Conditions: Mesothelioma
Keywords: Immunotoxin Mesothelin Targeted Therapy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 21
Healthy volunteers: no

Brief summary:
Background:

LMB-100 is a man-made protein. It is attracted to the mesothelin protein. This is found in many tumors, including mesothelioma. But it is found in only a very small number of normal tissues. After binding to mesothelin on tumors, LMB-100 attacks and kills cancer cells. Researchers want to test LMB-100 in people with advanced mesothelioma.

Objective:

To find a safe dose and anti-tumor activity of LMB-100 for people with advanced mesothelioma.

Eligibility:

Adults ages 18 and older with:

Advanced pleural or peritoneal mesothelioma that has not responded to platinum-based

therapy

Adequate organ function

Design:

Participants will be screened with:

Samples of tumor tissue or tumor fluid. These can be new or from a previous procedure.

Medical history

Physical exam

Blood, urine, and heart tests

Chest x-rays

Computed tomography (CT) or magnetic resonance imaging (MRI) scans

Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans

Participants will get LMB-100 on days 1, 3, and 5 of each 21-day cycle. It will be given through an intravenous (IV) catheter, a tube inserted in an arm vein. They will get standard medicines before each infusion to help prevent side effects. Each infusion lasts about 30 minutes. They will be monitored for up to 2 hours after.

During each cycle, participants will repeat the screening tests.

Participants will get the study drug for up to 4 cycles or until their disease worsens or they have intolerable side effects.

About 4-6 weeks after their last infusion, participants will have a follow-up visit. They will repeat the study tests.

Participants will have follow-up scans every 6 weeks until their disease gets worse.

Participants will be called about once a year to see how they are doing.

Detailed description:
Background:

* Although mesothelioma 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.
* For mesothelioma 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.
* Mesothelin, a tumor differentiation antigen, is expressed in over 95% of epitheloid mesothelioma. Mesothelin is a suitable candidate for targeted therapy due to its very limited expression in normal human tissue and its high expression in several tumors including mesothelioma.
* LMB-100 is a novel recombinant anti-mesothelin immunotoxin developed for the treatment of patients with solid tumors that express mesothelin. Mesothelin is targeted by linking a humanized fragment of the anti-mesothelin Fab to a de-immunized Pseudomonas exotoxin (PE).
* The clinical use of first generation immunotoxins such as SS1P was hampered mainly by their high immunogenicity. LMB-100 is a next generation PE-fusion protein that has been protein-engineered to maximally reduce its immunogenicity. LMB-100 has shown broad activity against different mesothelin expressing cancer cell lines and tumor xenograft models.

Objectives: Phase 1

To identify the recommended phase 2 dose (RP2D) of LMB-100 in patients with treatment refractory advanced epithelioid or biphasic mesothelioma and evaluate potential efficacy of the identified RP2D.

-Phase 2

To determine the efficacy of LMB-100 with respect to objective response rate in patients with treatment refractory advanced epithelioid or biphasic mesothelioma.

Eligibility:

* Age greater than or equal to 18 years
* Histologically confirmed advanced pleural or peritoneal mesothelioma
* Subjects must have had at least 1 prior chemotherapy regimen with last dose of previous therapy occurring at 3 weeks before the start of study treatment
* Adequate organ function
* Participants with central nervous system (CNS) metastases or prior pneumonectomy are excluded

Design:

* This is a Phase I, open-label study to evaluate the safety, pharmacokinetics, and activity of LMB-100 in patients with treatment refractory advanced epithelioid or biphasic mesothelioma.
* LMB-100 will be administered intravenously on days 1, 3 and 5 of each 21 day cycle for up to 4 cycles
* Tumor response will be assessed after every 2 cycles
* Optional tumor biopsies may be collected at baseline and after 2 cycles of therapy
* The accrual ceiling will be set at 30

Arms:
arm 1: De-escalating doses of LMB-100 in up to 18 subjects arm 2: Fixed dose of LMB-100 as determined in Arm A1 in up to 16 subjects arm 3: De-escalating doses of LMB-100 + fixed dose of nab-paclitaxel in up to 12 subjects arm 4: Fixed dose of LMB-100 as determined in Arm B1 + fixed dose of nab-paclitaxel in up to 16 subjects

