N/A: data not available
Note: Anti-drug (LMB-100) antibodies (ADAs) were measured pre-dose on C1D1. Inhibition percentages 41.8% 
indicate presence of pre-existing ADAs
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.
1.2.5
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. 


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Abbreviated Title: LMB-100 plus pembrolizumab
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1.2.5.1
Pharmaceutical and Therapeutic Information 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades.[18] Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such 
as melanoma.[19, 20]
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).[21, 22]
The structure of murine PD-1 has been resolved.[23] 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 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.[22, 24-26] 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.[27, 28] As a consequence, the PD-1/PD-L1 pathway is an attractive target for 
therapeutic intervention in mesothelioma. 
1.2.5.2
Preclinical and Clinical Trial Data
1.2.5.2.1 Preclinical Studies
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.


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Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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.B17 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.[29, 30] A point mutation (S228P) in the core hinge region in IgG4 has been shown to be 
sufficient to prevent the Fab-arm exchange.[29, 30] 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.
Assessment of Effects of PD-1 Blockade as Monotherapy and in Combination with 
Chemotherapy in Mouse Syngeneic Tumor Models
Antimouse 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. Antimouse 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 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 antimouse 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 antimouse 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 antimouse PD-1 J43 
surrogate antibody in combination with gemcitabine also showed enhanced efficacy in the mouse 
MC38 colon adenocarcinoma tumor model.
1.2.5.2.2 Clinical Investigations
Pharmacokinetics


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Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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).[31-33] 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.[31]
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.
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 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, 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, 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 


22
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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.
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 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. In previously treated participants with PD-L1 TPS ≥1% and 
disease progression following platinum-containing chemotherapy, pembrolizumab provided a 
statistically significant and clinically meaningful OS benefit compared to standard docetaxel 
chemotherapy. For participants with previously untreated metastatic NSCLC whose tumors 
express high levels of PD-L1, pembrolizumab demonstrated significant improvements in PFS 
and OS over standard of care chemotherapy.


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Pembrolizumab in combination with pemetrexed/carboplatin for the first-line treatment of 
metastatic nonsquamous NSCLC demonstrated both a statistically significant and clinically 
meaningful difference in ORR and a statistically significant benefit in PFS compared with 
pemetrexed/carboplatin alone.
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 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 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 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.[34, 35]
1.2.6
Rationale for Combination Therapy
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. Surviving 


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mice were protected from tumor re-challenge by 66C14 cells not expressing mesothelin, 
indicating the development of anti-tumor immunity.
Figure 2: LMB-100 and anti-CTLA-4 produces complete remissions but inactive LMB-100 (LMB-100-I) 
does not.
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 i.p. 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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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 
1.2.7
Justification for Study Doses
1.2.7.1
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 cycles of LMB100 will be administered as it is anticipated that a majority of patients 
will develop neutralizing antibodies after 2 cycles of treatment. 
1.2.7.2
Pembrolizumab


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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 participants 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 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.
Summary
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. Based on clinical trials of pembrolizumab in subjects with treatment 


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Abbreviated Title: LMB-100 plus pembrolizumab
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refractory pleural mesothelioma that show a response rate of 20% we propose a clinical trial of 
this combination to determine if administration of LMB-100 can improve the response rates seen 
with pembrolizumab alone i.e. improve response rate from 20% to 40%. Since the anti-tumor 
efficacy of pembrolizumab in patients with peritoneal mesothelioma is not know we have 
separated these patients into a separate cohort to get preliminary estimates of anti-tumor activity 
of this combination in this patient population.
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: 
2.1.1.2.1 Cohort 1: Histologically confirmed epithelial or biphasic pleural mesothelioma (with 
<50% sarcomatoid component) not amenable to potentially curative surgical resection. 
The diagnosis will be confirmed by the Laboratory of Pathology, CCR, NCI.
OR
2.1.1.2.2 Cohort 2: Histologically confirmed epithelial or biphasic peritoneal mesothelioma 
(with <50% sarcomatoid component) not amenable to potentially curative surgical 
resection. The diagnosis will be confirmed by the Laboratory of Pathology, CCR, NCI.
2.1.1.3
Have provided archival tumor tissue sample or newly obtained 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.
Note: If submitting unstained cut slides, newly cut slides should be submitted to the 
testing laboratory within 14 days from the date slides are cut. 
2.1.1.4
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.
2.1.1.5
Subjects must have at least one prior chemotherapy regimen that includes pemetrexed 
and cisplatin or carboplatin.
2.1.1.6
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. 
2.1.1.7
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.
2.1.1.8
Must have left ventricular ejection fraction >50%.
2.1.1.9
Must recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. 
Participants with ≤Grade 2 neuropathy may be eligible. If participant received major 
surgery, they must have recovered adequately from the toxicity and/or complications 
from the intervention prior to starting study treatment.
2.1.1.10 Must have recovered from all radiation-related toxicities, not require corticosteroids, 
and not have had radiation pneumonitis. A 1-week washout is permitted for palliative 
radiation (≤2 weeks of radiotherapy) to non-CNS disease.
2.1.1.11 If participant received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting study treatment.


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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:
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 The participant provides written informed consent for the trial.
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
Has severe hypersensitivity (≥Grade 3) to pembrolizumab, LMB-100 and/or any of 
their excipients.
2.1.2.4
Subjects who have received prior therapy with LMB-100, an anti-PD-1, anti-PD-L1, or 
anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-
cell receptor (e.g., CTLA-4, OX-40, CD137).
2.1.2.5
Has received prior systemic anti-cancer therapy including investigational agents within 
4 weeks prior to start of study therapy.
2.1.2.6
Has received prior radiotherapy within 2 weeks of start of study treatment. 
2.1.2.7
Has had a prior pneumonectomy
2.1.2.8
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, 


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Abbreviated Title: LMB-100 plus pembrolizumab
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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.
2.1.2.9
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. 
2.1.2.10 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. 
2.1.2.11 Has a history of (non-infectious) pneumonitis/interstitial lung disease(ILD) that 
required steroids or has current pneumonitis/ILD
2.1.2.12 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. 
2.1.2.13 Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
2.1.2.14 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.
2.1.2.15 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. 
2.1.2.16 Has a known history of Human Immunodeficiency Virus. 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)
2.1.2.17 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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Abbreviated Title: LMB-100 plus pembrolizumab
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2.1.2.18 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.
2.1.2.19 Has an active infection requiring systemic therapy.
2.1.3
Recruitment Strategies
Information about the study will be posted on NIH sites such as clinicaltrials.gov and the CCR 
recruitment website. The study will also be publicized on various NIH social media platforms. 
Subjects will also be drawn from patients seen at the mesothelioma clinic at the NIH Clinical 
Center as well as from referrals from outside providers. 
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
A waiver of consent for these activities has been requested in section 12.6.1.
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 study consent OR 
the consent for study 01-C-0129 (provided the procedure is permitted on that study) on which 
screening activities may also be performed. 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. 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. Note: with the exception of collection of fresh biopsy, this activity 
is covered under the waiver referenced above and may be performed prior to obtaining 
consent.
Performed within 28 days prior to start of study therapy or, if applicable, second course


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
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)

FDG-PET scan

Urinalysis
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 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 the 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
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Pleural mesothelioma
Up to 12 or up to 25 (depending on interim analysis) 
evaluable subjects with pleural mesothelioma
2
Peritoneal mesothelioma
Up to 6 or up to 10 (depending on interim analysis) evaluable 
subjects with peritoneal mesothelioma
Arms
Number
Name
Description
1
LMB-100+pembrolizumab
LMB-100 administered in cycles 1 & 2 + pembrolizumab 