Interventions: intervention 1: LMB-100 intervention 2: nab-paclitaxel
Intervention descriptions: intervention 1: Administered intravenous (IV) on days 1, 3 and 5 of a 21 day cycle for up to 4 cycles (Arms A1 and A2) or 2 cycles (Arms B1 and B2) intervention 2: Arms B1 and B2 only. Administered intravenous (IV) on days 1 and 8 of each 21 day cycle for up to 6 cycles

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
1
Abbreviated Title: LMB-100 in Mesothelioma
NIH Protocol #: 16C0127
NCT #: NCT02798536
Version Date: February 16, 2021
Title: A Phase I Study of the Mesothelin-Targeted Immunotoxin LMB-100 with or without Nab-
Paclitaxel (Abraxane) in Patients with Malignant Mesothelioma 
NCI Principal Investigator:
Raffit Hassan, M.D.
Thoracic and GI Malignancies Branch (TGMB), CCR, NCI
Building 10-CRC, Room 4-5330
9000 Rockville Pike
Bethesda, MD 20892
Phone: 240-760-6232
E-mail: hassanr@mail.nih.gov
Investigational Agent:    
Drug Name:
LMB-100 (formerly RO6927005)
IND Number:
152907
Sponsor:
Center for Cancer Research, NCI, NIH
Manufacturer:
F. Hoffmann-La Roche
Commercial Agent
Nab-paclitaxel


Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
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PRÉCIS 
Background:
Although mesothelioma 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. 
For mesothelioma 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. 
Mesothelin, a tumor differentiation antigen, is expressed in over 95% of epithelioid 
mesothelioma. Mesothelin is a suitable candidate for targeted therapy due to its very limited 
expression in normal human tissue and its high expression in several tumors including 
mesothelioma.
LMB-100 is a novel recombinant anti-mesothelin immunotoxin developed for the treatment 
of patients with solid tumors that express mesothelin.  Mesothelin is targeted by linking a 
humanized fragment of the anti-mesothelin Fab to a de-immunized Pseudomonas exotoxin 
(PE)
The clinical use of first generation immunotoxins such as SS1P was hampered mainly by 
their high immunogenicity. LMB-100 is a next generation PE-fusion protein that has been 
protein-engineered to maximally reduce its immunogenicity. LMB-100 has shown broad 
activity against different mesothelin-expressing cancer cell lines and tumor xenograft 
models.
The combination of LMB-100 plus nab-paclitaxel has shown anti-tumor efficacy in 
different mesothelioma patient derived xenograft (PDX) models compared to LMB-100 or 
nab-paclitaxel alone.
Objectives:
To identify the recommended phase 2 dose (RP2D) of LMB-100 +/- nab-paclitaxel in 
patients with treatment refractory advanced epithelioid or biphasic mesothelioma and 
evaluate potential efficacy of the identified RP2D. 
Eligibility:
Age ≥ 18 years
Histologically confirmed advanced pleural or peritoneal mesothelioma 
Subjects must have had at least 1 prior chemotherapy regimen with last dose of previous 
therapy occurring at least 3 weeks before the start of study treatment
Subjects enrolling in Arms B1 and B2 must not have received paclitaxel or nab-paclitaxel 
within 4 months prior to initiation of study therapy
Adequate organ function
Participants with CNS metastases or prior pneumonectomy are excluded
Design:
This is a Phase I, open-label study to evaluate the safety, pharmacokinetics, and activity of 
LMB-100 +/- nab-paclitaxel in patients with treatment refractory advanced epithelioid or 
biphasic mesothelioma.


Abbreviated Title: LMB-100 in Mesothelioma
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Subjects in Arms A1 and A2 (completed) will receive LMB-100 monotherapy; subjects in 
Arms B1 and B2 will receive LMB-100+nab-paclitaxel
LMB-100 will be administered intravenously on days 1, 3 and 5 of each 21 day cycle for up 
to 4 cycles in Arms A1 and A2 and up to 2 cycles in Arms B1 and B2
Nab-paclitaxel (Arms B1 and B2 only) will be administered intravenously on days 1 and 8 
of each 21 day cycle for up to 6 cycles
Tumor response will be assessed after every 2 cycles
Optional tumor biopsies may be collected at baseline and after 2 cycles of therapy
The accrual ceiling will be set at 34 