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Abbreviated Title: LMB-100 plus pembrolizumab
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administered in subsequent cycles 
Stratifications, Randomization and Arm Assignment
No stratification or randomization will occur on the study.
Subjects in Cohort 1 will be directly assigned to Arm 1. If 3 or more subjects among the first 12 
enrolled have an objective response, 13 additional evaluable subjects will be enrolled. 
Subjects in Cohort 2 will be directly assigned to Arm 1. If 1 or more subjects among the first 6 
enrolled have an objective response, 4 additional evaluable subjects will be enrolled.
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 pleural or peritoneal mesothelioma who have progressed on standard 
therapies. Patients will receive LMB-100 only at the single agent MTD, 140 mcg/kg*, on days 1, 
3 and 5 of a 21-day cycle for the first two cycles. Regardless of tumor response (CR/PR, SD, PD) 
after LMB-100 monotherapy, if conditions in section 3.3.2.1 are met, 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. Cycle 3 dosing will not be initiated until LMB-100 related toxicities have resolved to grade 
1 or better; however, if the initiation of cycle 3 is delayed for more than 4 weeks, the patient will 
be removed from study therapy.
If needed a dose level below the single agent MTD of LMB-100 will be explored.
Tumor biopsies will be performed at baseline, at the end of cycle 2 and at the end of cycle 4 to 
evaluate changes in the tumor immune microenvironment following treatment with LMB-100 
and 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 100kg.


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3.1.1
Schema
3-week cycles; Response evaluation every 2 cycles; biopsy at baseline, at the end of cycle 2 and at the end of 
cycle 4. Pembrolizumab may continue for a maximum of 2 years. 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.
Cycles 1 & 2
Cycle 3 
onwards
3.1.2
Second Course
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


35
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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 (QOD× 3) 
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 be under 
close supervision of the investigator or delegate at all times. 
The compatibility and stability of the active ingredient was tested under simulated 
preparation/administration conditions.
3.2.1.1
Preparation 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 appropriate 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 


36
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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.
 
Figure 5. 
Schematic view of the administration set-up.
The LMB-100 drug product should be filtered using an in-line filter as depicted. 
If using a peripheral IV, the IV line should remain in place for 2 hours after the end of the 
infusion. If no infusion related symptoms occur during this time, the infusion line may be 
removed. For subsequent infusions and if no IRR has been reported, the IV line 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. 


37
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
During infusion, vital signs (including, if possible, supine diastolic and systolic blood pressure, 
pulse rate, and temperature) must be monitored pre-infusion, every 15 minutes (± 5 minutes) until 
the end of the infusion, and thereafter, every 30 minutes (± 10 minutes) until the infusion line is 
removed. 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 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.
3.2.1.3
Premedications 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 3. Premedication for LMB-100
Dose (mg)
Route
Acetaminophen
650
Orally
Ranitidinea
150
Orally
Diphenhydramineb
25-50
Orally or IV
a or alternative H2 blocker at an adequate dose 
b or alternative antihistamine at an adequate dose.
(See section 3.3.1 for complete instructions on response to IRRs)
3.2.2
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 3.3.2.1 are met) for up to 2 years unless criteria for removal from therapy 
(3.5.1) are met. Note: As indicated in section 3.1.2, 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). 
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.


38
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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 conditions (such as 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 4. The table also provides guideline on how to manage some 
toxicities anticipated with LMB-100. 
Table 4. 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


39
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
Event
Action to Be Taken
Capillary leak syndrome
In the event of Grade ≥2 CTCAE capillary leak syndrome 
(medical 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 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
o
In the event of pleuritis resulting in mild to severe 
pleuritic pain, treat with analgesics or steroids as 


40
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
Event
Action to Be Taken
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
3.3.2
Pembrolizumab
3.3.2.1
Dose delays
Cycle 3 day 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.
3.3.2.2
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 5.


41
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
Table 5: 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 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, 
or 
recurrent 
Grade 2
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg 
prednisone 
or 
equivalent) 
followed by taper

Monitor participants for 
signs and symptoms of 
pneumonitis

Evaluate participants with 
suspected 
pneumonitis 
with radiographic imaging 
and initiate corticosteroid 
treatment

Add 
prophylactic 
antibiotics 
for 
opportunistic infections
Diarrhea 
/ 
Colitis 
Grade 2 or 3
Withhold

Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg 
prednisone 
or 
equivalent) 
followed by taper

Monitor participants for 
signs and symptoms of 
enterocolitis (i.e., diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 


42
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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 
Grade 4
Permanently 
discontinue
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
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) 


43
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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 
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
Intolerable/ 
persistent 
Grade 2
Withhold
Grade 3
Withhold 
or 
discontinue 
based 
on 
the 
type of event. 
Events 
that 
require 
discontinuation 
include and not 
limited 
to: 
Gullain-Barre 
Syndrome, 
encephalitis
All 
other 
immune-related 
AEs
Grade 
4 
or 
recurrent 
Grade 3 
Permanently 
discontinue

Based on type and 
severity 
of 
AE 
administer 
corticosteroids 

Ensure 
adequate 
evaluation 
to 
confirm 
etiology and/or exclude 
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). 


44
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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 6. 
Table 6: 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
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
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).
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 
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
No subsequent dosing


45
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
initial 
improvement; 
hospitalization indicated 
for 
other 
clinical 
sequelae 
(e.g., 
renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
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.
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 interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should be 
placed back on study therapy within 3 weeks of the scheduled interruption. The reason for 
interruption should be documented in the patient's study record.


46
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
3.4
STUDY CALENDAR
1 cycle =21 days
Screening assessments will occur within 28 days prior to start of study therapy unless otherwise indicated. If screening assessments 
are performed within 3 days prior to dosing, 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 after may be delayed up to three weeks for the same reasons; however, cycle 3 
may be delayed for longer as described in section 3.3.2.1.
Cycles 1 & 2
Subsequent Cycles 
(for a maximum of 2 
years after initial 
pembrolizumab therapy 
and, if applicable, 
through second course)15
Procedure
Scree
ning
Da
y 1
Da
y 3
Da
y 4
Da
y 5
Da
y 8
Day 
1514
Day 1
Safety Follow-
Up Visit (~30 
days after 
completion of 
study 
therapy)16
Safety Follow-
Up Visit (~ 90 
days after 
completion of 
study 
therapy)16
Long-Term 
Follow Up 
(every 6 – 12 
weeks)17
LMB-100
X
X
X
Pembrolizumab
X
History and PE
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
Height
X
Vital signs1
X
X
X
X
X
X
X
X
X
Performance 
Score
X2
X
X
Labs3
X4
X5
X
X
X
X
X
X
X
Urinalysis
X
X
X


47
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
Cycles 1 & 2
Subsequent Cycles 
(for a maximum of 2 
years after initial 
pembrolizumab therapy 
and, if applicable, 
through second course)15
Procedure
Scree
ning
Da
y 1
Da
y 3
Da
y 4
Da
y 5
Da
y 8
Day 
1514
Day 1
Safety Follow-
Up Visit (~30 
days after 
completion of 
study 
therapy)16
Safety Follow-
Up Visit (~ 90 
days after 
completion of 
study 
therapy)16
Long-Term 
Follow Up 
(every 6 – 12 
weeks)17
Urine 
albumin/creatin
ine ratio
Days1-6 (+4 days if patient still in 
hospital)
HLA 
Typing 
(Class I and 
Class II)
X6
Urine or serum 
hCG in women 
of childbearing 
potential7
X8
X8
X
X
X
Confirmation 
of dx9
X
NIH Advance 
Directives 
Form
X10
Biopsy 
(optional)
X6
C3 and C5 1st course only
Correlative 
Research 
Studies 
Please see section 5.2
CT CAP and/or 
MRI11
X
Every2 cycles ± 7 days
X12
X12
X