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TABLE OF CONTENTS 
PRÉCIS......................................................................................................................................2
TABLE OF CONTENTS...........................................................................................................4
STATEMENT OF COMPLIANCE...........................................................................................9
1
Introduction.......................................................................................................................9
1.1
Study Objectives .........................................................................................................9
1.1.1
Primary Objective:................................................................................................9
1.1.2
Secondary Objectives............................................................................................9
1.1.3
Exploratory Objectives: ........................................................................................9
1.2
Background and Rationale ........................................................................................10
1.2.1
Background on Mesothelioma............................................................................10
1.2.2
Mesothelin as a target for cancer therapy ...........................................................10
1.2.3
LMB-100.............................................................................................................12
1.2.4
Comparison of toxicity and immunogenicity of LMB-100 to SS1P ..................26
1.2.5
Rationale for the study........................................................................................27
2
Eligibility Assessment and Enrollment...........................................................................28
2.1
Eligibility Criteria .....................................................................................................28
2.1.1
Inclusion Criteria (All Arms)..............................................................................28
2.1.2
Exclusion Criteria (All Arms).............................................................................29
2.1.3
Exclusion Criteria (Arm B only).........................................................................30
2.2
Screening Evaluation ................................................................................................30
2.3
Registration Procedures ............................................................................................31
2.3.1
Treatment Assignment Procedures .....................................................................31
3
Study Implementation.....................................................................................................32
3.1
Study Design .............................................................................................................32
3.1.1
Dose Limiting Toxicity (Dose de-escalation cohorts only)................................33
3.1.2
Dose De-Escalation (Arm A1)............................................................................34
3.1.3
,Dose De-Escalation (Arm B1)...........................................................................35
3.2
Drug Administration .................................................................................................36
3.2.1
LMB-100.............................................................................................................36
3.2.2
Nab- paclitaxel (Arms B1 and B2 Only) ............................................................39
3.2.3
Co-administration of Nab-paclitaxel and LMB-100 (Arms B1 and B2 only)....40
3.3
Dose Modifications ...................................................................................................40


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3.3.1
For Arm A1 Subjects Treated at 170 mcg/kg only.............................................40
3.3.2
For all Subjects ...................................................................................................40
3.3.3
Nab-paclitaxel.....................................................................................................42
3.4
Study Calendar..........................................................................................................43
3.4.1
Arms A1 and A2 Calendar..................................................................................43
3.4.2
Arms B1 and B2 Calendar..................................................................................46
3.5
Criteria for Removal from Protocol Therapy and Off Study Criteria.......................49
3.5.1
Criteria for removal from protocol therapy ........................................................49
3.5.2
Follow Up ...........................................................................................................49
3.5.3
Off-Study Criteria...............................................................................................49
3.5.4
Off Protocol Therapy and Off Study Procedure .................................................49
4
Concomitant Medications/Measures...............................................................................49
4.1.1
Permitted Therapy...............................................................................................49
4.1.2
Prohibited Therapy..............................................................................................50
5
Biospecimen Collection..................................................................................................50
5.1
Correlative Studies for Research/Pharmacokinetic Studies......................................50
5.1.1
Pharmacokinetic Assessments ............................................................................50
5.1.2
Assessment of anti-drug antibodies (ADAs) ......................................................51
5.1.3
Mesothelin and Megakaryocyte Potentiating Factor (MPF) Serum Samples:....52
5.1.4
Retrospective Analysis of Mesothelin Expression in tumor tissue.....................53
5.1.5
Cytokines for identification of mechanism for PE-mediated capillary leak syndrome
.............................................................................................................................53
5.1.6
Gene expression-based characterization of the immune landscape before and after 
treatment with LMB-100 ....................................................................................54
5.1.7
Mapping T cell epitopes in LMB-100. ...............................................................55
5.1.8
Assessment of Myeloid Derived Suppressor Cells (MDSC) in Subjects with 
Mesothelioma......................................................................................................56
5.2
Sample Collection schedule ......................................................................................57
5.2.1
Arms A1 and A2 sample collection schedule.....................................................57
5.2.2
Arms B1 and B2 Sample Collection Schedule ...................................................60
5.3
Sample Storage, Tracking and Disposition...............................................................63
5.3.1
Clinical Pharmacology Program.........................................................................63
5.3.2
Leidos Biomedical, Inc. Lab...............................................................................63