48
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
Cycles 1 & 2
Subsequent Cycles 
(for a maximum of 2 
years after initial 
pembrolizumab therapy 
and, if applicable, 
through second course)15
Procedure
Scree
ning
Da
y 1
Da
y 3
Da
y 4
Da
y 5
Da
y 8
Day 
1514
Day 1
Safety Follow-
Up Visit (~30 
days after 
completion of 
study 
therapy)16
Safety Follow-
Up Visit (~ 90 
days after 
completion of 
study 
therapy)16
Long-Term 
Follow Up 
(every 6 – 12 
weeks)17
FDG-PET
X
Every 2 cycles ± 7 days
X12
X12
X
ECG13
X
X
X
X
X
X
X
Echocardiogra
m
X
Adverse Events
Monitored continuously
Concomitant 
Medications
Monitored continuously
Telephone/ema
il follow-up q 3 
months
X
1
At screening: heart rate, blood pressure, body temperature, pulse oximetry. During the infusions of LMB-100 in Cycle 1, vital signs (heart 
rate, blood pressure, body temperature) must be monitored pre-infusion and every 15 minutes (± 5 minutes) during the infusion and then every 
30 minutes (± 10 minutes) from the end of the infusion until the infusion line is removed. 
2
Performed within 7 days prior to start of study therapy
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, TSH, 
free T4, total T3.
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).


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Abbreviated Title: LMB-100 plus pembrolizumab
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8
Performed within 3 days prior to start of study therapy. Must be repeated on C1D1 (pre-treatment) if more than 72 hours have passed since 
screening assessment and actual treatment initiation.
9
Please see section 2.2 for tissue requirements
10
As indicated in section 12.3, all subjects will be offered the opportunity to complete an NIH advance directives 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
MRIs are only performed for clinical reasons on this study. Under those circumstances, gadolinium is used only if clinically indicated.
12
Performed only if patient removed from study therapy for reason other than progressive disease on pembrolizumab
13
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.
14
Day 15 laboratory assessments may be performed outside of NIH. History may be performed remotely, and physical exam is only required in 
subjects seen at NIH.
15
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.
16
Follow up visit will occur within +/- 1 week of indicated time. 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. 
17
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


50
Abbreviated Title: LMB-100 plus pembrolizumab
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3.5
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.
3.5.1
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 3.1.2. 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 4.2)

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 
3.5.2
Off-Study Criteria

Screen failure

Investigator decision to end the study

Participant requests to be withdrawn from study

Study drug no longer available

Lost to follow up

Death
3.6
CLINICAL CRITERIA FOR EARLY TRIAL TERMINATION
This is a sequential study of LMB-100 followed by Pembrolizumab. The single agent maximum 
tolerated dose of both agents has been previously established in phase I studies. Although the 
half-life of LMB-100 is less than 1 hour and we do not expect any LMB-100 present in the blood 
when pembrolizumab is initiated (at least 16 days from last dose of LMB-100), we have put the 
following safety parameters in place in case pre-administration of LMB-100 increases toxicity of 
pembrolizumab.  
If any of the following occur, enrollment of new patients will be halted until the association with 
treatment is fully established and mitigation strategies are put in place.


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Abbreviated Title: LMB-100 plus pembrolizumab
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1. Any grade 5 toxicity related to treatment.
2. Any new grade 3 or 4 toxicity not previously associated with pembrolizumab.
3. Increased incidence of adverse events known to be associated with pembrolizumab 
Mitigation strategies will be submitted as amendments to the FDA and IRB.  Should the 
regulatory bodies approve the amendment, the study will resume enrollment. 
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
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.
4.2
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:

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. 


52
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21

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.
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
BIOSPECIMEN COLLECTION
5.1
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES
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 
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 NCIBloodcore@mail.nih.gov.
Upon arrival in the CPP the following procedures should be followed:


53
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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 the below address for analysis.
Leidos Biomedical, 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 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. 
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 the below address for analysis.
Leidos Biomedical, Inc.


54
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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 and PD-L1 Expression in tumor tissue
IHC analysis will be performed by the Laboratory of Pathology at NCI to determine mesothelin 
and anti PL-L1 expression within the tumor at any time after study enrollment. Leftover tissue 
from archival specimens or tumor biopsies obtained at screening or from optional collections at 
baseline, C3D1 and C5D1 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 2, ideally 4 core biopsies will be obtained 
at each time point (baseline and after cycle 1). Fine needle aspiration and 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 into a 3.5-mL 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).


55
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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 above, optional tumor biopsies will be performed in consenting patients when 
deemed feasible at the following time points: before initiation of therapy (archival tissue may 
also be used), at the end of cycle 2 and at the end of cycle 4. We will evaluate tumor 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 


56
Abbreviated Title: LMB-100 plus pembrolizumab
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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
Tumor Microenvironment Studies Using Multiplex Staining Technologies
As referenced above, optional tumor biopsy will be performed in consenting patients when 
deemed feasible at the following time points: before initiation of therapy (archival tissue may 
also be used) and after two cycles of therapy. Portions of the tumor tissue collected at both 
timepoints and stored in the Hassan lab (see section 5.1.5) will be provided to the CAT-I, the 
laboratory of Dr. Ronald Germain. The tissue will be analyzed for cancer associated immune 
biomarker alterations including the immune cell and tumor cell co-localization with confocal 
microscopy and histo-cytometry. The CAT-I lab will return confocal images and quantitative 
analyses of these images in figure format to the Hassan lab. 
Samples will be coded in the laboratory of Dr. Raffit Hassan and sent to CAT-I for imaging 
studies using multiplex staining technologies. The code key will be retained by individuals in the 
Hassan laboratory and will not be provided to members of the CAT-I lab.
5.1.7
Retrospective analysis of MSI status 
Retrospective DNA analysis for microsatellite instability (MSI) will be performed in subjects 
that demonstrate either partial or complete response. The analysis will be performed by the 
Laboratory of Pathology at NCI to determine MSI status within the tumor once the best overall 
response for a participant has been determined. Leftover tissue from archival specimens or tumor 
biopsies obtained at screening or from optional collections referenced above may be used for this 
purpose. 
5.1.8
Mechanism of Capillary Leak Syndrome (CLS)
We hypothesize that treatment with LMB-100 damages proximal tubule cells of the kidney 
which then lose their ability to efficiently recycle albumin. This results in a fall in serum albumin 
and edema. To test this hypothesis, we will document proximal tubule damage by measuring 
KIM-1 in urine and document albumin loss by measuring the albumin to creatinine ratio in urine. 
KIM-1 levels will also be measured in blood.
5.1.8.1
Sample Collection
Urine will be collected at the timepoints indicated in section 5.2 
No additional samples will be collected for measurement in blood. Leftover frozen blood 
samples collected for other research purposes will be used.
5.1.8.2
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.