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5.3.3
Laboratory of Dr. Raffit Hassan .........................................................................64
5.3.4
NIH Flow Cytometry Laboratory .......................................................................64
5.3.5
Protocol Completion/Sample Destruction ..........................................................64
6
Data Collection and Evaluation ......................................................................................65
6.1
Data Collection..........................................................................................................65
6.2
Data Sharing Plans ....................................................................................................65
6.2.1
Human Data Sharing Plan...................................................................................65
6.2.2
Genomic Data Sharing Plan................................................................................66
6.3
Response Criteria ......................................................................................................66
6.3.1
Definitions...........................................................................................................66
6.3.2
Peritoneal Mesothelioma ....................................................................................67
6.3.3
Pleural Mesothelioma .........................................................................................72
6.3.4
Duration of Response..........................................................................................73
6.3.5
Progression-Free Survival...................................................................................73
6.3.6
Objective Response Rate ....................................................................................74
6.3.7
Disease Control Rate...........................................................................................74
6.3.8
Overall Survival..................................................................................................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...............................................................................74
7.4
NIH Required Data and Safety Monitoring Plan ......................................................75
7.4.1
Principal Investigator/Research Team................................................................75
7.4.2
Safety Monitoring Committee (SMC) ................................................................75
8
Sponsor Safety Reporting ...............................................................................................75
8.1
Definitions.................................................................................................................75
8.1.1
Adverse Event.....................................................................................................75
8.1.2
Serious Adverse Event (SAE).............................................................................75
8.1.3
Life-threatening...................................................................................................76
8.1.4
Severity ...............................................................................................................76


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8.1.5
Relationship to Study Product ............................................................................76
8.2
Assessment of Safety Events ....................................................................................76
8.3
Reporting of Serious Adverse Events .......................................................................77
8.4
Reporting Pregnancy.................................................................................................77
8.4.1
Maternal exposure .............................................................................................77
8.4.2
Paternal exposure................................................................................................78
8.5
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND.............78
9
Clinical Monitoring Plan.................................................................................................78
10
Statistical Considerations................................................................................................78
10.1
Arms A1 and A2 .......................................................................................................79
10.2
Arms B1 and B2........................................................................................................80
10.3
Justification of accrual ceiling ..................................................................................80
11
Collaborative Agreements ..............................................................................................80
11.1
Clinical Trial Agreement...........................................................................................80
12
Human Subjects Protections ...........................................................................................80
12.1
Rationale for Subject Selection.................................................................................80
12.2
Participation of Children...........................................................................................81
12.3
Participation of Subjects Unable to Give Consent....................................................81
12.4
Evaluation of Benefits and Risks/Discomforts .........................................................81
12.4.1 Risks from Study Drugs......................................................................................81
12.4.2 Radiation Risks...................................................................................................81
12.5
Risks/Benefits Analysis ............................................................................................81
12.6
Consent Process and Documentation........................................................................82
12.6.1 Telephone re-consent procedure.........................................................................82
13
REGULATORY AND OPERATIONAL CONSIDERATIONS...................................82
13.1
Quality Assurance and Quality Control ....................................................................82
13.2
Conflict of Interest Policy .........................................................................................83
13.3
Confidentiality and Privacy.......................................................................................83
14
Pharmaceutical Information............................................................................................84
14.1
LMB-100 (IND # 152907)........................................................................................84
14.1.1 Source .................................................................................................................84
14.1.2 Toxicity...............................................................................................................84
14.1.3 Formulation and preparation...............................................................................86


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14.1.4 Stability and Storage...........................................................................................86
14.1.5 Administration procedures..................................................................................86
14.1.6 Incompatibilities .................................................................................................86
14.2
Nab-paclitaxel ...........................................................................................................87
14.2.1 Source .................................................................................................................87
14.2.2 Toxicity...............................................................................................................87
14.2.3 Formulation and preparation...............................................................................88
14.2.4 Stability and Storage...........................................................................................89
14.2.5 Administration procedures..................................................................................90
14.2.6 Incompatibilities .................................................................................................90
15
REFERENCES ...............................................................................................................91
16
APPENDICES ................................................................................................................95
16.1
Appendix A – Performance Status Criteria...............................................................95
16.2
Appendix B – Cockcroft-Gault Formula for Calculation of Creatinine Clearance ..96


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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective:

To identify the recommended phase 2 dose (RP2D) of LMB-100 +/- nab-paclitaxel in 
patients with treatment refractory advanced epithelioid or biphasic mesothelioma. 
1.1.2
Secondary Objectives

To define the pharmacokinetics characteristics of LMB-100 +/- nab-paclitaxel, 
including the number of effective cycles of LMB-100 therapy that can be given before 
the development of anti-LMB-100 antibodies

To assess the safety and tolerability of LMB-100 +/- nab-paclitaxel in patients with 
treatment refractory epithelioid or biphasic mesothelioma

To determine the duration of response, progression free survival and overall survival

To determine the efficacy at the RP2D of LMB-100 +/- nab-paclitaxel with respect to 
objective response rate in patients with treatment refractory advanced epithelioid or 
biphasic mesothelioma.
1.1.3
Exploratory Objectives:

To establish the correlation of response to treatment with tumor mesothelin expression; 

To evaluate changes in the tumor microenvironment following treatment with LMB-
100 +/- nab-paclitaxel 

To identify the mechanism for Pseudomonas exotoxin-mediated capillary leak 
syndrome

To investigate the potential of soluble mesothelin levels and levels of megakaryocyte 


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potentiating factor to predict any therapeutic response
1.2
BACKGROUND AND RATIONALE
1.2.1
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.  
1.2.2
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 and 
pericardium. 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).[8] 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.[9]
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.[10] The Laboratory of Molecular Biology (LMB) and the 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.
1.2.2.1
Recombinant Immunotoxins (RITs) 
1.2.2.1.1 Mechanism and structure of RITs
RITs are antibody-based therapeutics that carry a toxin payload.  RITs that target mesothelin 
contain a genetically engineered variant of Pseudomonas exotoxin A (PE) in which the native cell-


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11
binding domain of PE is replaced by a mesothelin-binding antibody fragment. In this way, the RIT 
binds specifically to mesothelin on the cell surface and gets internalized through endocytic 
processes. In the cytosol, PE catalyzes an irreversible, inactivating modification of eukaryotic 
Elongation Factor-2 (eEF-2). This prevents the elongation step of protein synthesis, halting 
production of new cellular proteins, a stressor that triggers apoptosis. This mechanism of action 
results in cytotoxicity to both proliferating and non-dividing cells, therefore proper targeting is 
critical to the safety profile.[11]  
Tumor-targeted bacterial toxins that inhibit the protein synthesis of cancer cells have previously 
shown signs of preclinical and clinical efficacy. For instance, SS1P, a classical immunotoxin 
format molecule consisting of the mouse anti-mesothelin Fv, SS1 and a 38 kDa PE toxin fragment 
(PE38) is one example. Besides SS1P, the most clinically advanced PE-based immunotoxins are 
moxetumomab pasudotox, a CD22-targeted fusion protein in development by LMB/Astra Zeneca/ 
Medimmune, and LMB2, a CD25-targeted PE fusion protein developed by LMB. Both agents 
have shown encouraging signs of efficacy in different hematological malignancies and are 
currently in Phase II and III clinical trials. Denileukin difitox is the only immunotoxin approved 
by the US Food and Drug Administration (FDA); a fusion protein of diphtheria toxin with 
interleukin-2 that is clinically used for intravenous treatment of cutaneous T cell lymphoma. 
1.2.2.1.2 SS1P - a recombinant immunotoxin targeting mesothelin
The first mesothelin directed agent to enter the clinic was the recombinant immunotoxin (RIT) 
SS1P. The safety and tolerability of SS1P was determined in two phase I clinical trials in patients. 
In one trial SS1P was given as a bolus infusion over 30 minutes and the dose-limiting toxicity was 
pleuritis.[12] In another trial SS1P was given as a continuous infusion for 10 days. Dose-limiting 
side effects were very similar to the bolus infusion trial.[13] In neither trial were major responses 
observed, although there was shrinkage of small volume disease in some patients. Phase I studies 
established a maximum tolerated dose (MTD) of 45 mcg/kg for SS1P given every other day for 
three total doses per cycle. Dose limiting toxicities (DLTs) were pleuritis, an expected on-target 
off-tumor toxicity caused by SS1P-induced inflammation of the normal pleura, and secondly, 
vascular leak syndrome (VLS).  
These early trials demonstrated that the efficacy of SS1P is limited by its immunogenicity. Anti-
SS1P neutralizing antibodies (Nabs) formed after one cycle in ~90% of patients preventing 
effective drug exposure in subsequent cycle.[12, 14] Development of human antibody response to 
immunotoxins in patients with solid tumors has been a significant impediment to their clinical 
development and previous efforts to limit their immunogenicity by treatment with single agents 
such as steroids, cyclophosphamide, cyclosporine or rituximab have not been successful.[15-17] 
However, we have recently shown that when SS1P was administered with a lymphocyte-depleting 
conditioning regimen of pentostatin and cyclophosphamide, it delayed the development of anti-
SS1P antibodies in immunocompetent mice.[18] 
This strategy of using pentostatin and cyclophosphamide to prevent human antibody response to 
SS1P was evaluated in a pilot study of heavily pre-treated chemotherapy refractory mesothelioma 
patients. Eleven patients were enrolled in the study and received pentostatin and 
cyclophosphamide prior to SS1P administration. This regimen was well tolerated and no patient 
developed opportunistic infections. As predicted this regimen decreased the development of 
human antibodies to SS1P; only two of ten patients developed antibodies after cycle 1 of therapy, 
which was significantly better than in prior clinical trials where about 90% of patients developed 
antibodies after one cycle of therapy.[19]   Remarkably, three of the ten evaluable patients with 