57
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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.
Urine samples must be frozen within 2 - 4 hours of collection. 
5.1.8.3
Sample Analysis
Samples will be batched and shipped per instructions provided by the vendor and study team to 
Pacific Bio, a commercial laboratory, for analysis.. 


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Abbreviated Title: LMB-100 plus pembrolizumab
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5.2
SAMPLE COLLECTION SCHEDULE
PK
(5.1.1)
ADA
(5.1.2)
Tumor Samplea
(5.1.3,5.1.5,5.1.6,5.1.7)
Serum 
mesothelin 
and MPF
(5.1.4)
CLSb
(5.1.8)
Cycle
Day
2 mL 
K2EDTA 
tube
2 mL 
K2EDTA 
tube
NA
2 mL blood in 
3.5 mL SST 
tube
≥ 0.5 mL of 
urine
Screening
Screening 
period ± 3 
days
Xa
1
Pre-dose, 
EOI, 1, 2, 
3, 4, and 6 
hours after 
start of 
infusion
Pre-dose
Xc
X
Pre-dose
3
X
5
Pre-dose 
and EOI
6
X
1
8
X
1
Pre-dose, 
EOI, 1, 2, 
3, 4, and 6 
hours after 
start of 
infusion
Pre-dose
2
5
Pre-dose 
and EOI
3
1
X
Xc
5
1
Xc
End 
of 
Treatmentd
X
a.
Archival or if not available, a fresh Biopsy or Tumor Effusion (mandatory). Even if archival 
sample is available, patient may be asked for optional biopsy sample. 
b.
Except for day 1, samples may be collected ± 1 day from indicated time. Day 1 samples may be 
collected within 1 day prior to initial dosing
c.
Optional biopsies – collected at baseline (biopsy if collected at screening can be used as baseline 
sample) and on day 1 ± 3 days of cycles 3 and 5.


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Abbreviated Title: LMB-100 plus pembrolizumab
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d.
Refers to the end of the first course. No additional research samples will be collected during the 
second course.


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Abbreviated Title: LMB-100 plus pembrolizumab
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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
Clinical Pharmacology Program
All samples sent to the Clinical Pharmacology Program (CPP) will be barcoded, with data 
entered and stored in Labmatrix utilized by the CPP. This is a secure program, with access to 
Labmatrix 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 all 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 the 
processing method (delay in sample processing, storage conditions on the ward, etc.).
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C 
according to stability requirements.  These freezers are located onsite in the BPC 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 the 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.
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following OHSRP/IRB approval of an additional protocol, 
granting the rights to use the material or if the use is not considered to be human subjects 
research.
5.3.2
Leidos Biomedical, 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 to 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, Inc. Lab in Frederick, MD. Samples will be 


61
Abbreviated Title: LMB-100 plus pembrolizumab
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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, 
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 to 
personal data 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
CAT-I Laboratory
The CAT-I laboratory (CAT-I) will obtain coded samples from the Hassan laboratory. Upon 
acquisition, members of the CAT-I laboratory will enter these samples into CEREBRO, an 
advanced sample labeling system that tracks each sample through every step of the workflow. To 
meet requirements for availability of primary data and for quality assurance checks, CAT-I will 
maintain a detailed inventory of the type (slide, paraffin block, tissue, frozen OCT block) and 
location of each sample in the laboratory. More specifically, paraffin blocks and accompanying 
slides will be maintained at room temperature in the CAT- I laboratory. Tissues provided by the 


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Hassan laboratory will be fixed, frozen, and stored in the CAT-I’s -80°C freezer. The CAT-I 
laboratory will be locked when CAT-I lab members are not present. Unprocessed samples will 
be held by the CAT-I or returned to the Hassan laboratory upon their request. Finally, CAT-I will 
comply with requirements for annual Biospecimen Reporting at the NIH.
5.3.6
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 record any loss or unanticipated destruction of samples as a deviation. Reports will 
be made per the requirements of section 7.2.
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. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. 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 removal 
from study treatment (first course and if applicable, second course) or until off-study, whichever 
comes first. Adverse events occurring more than 90 days after the last dose of study therapy (first 
course and if applicable, second course) are required to be recorded only if they are considered to 
be serious and related to the investigational agent/intervention. 
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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
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, will be reported expeditiously per 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)

Identified or coded, linked data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 

Data will be shared through:

An NIH-funded or approved public repository (clinicaltrials.gov).

BTRIS (automatic for activities in the Clinical Center)

Approved outside collaborators under appropriate individual agreements.

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
No large scale genomic data will be generated on this study; therefore, the NIH GDS policy does 
not apply.
6.3
RESPONSE CRITERIA
For the purposes of this study, patients should be re-evaluated for response every 2 cycles (every 
6 weeks if scanning continues beyond end of treatment). 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.


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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.
For peritoneal mesothelioma, the international criteria proposed by the revised Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)[36] will be used. Changes 
in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest 
diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
For pleural mesothelioma, modified RECIST for MPM (malignant pleural mesothelioma)[37] 
should be used as described in section 6.3.2.
iRECIST described in section 6.3.3, based on RECIST 1.1, but adapted to account for the unique 
tumor response seen with immunotherapeutic drugs, will also be utilized for pleural and 
peritoneal mesothelioma as follows. 
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 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
Peritoneal Mesothelioma
6.3.1.1
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 


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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 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. 
6.3.1.2
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 


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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 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.[38-40] 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.[41]
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 


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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 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.
6.3.1.3
RECIST version 1.1 Response Criteria
6.3.1.3.1 Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum 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.
6.3.1.3.2 Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).


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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).
6.3.1.3.3 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
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.


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**
Only for non-randomized trials with response as primary endpoint.
***
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression.
Note:
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)
n-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
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
Pleural Mesothelioma
Malignant pleural mesothelioma (MPM) lesions are difficult to measure reliably.[37] Therefore, 
modified criteria were defined in 2004 adjusting target lesion measurements to the specific needs 
of this disease.
6.3.2.1
Modified RECIST Criteria for MPM
Target lesion: 
Measurable at baseline and defined as tumor thickness measurements perpendicular to the chest 
wall or mediastinum in two positions at three separate levels on transverse cuts of CT scan. The 
sum of those 6 measurements define a pleural unidimensional measure. For reproducibility of 
lesion identification in follow up scans, cuts were taken at least 1 cm apart and close to 
anatomical landmarks in the thorax. Reassessments should be done at same position at the same 
level and by the same reader. Nodal, subcutaneous, and other measurable lesion were measured 
as per RECIST criteria. All unidimensional measurements were added to obtain total tumor 
measurement.
Evaluation of target lesions 

Complete Response (CR): Disappearance of all target lesions with no evidence of tumor 
elsewhere. 

Partial Response (PR): At least a 30% decrease in the total tumor measurement 

Confirmed response (PR and CR): require a repeat scan at least 4 weeks apart 

Progressive Disease (PD): At least a 20% increase in the total tumor measurement, 
taking as reference the smallest sum on study (this includes the baseline sum if that is 


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the smallest on study). (Note: the appearance of one or more new lesions is also 
considered progression). 

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
6.3.2.2
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 achievement of both measurement and confirmation criteria.
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best 
Response 
for 
this 
Category Also Requires:
CR
CR
No
CR
>4 wks. confirmation
CR
Non-CR/Non-
PD
No
PR
PR
Non-PD
No
PR
>4 wks. confirmation
SD
Non-PD
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
*
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
Note: 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.
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status.
6.3.3
iRECIST
6.3.3.1
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment.