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12
extensive tumor burden had durable partial response and two of these patients had complete 
metabolic response by PET scan. All three patients were alive after 27, 25 and 22 months of 
starting therapy. In addition, two patients who did not initially respond to SS1P had a dramatic 
anti-tumor response when treated with chemotherapy to which they had not previously responded. 
SS1P plus pentostatin/cyclophosphamide regimen is currently being evaluated in more patients 
with mesothelioma. Major tumor shrinkage in the neck and abdomen of a patient with metastatic 
peritoneal mesothelioma treated with SS1P in combination with pentostatin and 
cyclophosphamide is shown in Figure 1. 
These results provide a proof of principle that RITs can have meaningful clinical efficacy in 
patients with advanced solid tumors. A new generation of immunotoxin molecules with reduced 
immunogenicity and non-specific toxicity has been developed through protein engineering 
techniques. 
Figure 1.  Representative response to SS1P in a mesothelioma patient
1.2.3
LMB-100
1.2.3.1
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 2 for structure) is a next generation PE-fusion protein that has been protein-
engineered to maximally reduce its immunogenicity by:

Using a fully humanized Fab fragment derived from the anti-mesothelin antibody SS1 for 
tumor targeting


Abbreviated Title: LMB-100 in Mesothelioma
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13

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

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,[20] but has also resulted in reduced incidents of VLS in animal 
models of VLS.[21]
1.2.3.2
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 2).  
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.[21, 22] 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. 
Figure 2. 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. 
1.2.3.3
Nonclinical Studies
1.2.3.3.1 Nonclinical Pharmacology
LMB-100


Abbreviated Title: LMB-100 in Mesothelioma
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14
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.[23, 24] 
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 
high mesothelin expressing A431/H9 cell line or the pancreatic cancer cell line KLM1. Synergy 
was also observed in the HCC70 and MKN-28 cell lines. These results support evidence that LMB-
100 in monotherapy or in combination with standard chemotherapies may provide clinical benefit 
to patients with cancer.
1.2.3.3.2 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 


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15
monkeys developed ADAs upon treatment, while induction of high ADA levels impaired the 
exposure of free drug. In some cases the induction of ADAs may have induced a slight increase in 
exposure
The relationship between systemic drug exposure and anti-tumor activity of LMB-100 was 
investigated on human lung cancer NCI-H596 xenograft growth in female SCID beige mice. Free 
and total drug profiles were similar in mice. Modeling estimated a plasma concentration of 6800 
ng/mL ( 36%) to trigger a half maximal rate of tumor regression. Concentrations of LMB-100 
above this level resulted in potent tumor regression after dosing. Normalized for exposure, SS1P 
was found to be ~3-fold more potent than LMB-100 in terms of tumor growth inhibition.
1.2.3.3.3 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 
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 


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16
macroscopic or serum chemistry findings consistent with VLS. Ultrasound evaluation in the NHP 
GLP study revealed minimal accumulation of pericardial fluid with limited biological significance 
at the highest dose of 1 mg/kg. No appreciable accumulation of pleural fluid was observed at 
necropsy.
In vitro evaluation of LMB-100 in human whole blood assay indicated a low risk for cytokine-
mediated infusion related reaction (IRR)/cytokine release syndrome (CRS) upon first 
administrations. LMB-100 caused no hemolysis when added to human peripheral blood up to the 
highest concentrations of 0.5 mg/L.
1.2.3.3.4 LMB-100 (formerly RG7787) plus nab-paclitaxel (Abraxane) against mesothelioma 
patient derived xenografts (PDX)
Since our prior studies have shown remarkable synergy between immunotoxins and taxanes we 
evaluated the efficacy of nab-paclitaxel with LMB-100. We chose to use nab-paclitaxel instead of 
paclitaxel since clinical trials of paclitaxel have shown no activity in patients with 
mesothelioma.[25, 26] Nab-paclitaxel is an albumin bound paclitaxel that has distinct 
pharmacologic properties compared to paclitaxel including greater uptake by and retention within 
tumor, which could make it efficacious to treat solid tumors.[27]  Potential toxicities of nab-
paclitaxel are listed in section 14.2.2 and product package insert.
Primary mesothelioma cells are much more sensitive to LMB-100 than SS1P: 
Primary mesothelioma cell lines NCI-Meso16, NCI-Meso19, NCI-Meso21 and NCI-Meso29 
established from patients were evaluated for sensitivity to the anti-mesothelin immunotoxins.[28] 
All four of these cell lines are sensitive to killing by LMB-100 with IC50 of 0.3 to 10 ng/ml with 
NCI-Meso21 being most sensitive with an IC50 of 0.3 ng/mL (Figure 3). Surprisingly, most of 
these primary mesothelioma cells except NCI-Meso16 were 2 to 9-fold more sensitive to LMB-
100 than SS1P. In case of nab-paclitaxel, NCI-Meso16, NCI-Meso21 and NCI-Meso29 were 
sensitive to nab-paclitaxel with IC50 of 10, 20 and 25 ng/ml respectively, while as NCI-Meso19 
was resistant with IC50 >100ng/mL (Figure 3). 
Figure 3: Cytotoxicity of LMB-100 and nab-paclitaxel 
against primary mesothelioma cell lines
The in-vitro activity of LMB-100 in combination with nab-paclitaxel was evaluated using NCI-
Meso16, NCI-Meso21 and NCI-Meso29 cell lines since they are sensitive to both LMB-100 and 
nab-paclitaxel. The combination of LMB-100 and nab-paclitaxel resulted in decreased cell 
viability compared to untreated cells, LMB-100 or nab-paclitaxel alone treated cells for all three 
cell lines. This was especially pronounced for NCI-Meso16 cells that had an IC50 of 0.01 for LMB-
100 plus nab-paclitaxel compared to their single agent IC50 of 10 ng/ml (Figure 4A). There was 


Abbreviated Title: LMB-100 in Mesothelioma
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17
also a sharp increase in the % of apoptotic cells when nab-paclitaxel and LMB-100 were used in 
combination vs. nab-paclitaxel or LMB-100 alone (Figure 4B). 
Figure 4: In-vitro synergy between LMB-100 and nab-paclitaxel (A) as well as induction of 
apoptosis (B) against NCI-Meso16 cells.
LMB-100 plus nab-paclitaxel have marked anti-tumor efficacy against mesothelioma PDX 
models:
Figure 5 describes the anti-tumor activity of LMB-100, nab-paclitaxel or combination of the two 
against NCI-Meso16 tumor xenografts. As shown, treatment with LMB-100 or nab-paclitaxel 
slowed tumor growth but after treatment was stopped the tumors rapidly increased in size. 
However, in mice that were treated with LMB-100 plus nab-paclitaxel there was complete tumor 
regression in all mice with 5 /7 mice being tumor free when the experiment was terminated on day 
142. Evaluation of tumors in mice treated with LMB-100 plus nab-paclitaxel showed increased 
apoptosis, decreased Ki-67 staining and decreased mesothelin positive cells compared to LMB-
100 or nab-paclitaxel alone treated mice. Similar anti-tumor efficacy of LMB-100 plus nab-
paclitaxel was also seen against NCI-Meso21 and NCI-Meso29 PDX models. These pre-clinical 
studies provide strong rationale for clinical trial of LMB-100 alone or with nab-paclitaxel to treat 
patients with mesothelioma.
Figure 5: Anti-tumor efficacy of LMB-100 plus nab-paclitaxel against 
mesothelioma PDX NCI Meso-16.
Serum mesothelin is a biomarker of tumor response in mesothelioma PDX models:
Since the NCI-Meso16, NCI-Meso21 and NCI-Meso29 tumors highly express mesothelin we 
hypothesized that these tumors could release human mesothelin in mouse blood and therefore 