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6.3.3.2
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)
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.
6.3.3.3
Assessment at the Confirmatory Imaging


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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).
6.3.3.4
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
6.3.3.5
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.
6.3.3.6
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.


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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.
6.3.3.6.1 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.
6.3.3.6.2 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
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 
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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.[42]
6.3.4
Duration of Response
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
6.3.5
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.
6.3.6
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 AND 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 t 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. 
7.3
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, all deaths 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.
7.4
DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients. 
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 in the appropriate timeframes. 
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. 
7.4.2
Safety Monitoring Committee (SMC)
This protocol will require oversight from the Safety Monitoring Committee (SMC). 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. For initial and subsequent 
reviews, protocols will not be reviewed if there is no accrual within the review period. 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.


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8
SPONSOR REPORTING CRITERIA 
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 section 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
Events to Be Treated as Adverse Events for Manufacturer Reporting

In addition to the above SAE criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes.

Is a new cancer (that is not a condition of the study);


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
Is associated with an overdose.
8.1.4
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)
8.1.5
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.
8.1.6
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.
8.1.7
Overdose
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).
8.1.8
Events of clinical interest

an overdose of Merck product, as defined in Section 8.1.7 

an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. 
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.


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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.
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets a 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.
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 
and 
instructions 
can 
be 
found 
at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842.
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
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
8.4.1
Reported by Sponsor to Manufacturer
All events listed below must be reported within 24 hours of investigator knowledge of event to 
OSROSafety@mail.nih.gov. 
ORSO will send all reports to the manufacturer as described below.

All AEs meeting serious criteria, from the time of treatment allocation through 90 days 
following cessation of study treatment regardless of initiation of subsequent anticancer 
therapy. 

All pregnancies and exposure during breastfeeding, from the time of treatment allocation 
through 180 days following cessation of study treatment, or 30 days following cessation 
of study treatment if the participant initiates new anticancer therapy must be reported by 
the investigator. 

Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately by the investigator if the 
event is considered to be drug-related.


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Investigators are not obligated to actively seek AE or SAE or other reportable safety 
events in former study participants. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, and 
he/she considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify Merck.
8.4.1.1
Reporting of Overdose to Merck
If an adverse event(s) is associated with (“results from”) the overdose (see section 8.1.7) of a 
Merck product, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 2 working 
days hours to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229)
8.4.1.2
Reporting of Pregnancy and Lactation to Merck
Although pregnancy and infant exposure during breast feeding are not considered adverse events, 
it is the responsibility of investigators or their designees to report any pregnancy or lactation in a 
participant (spontaneously reported to them) that occurs during the study.
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment. The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated. The outcome of the pregnancy will be reported to Merck within 2 
working days if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn). The 
study Investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to Merck. If a male participant 
impregnates his female partner, the study personnel at the site must be informed immediately and 
the pregnancy must be reported to Merck and followed as described below.
Pregnancies and infant exposures during breastfeeding that occur after the consent form is signed 
but before treatment allocation must be reported by the investigator if they cause the participant 
to be excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
allocation through 180 days following cessation of the Merck product, or 30 days following 
cessation of treatment if the participant initiates new anticancer therapy, whichever is earlier, 
must be reported by the investigator. All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage 
and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy 
continues to term, the outcome (health of infant) must also be reported.


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Such events must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229)
8.4.1.3
Immediate Reporting of Adverse Events to Merck
8.4.1.3.1 Serious Adverse Events and Events to Be Treated as Serious Adverse Events
Refer to sections 8.1.2 and 8.1.3 for definitions of SAE and events to be treated as SAEs 
respectively.
For the time period beginning when the consent form is signed until treatment allocation, any 
serious adverse event, or follow up to a serious adverse event, including death due to any cause 
that occurs to any participant must be reported within 2 working days to Merck Global Safety if 
it causes the participant to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure.
For the time period beginning at treatment allocation through 90 days following cessation of 
treatment, regardless of initiation of subsequent anticancer therapy, any serious adverse event, or 
follow up to a serious adverse event, including death due to any cause whether or not related to 
the Merck product, must be reported within 2 working days to Merck Global Safety.
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time following consent through the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to Merck Global Safety.
All participants with serious adverse events must be followed up for outcome.
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number: +1-215-661-6229
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to FDA.
8.4.1.4
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and are defined in section 8.1.8. These events must be reported within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229).
For the time period beginning when the consent form is signed until treatment allocation, any 
ECI, or follow up to an ECI, that occurs to any participant must be reported within 2 working 
days to Merck Global Safety if it causes the participant to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.


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For the time period beginning at treatment allocation through 90 days following cessation of 
treatment regardless of initiation of subsequent anticancer therapy, any ECI, or follow up to an 
ECI, whether or not related to Merck product, must be reported within 2 working days to Merck 
Global Safety.
8.4.2
Reported by Study Team to Manufacturer

All AEs from the time of treatment allocation through 90 days following cessation of 
study treatment must be reported by the investigator. AEs will be reported per 
manufacturer’s instructions.
8.5
REPORTING PREGNANCY 
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 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 PLAN
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, 


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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
The primary objective of this trial is to determine if LMB-100 followed by pembrolizumab is 
associated with an adequately high response rate in each of two separate cohorts of 
mesothelioma patients. This will require exceeding the response rate of pembrolizumab alone in 
patients who have pleural mesothelioma that have failed standard therapies, and will require 
identifying a modest response rate in patients with peritoneal mesothelioma. 
The secondary objectives are to evaluate safety, duration of response, overall survival (OS), and 
progression-free survival (PFS) in all patients included in this phase II evaluation. Exploratory 
objectives include evaluation of a set of laboratory parameters, to be performed only if the 
treatment combination has a beneficial effect.
10.2 SAMPLE SIZE DETERMINATION
Since published data indicate that a response rate for pembrolizumab alone in patients with 
pleural mesothelioma who have failed standard treatments is approximately 20%, this trial will 
try to demonstrate if a response rate substantially more than 20% may be realized by the addition 
of LMB-100 in those patients.
Patients with pleural mesothelioma will be enrolled in a cohort and evaluated for response using 
a Simon optimal two-stage phase II trial design (Simon R, Controlled Clinical Trials 10:1-10, 
1989) to rule out an unacceptably low PR+CR rate of 20% (p0=0.20) in favor of an improved 
response rate of 40% (p1=0.40). 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 determine the response rate in the 12 evaluable patients who are treated at the safe 
combination, and if 0 to 2 of the 12 have a clinical response, then no further patients will be 
accrued. If 3 or more of these 12 patients have a response, then accrual would continue until a 
total of 25 evaluable patients have been treated. 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 3 to 7 patients with a 
response out of 25 patients, this would be an uninterestingly low response rate. If there were 8 or 
more of 25 (32%) who experienced a response, this would be sufficiently interesting to warrant 


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further study in later trials. Under the null hypothesis (20% response rate), the probability of 
early termination is 55.8%.
Patients with peritoneal mesothelioma have limited data on clinical responses, and will be 
enrolled in their own cohort and evaluated for response using a separate, small Simon minimax 
two-stage phase II trial design[43] to rule out an unacceptably low PR+CR rate of 5% (p0=0.05) 
in favor of an improved response rate of 30% (p1=0.30). 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 determine the response rate in 6 evaluable patients, and if 0 
of the 6 have a clinical response, then no further peritoneal mesothelioma patients will be 
accrued. If 1 or more of these 6 patients have a response, then accrual would continue until a 
total of 10 evaluable patients with peritoneal disease have been treated. 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 is 
exactly 1 patient with a response out of 10 patients, this would be an uninterestingly low 
response rate. If there were 2 or more of 10 (20%) 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 73.5%.
It is expected that approximately 15-20 patients per year may enroll onto this trial. Thus, it is 
expected that 18 months may be required to enroll up to 35 evaluable patients (up to 25 with 
pleural disease and 10 with peritoneal disease). To allow for a small number of inevaluable 
patients, the accrual ceiling will be set at 38 patients.
10.3 POPULATIONS FOR ANALYSES
Modified Intention-to-Treat: participants who took at least one dose of study intervention will be 
included in analyses as described below
10.3.1 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.
10.3.2 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.
10.4 STATISTICAL ANALYSES
10.4.1 General Approach
Patients enrolled in the two cohorts will have the fraction of patients responding reported along 
with 80% and 95% confidence intervals.
10.4.2 Analysis of the Primary Endpoints
Clinical responses will be analyzed by reporting the fraction of evaluable patients in each of the 
two cohorts who experience a response, along with 80% and 95% two-sided confidence intervals, 
separately by cohort. 


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10.4.3 Analysis of the Secondary Endpoints
Duration of response will be calculated from the date of clinical response determination until 
disease progression on or after pembrolizumab or last follow-up without progression on or after 
pembrolizumab. OS will be determined from on-study date until date of death or date last known 
alive. PFS will be determined from the on-study date until the date of progression on or after 
pembrolizumab or date of death without progression (as events) or until the date of last follow-
up if not progressed (as a censored observation). All three of these measures will be calculated as 
probabilities as a function of time using the Kaplan-Meier method, and will be evaluated on all 
evaluable patients, separately by cohort, as well as for both cohorts combined if the results are 
sufficiently similar to permit pooling (p>0.30 for difference between the cohorts), with 
appropriate caveats if necessary.
10.4.4 Safety Analyses
Safety of LMB-100 followed by 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. 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.
10.4.5  Baseline Descriptive Statistics
Basic descriptive statistics on study participants will be summarized in the final publication.
10.4.6 Planned Interim Analyses
The number of patients with a clinical response after the first stage of the two-stage phase II 
cohort will be determined to permit the trial to accrue to the second stage.
10.4.7 Sub-Group Analyses
No formal sub-group analyses are planned.
10.4.8 Tabulation of individual Participant Data
No individual participant data tabulation will be required. Tables showing results of participants 
may be presented if warranted.
10.4.9 Exploratory Analyses
Patients who undergo biopsies at baseline as well as after two cycles of LMB-100 and/or two 
cycles of pembrolizumab will have the differences in the parameters obtained by the biopsies 
compared from baseline to each of the two subsequent time points, as well as between the post-
LMB-100 biopsy and the post-pembrolizumab biopsy. These analyses will be done using 
appropriate paired tests (paired t-test or Wilcoxon signed rank test depending on the normality of 
the differences). All tests will be done with exploratory intent, separately by cohort, without 
adjustment for multiple comparisons but presented in the context of the number of tests 
performed.
11 COLLABORATIVE AGREEMENTS
11.1 CLINICAL TRIALS AGREEMENT (CTA)
The study agent pembrolizumab is supplied under a CTA (# 1101) with the manufacturer, Merck.


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Abbreviated Title: LMB-100 plus pembrolizumab
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12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
LMB-100 is a mesothelin-targeted 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 advanced/metastatic mesothelioma 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.
12.2 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.
12.3 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 12.5), 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 assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate. For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for 
appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and 
(b) who do not have a legal guardian or durable power of attorney, will be followed.
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
12.4.1 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 study agent as discussed in section 13. 
12.4.2 Blood Collection
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 


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12.4.3 CT Scans
In addition to the radiation risks discussed below, CT scans may include the risks of an allergic 
reaction to the contrast. Participants might experience hives, itching, headache, difficulty 
breathing, increased heartrate and swelling. 
12.4.4 Image Guided Biopsy Collection
The risks of the research biopsies collected at baseline, on C2D1 and C4D1 include pain, 
bleeding and infection at the biopsy site. In addition, as the biopsies may be collected under CT 
guidance, subjects in this study may be exposed to radiation as discussed below.
12.4.5 Radiation 
The study will involve radiation from the following sources:

Up to 3 CT scans as referenced above for the collection of biopsies

Up to 9 CT scans per year for disease assessment

Up to 9 FDG-PET scans  per year for disease assessment
Subjects in this study may be exposed to approximately 17.7 rem. This amount is more than 
would be expected from everyday background radiation. Being exposed to excess radiation can 
increase the risk of cancer. The risk of getting cancer from the radiation exposure in this study is 
1.8 out of 100 (1.8%) and of getting a fatal cancer is 0.9 out of 100 (0.9%). 
12.5 RISKS/BENEFITS ANALYSIS
Patients with advanced and/or metastatic pleural or peritoneal mesothelioma 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 mesothelioma. 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 mesothelioma 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 
12.6 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided to the participant or consent designee(s) (e.g., 
legally authorized representative [LAR] if participant is an adult unable to consent) 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.


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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) 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 for the optional biopsies performed on this study will be obtained at the time of the 
procedure. If the patient refuses the optional biopsy at that time, the refusal will be documented 
in the medical record and in the research record.
12.6.1 Request for Waiver of Consent for Screening Activities
Prior to the subject signing the consent for this study pre-screening activities listed in section 
2.2.1 may be performed. 
We request a waiver of consent for these activities as they involve only minimal risk to the 
subjects.  A waiver will not adversely affect the rights and welfare of the subjects given that the 
activities are only intended to determine suitability for screening for participation in research 
protocols.  These activities could not practicably be carried out without the wavier as central 
recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for 
multiple studies and obtaining consent for each one is beyond their resources.  The subjects will 
be provided with additional pertinent information after participation as they will be informed 
whether or not they are eligible to sign a consent for additional screening.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 QUALITY ASSURANCE AND QUALITY CONTROL
Each 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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Abbreviated Title: LMB-100 plus pembrolizumab
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13.2 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 NCI CCR 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.
13.3 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 each 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 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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Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
14 PHARMACEUTICAL INFORMATION 
14.1 LMB-100 (IND # 152907)
14.1.1 Source 
Initially LMB-100 on this trial was transferred to the NIH CC Pharmacy by Roche, the first 
manufacturer of the drug. As of Amendment H, the drug supply manufactured by Selecta 
Biosciences and transferred to the NIH CC Pharmacy will be utilized. Please note, the Roche 
supply may continue to be used until expiration, per PI/sponsor/pharmacy discretion.  
14.1.2 Toxicity 
Information in this section is based on preclinical studies with LMB-100, and clinical studies of 
the cytolytic fusion protein SS1-P. Patients should receive a full dose of LMB-100 unless a DLT 
and/or a treatment limiting toxicity is observed. In case of DLT and/or treatment limiting 
toxicities, treatment with LMB-100 will be stopped until resolution of toxicity to NCI CTCAE 
Grade  2 hematological toxicities or Grade  1 non-hematological toxicities. A delay of LMB-
100 administration for up to two weeks of the planned schedule will be acceptable to allow for 
resolution of toxicity to NCI CTCAE Grade  2 hematological toxicities or Grade  1 non-
hematological toxicities. If toxicity does not resolve to NCI CTCAE Grade  2 hematological 
toxicities or Grade  1 non-hematological toxicities and the patient is unable to resume treatment 
with LMB-100 after this time, no additional doses will be administered and the patient will be 
withdrawn from study treatment.
14.1.2.1 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 1.2.4.3.3). 
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.
14.1.2.2 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.[44]


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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.
14.1.2.3 Risk of Inflammatory Reactions to Serosal Membranes 
LMB-100 administration may cause inflammatory reactions to serosal membranes including 
pleuritis, characterized by pleuritic chest pain, dyspnea, and hypoxia and pericarditis, 
characterized by precordial chest pain, congestive heart failure, hypotension, and uremia. 
Clinical trials with SS1P monotherapy have led to reversible pleuritis and pericarditis. Patients 
who develop symptoms of serosal inflammation should be closely monitored and receive standard 
treatments which may include corticosteroids.
14.1.2.4 Risk of Capillary Leak Syndrome
LMB-100 administration may cause CLS characterized by hypotension, hypoalbuminemia, 
edema, weight gain, and hemoconcentration. Clinical trials with SS1P monotherapy have led to 
the development of reversible CLS. Patients will be monitored with frequent assessments of 
weight, edema, blood pressure, and serum albumin levels prior to and during treatment. Patients 
who develop symptoms of CLS should be closely monitored and receive standard symptomatic 
treatments.
14.1.2.5 Risk of Cardiac Toxicity
There may be a risk for cardiac immune-related adverse events, specifically myocarditis, as a 
rare but serious complication after treatment with LMB-100. During clinical trial 19C0128, a 
patient with history of intrahepatic cholangiocarcinoma arising out of primary sclerosing 
cholangitis, initiated C1 tofacitinib + apixaban treatment on Day 1 and LMB-100 on Day 4. The 
patient began experiencing fatigue and pleuritic pain symptoms on Day 5.  A cardiac MRI was 
performed that suggested a component of inflammatory myocarditis in addition to capillary leak 
syndrome.
14.1.2.6 Risk of Rhabdomyolysis
There may be a risk of rhabdomyolysis as a rare, but serious complication of treatment with 
LMB-100. A single patient on this study experienced grade 4 CPK increased, assessed as being 
due to a grade 2 event of rhabdomyolysis within one week of initial dose of LMB-100. This was 
determined by the sponsor to be related to the LMB-100. 
14.1.2.7 Risk of Renal Toxicity
LMB-100 administration may cause renal toxicity characterized by increased creatinine, BUN, 
and proteinuria. In preclinical cynomolgus monkey studies, LMB-100 has shown increases in 
creatinine and histological changes including regenerative and degenerative changes to the tubular 
epithelium. Hemolytic uremic syndrome has been reported for other cytolytic fusion antibodies 
in development.
Patients should be monitored with renal laboratory assessments including creatinine, BUN, and 
urinalysis.
14.1.2.8 Injection Site Reactions
LMB-100 administration may cause adverse reactions at the infusion site characterized by pain, 
swelling, induration, and nodules. In preclinical NHP studies for both SS1P and LMB-100 


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reddening and swelling of the infusion site were noted. Patients who develop symptoms of 
infusion site reactions can be administered pain relieving medication (analgesic) as required, and 
rotation of infusion sites is recommended.
14.1.3 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.
14.1.4 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.
14.1.5 Stability and Storage 
14.1.5.1 Stability
Stability tests are ongoing for intact LMB-100 vials.
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).
14.1.5.2 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.
14.1.6 Administration procedures
Please refer to section 3.2.1.
14.1.7 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.
14.1.7.1 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 


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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 kD 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.
14.1.7.2 Molecular Weight: approximately 73 kDa
14.1.7.3 Chemical Structure
H1L1 polypeptide structure consisting of one variable heavy chain containing the Pseudomonas 
Exotoxin A moiety and one variable light change held together by a disulfide bond.


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Abbreviated Title: LMB-100 plus pembrolizumab
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14.2 PEMBROLIZUMAB
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of product in 
accordance with the protocol and any applicable laws and regulations.
14.2.1 Source 
Commercially available pembrolizumab will be supplied under a CTA with the manufacturer, 
Merck.
14.2.2 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.
14.2.3 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 7. 
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 7: 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.
a.
Includes all subjects who received at least one dose of MK-3475 in KN001 Part B1, B2, B3, D, 


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Reference Safety Dataset for Pembrolizumaba
Preferred Term
N
(%)
C, F1, F2, F3; KN002 (original phase), KN006, and KN010.
 
Table 8: 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.
Anemia (NSCLC Combo 
Tx, UC)
Hemolytic anemia
Blood and 
lymphatic 
system disorders
Autoimmune myocarditis
Myocarditis 
Cardiac 
failure (MEL)
Cardiac
Adrenal insufficiency


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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.
Adrenocortical 
insufficiency acute
Autoimmune thyroiditis
Hyperthyroidism
Hypophysitis
Hypopituitarism
Hypothyroidism
Lymphocytic 
hypophysitis
Secondary adrenocortical 
insufficiency
Thyroid disorder
Thyroiditis
Autoimmune uveitis
Iridocyclitis
Iritis
Ocular myasthenia
Eye disorders
Uveitis
Abdominal discomfort 
(UC)
Abdominal pain (MEL, 
UC)
Gastrointestinal 
disorders
Abdominal pain lower 
(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.
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)
Pancreatitis Oral lichen 
planus
Pancreatitis acute


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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.
Vomiting (MEL, 
NSCLC, NSCLC Combo 
Tx, HNSCC, cHL, 
UC)Pancreatitis 
necrotizing
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)
General 
disorders and 
administration 
site conditions
Pyrexia
Autoimmune hepatitis
Drug-induced liver injury
Hepatitis Hepatic pain 
(UC)
Hepatitis acute
Hepatobiliary 
disorders


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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.
Hepatitis fulminant
Hepatitis toxic (UC)
Hyperbilirubinemia (UC)
Liver injury (UC)
Anaphylactic reaction
Anaphylactoid reaction
Cytokine release 
syndrome
Drug hypersensitivity
Graft versus host disease 
(cHL)
Hypersensitivity
Immune system 
disorders
Serum sickness
Gastroenteritis (cHL, 
UC)
Herpes zoster (cHL)
Pneumonia (NSCLC, 
HNSCC, cHL, UC)
Infections and 
infestations
Rash pustular


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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.
Septic shock (cHL)
Sepsis (UC)
Upper respiratory tract 
infection (NSCLC 
Combo Tx, cHL)
Urinary tract infection 
(UC)
Urosepsis (UC)
Injury, poisoning 
and procedural 
complications
Infusion related reaction
Alanine 
aminotransferase 
increased (UC)
Aspartate 
aminotransferase 
increased (UC)
Investigations
Blood bilirubin 
increased (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.
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)
Decreased appetite 
(MEL, NSCLC, 
NSCLC Combo Tx 
HNSCC, UC)
Diabetic ketoacidosis
Fulminant type 1 
diabetes mellitus
Hyponatremia (UC)
Metabolism and 
nutritional 
disorders
Latent autoimmune 
diabetes in adults


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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.
Type 1 diabetes 
mellitus
Arthralgia (MEL, 
NSCLC, NSCLC 
Combo Tx, cHL, UC)
Arthritis
Back pain (MEL, 
NSCLC, cHL, UC)
Bone pain (cHL, UC)
Flank pain (UC)
Musculoskeletal chest 
pain (cHL, 
UC)Immune-mediated 
necrotizing myopathy
Musculoskeletal 
discomfort (cHL, UC)
Musculoskeletal 
and connective 
tissue disorders
Musculoskeletal pain 
(cHL, UC)
Neoplasms 
benign, 
malignant and 
unspecified (incl 
cysts and 
polyps)
Tumor pain (UC)
Axonal neuropathy
Nervous system 
disorders
Demyelinating 
polyneuropathy


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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.
Dizziness (NSCLC 
Combo Tx)Diabetic 
ketoacidotic 
hyperglycemic coma
Dysgeusia (NSCLC 
Combo Tx)
Dysesthesia (cHL)
Guillain-Barre 
syndrome
Headache (MEL, 
NSCLC Combo Tx, 
cHL)Hypoesthesia 
(cHL)
Lethargy (UC)
Miller Fisher syndrome
Myasathenia 
gravisMyasthenia 
gravis crisis
Myasthenic syndrome
Myelitis
Neuropathy peripheral 
(MEL, cHL)


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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.
Paresthesia 
(cHL)Peripheral 
sensory neuropathy 
(cHL)Polyneuropathy 
(MEL, cHL)
Psychiatric
Confusional state 
(HNSCC)
Insomnia (NSCLC 
Combo Tx)
Acute kidney injury 
(NSCLC Combo Tx, 
UC)
Autoimmune nephritis
Chromaturia (UC)
Glomerulonephritis
Glomerulonephritis 
membranous
Hematuria (UC)
Nephritis
Nephrotic syndrome
Renal and 
urinary disorders
Tubulointerstitial 
nephritis


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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.
Reproductive 
system and 
breast disorders
Pelvic pain (UC)
Cough (MEL, NSCLC, 
NCSLC Combo Tx, 
cHL, UC)
Dyspnea (MEL, 
NSCLC, NSCLC 
Combo Tx, HNSCC, 
cHL, UC)
Dyspnea exertional 
(cHL, UC)
Interstitial lung disease
Respiratory, 
thoracic and 
mediastinal 
disorders
Pneumonitis
Productive cough 
(cHL, UC)
Respiratory failure 
(HNSCC)
Wheezing (cHL, UC)
Skin and 
subcutaneous 
Acute febrile 
neutrophilic dermatosis


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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.
Dermatitis
Dermatitis acneiform 
(cHL, UC)
Dermatitis bullous
Dermatitis exfoliative 
Dermatitis contact 
(cHL, UC)
Dermatitis psoriasiform 
(cHL)
Drug eruptionDrug 
reaction with 
eosinophilia and 
systemic symptoms
Eczema
Eczema asteatotic 
(cHL, UC)
Erythema (UC)
tissue disorders
Erythema multiforme


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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.
Lichen planus
Lichenoid keratosis 
(UC)Palmar-plantar 
erythrodysesthesia 
syndrome
Pemphigoid
Pruritus Perivascular 
dermatitis
Psoriasis
Rash
Rash erythematous
Rash generalized
Rash macular
Rash maculo-papular
Rash papular Rash 
morbilliform
Rash pruritic
Skin disorder


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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 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
rare


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Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
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
14.2.4 Formulation and preparation 
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg/ 4mL
Solution for Injection
14.2.5 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.
14.2.6 Administration procedures
Please refer to section 3.2.2.
14.2.7 Incompatibilities 
None


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14.2.8 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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Association for Cancer Research 2007, 13(17):5144-5149.


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16 APPENDICES
16.1 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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16.2 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 2.1.1.10: 

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 9 when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant.


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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 9 
during the protocol-defined time frame in Section 2.1.1.10. 
Table 9: 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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16.3 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 
or 
mRECIST 
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., mRECIST = Modified RECIST Criteria for malignant pleural 
mesothelioma


118
Abbreviated Title: LMB-100 plus pembrolizumab
Version Date:  02/16/21
16.4 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 2 cycles ±7 days) after the restart 
of treatment. Subsequent tumor imaging should be performed every 2 cycles ±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.

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/24/2020
Page 1 of 6
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
RINCIPAL INVESTIGATOR:
Raffit Hassan, MD
STUDY TITLE:
Phase II Study of the Anti-Mesothelin Immunotoxin 
LMB-100 Followed by Pembrolizumab in Malignant 
Mesothelioma
STUDY SITE:
NIH Clinical Center
Cohort: 
Treatment Beyond Progression 
Consent Version:
07/24/2020
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Raffit Hassan, M.D. by phone at 240-760-6232 or email raffit.hassan@nih.gov 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
After you began treatment with pembrolizumab on this study, it appears as if your tumors might 
have grown according to our scans.  However, studies have shown that therapies such as 
pembrolizumab that target the immune system sometimes initially cause tumors to grow and then 
to later shrink.  The initial growth is referred to as a tumor flare.  Because of this feature of 
pembrolizumab, we cannot be certain after the first assessment that the study therapy is not 
working.  Furthermore, your clinical condition has not gotten worse. 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/24/2020
Page 2 of 6
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
We would therefore like to continue treatment with pembrolizumab until we can be certain that 
the apparent increase in tumor size is not due to the tumor flare and is truly because your tumor is 
not responding to the pembrolizumab.  It might take us several more cycles of therapy and several 
more scans to decide how to categorize your results.
Because it is standard practice to discontinue therapy at the first sign of tumor progression, we are 
asking your permission to continue with pembrolizumab therapy beyond this point. 
Refusing to do so will not affect your participation on this study.  We would still want to keep in 
touch with you about your disease and any new therapies you might have started
DESCRIPTION OF RESEARCH STUDY
If you choose to remain on study therapy, you will continue to receive pembrolizumab as described 
in the standard study consent and continue to have the same assessments (clinical and research).  
You will be required to continue on birth control as described in the standard consent
RISKS OR DISCOMFORTS OF PARTICIPATION
In addition to the risks described in the standard consent, continuing treatment as this point might 
lead you to miss out on alternative approaches as described below.
POTENTIAL BENEFITS OF PARTICIPATION
The potential benefits are similar to what is described in the standard consent; however, as your 
tumor has grown, it is more likely at this point than it was before that pembrolizumab may not 
have worked against your tumors.
WHAT OTHER CHOICES DO I HAVE IF I DO NOT CONTINUE PEMBROLIZUMAB? 
Instead of continuing pembrolizumab on this study, you have these options:
•
Getting treatment or care for your cancer without being in a study
•
Taking part in another study
•
Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY
There is no change in the criteria for stopping therapy and you will be allowed to discontinue 
therapy at any time you chose. 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/24/2020
Page 3 of 6
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses.  These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you.  It is also possible that the stored specimens and data may never be used.  Results of research 
done on your specimens and data will not be available to you or your doctor.  It might help people 
who have cancer and other diseases in the future.  
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
Compensation on this study remains as described in the standard consent.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
•
If some tests and procedures performed outside the NIH Clinical Center, you 
may have to pay for these costs if they are not covered by your insurance 
company.
•
Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.
•
Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/24/2020
Page 4 of 6
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:
•
The National Cancer Institute and other government agencies, like the Food and Drug 
Administration (FDA), which are involved in keeping research safe for people.
•
National Institutes of Health Intramural Institutional Review Board
•
Qualified representatives from Merck, the pharmaceutical company who produces 
pembrolizumab.
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/24/2020
Page 5 of 6
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting,  to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Raffit Hassan, 
M.D., Raffit.Hassan@nih.gov, 240-760-6232. You may also call the NIH Clinical Center Patient 
Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you 
have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 07/24/2020
Page 6 of 6
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: 
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
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