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18
measuring the levels could be used to assess response to therapy. As shown in Figure 6 in mice 
with NCI-Meso16 tumors, the serum mesothelin levels increased in the control group and 
decreased in the LMB-100 and nab-paclitaxel group and became undetectable in the combination 
group. There was excellent correlation between tumor size and serum mesothelin levels in these 
mice (r=0.89; p<0.0001). Similarly, in the NCI-Meso21 and NCI-Meso29 tumor model there was 
very good correlation between tumor size and serum mesothelin in the different treatment groups. 
These results provide pre-clinical evidence that serum mesothelin is a robust marker of tumor 
response in mesothelioma and supports earlier clinical observations by us and others that serum 
mesothelin levels correlate with radiologic tumor response in patients.[29-31] 
Figure 6:  Correlation between tumor size, tumor response and serum mesothelin for NCI-
Meso16 tumors.
Based on these data, and the lack of response to single agent LMB-100 (see section 1.2.3.5), with 
this amendment two additional arms will be added to the study to receive combination therapy 
with LMB-100 and nab-paclitaxel.
1.2.3.3.4.1 Nab-paclitaxel dose justification
The standard dose for nab-paclitaxel in non small cell lung cancer is 100 mg/m2 on days 1, 8 and 
15 of each 21 day cycle.  The same dose will be used on this study; however, administration will 
be less frequent (days 1 and 8 of each 21-day cycle) in order to decrease possible toxicity due to 
the combination.  Given the expected side effects of nab-paclitaxel including peripheral sensory 
neuropathy, fatigue and grade 3/4 neutropenia we have reduced the dose frequency of nab-
paclitaxel by 33% to 100 mg/m2 given on days 1 and 8 of each 21-day cycle.
1.2.3.4
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 yrs 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), 


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19
pancreatic cancer (3), and gastroesophageal cancer (2). Tumors from 13 of the 15 participants 
treated had moderately to strongly positive MSLN expression as measured by central IHC analysis. 
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 vascular 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 vascular leak syndrome and proteinuria
NE, Study terminated before DLT assessment period was complete and 
patients only received single dose of LMB-100
1.2.3.4.1 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 
vascular leak syndrome, pyrexia, atrial flutter, 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.  All of 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 


Abbreviated Title: LMB-100 in Mesothelioma
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VLS which manifested with hypotension, respiratory compromise, serosal membrane reaction and 
hyponatremia as well as the hypoalbuminemia and edema that can be seen with mild VLS. Other 
symptoms associated with the DLT dose were fatigue, nausea, vomiting, decreased appetite and 
mild elevation of transaminases.  Table 2 summarizes any adverse event related to LMB-100 while 
as Table 3 summarizes grade 3 or 4 toxicity related to LMB-100. As shown in Table 3 most grade 
3 or 4 toxicity were seen in patients treated at 250 mcg/kg dose level. However, patients receiving 
LMB-100 doses less than 250 mcg/kg had mainly grade 1-2 adverse events except 1 patient having 
grade 3 arthritis and 1 patient with grade 3 anemia.
Table 2: Adverse Events attributed to LMB-1001
Dose (mcg/kg)
45
65
100
170
250
ALL
# of patients treated
1
1
3
4
4
13
Vascular Leak
-
-
1
1
2
4
grade 3 or 4 vascular leak
-
-
-
-
1
1
hypotension
-
-
-
-
2
2
hypoalbuminemia
-
1
3
2
3
9
peripheral edema
1
1
3
2
4
11
facial edema
-
1
2
-
1
4
weight gain
-
-
1
-
1
2
hyponatremia
-
-
-
-
3
3
hypophosphatemia
-
-
-
-
1
1
dyspnea
-
1
-
-
2
3
Infusion related reaction
-
-
2
-
2
4
Constitutional 
 
 
 
 
 
 
fatigue
-
-
-
1
4
5
asthenia
-
-
3
-
-
3
fever
1
-
2
1
2
6
Musculoskeletal
 
 
 
 
 
 
myalgia
-
-
1
1
2
4
arthralgia
1
-
-
-
1
2
arthritis
-
-
1
-
-
1
muscle spasm
-
-
-
1
-
1
Cardiac
 
 
 
 
 
 
pericardial effusion
-
-
-
-
1
1
Atrial flutter
-
-
-
1
-
1
Renal Disorders
 
 
 
 
 
 
glomerulonephritis minimal
-
-
-
1
-
1
proteinuria
-
-
-
1
1
2
Creatinine increase
-
-
-
-
2
2
Gastrointestinal
 
 
 
 
 
 
decreased appetite
-
1
-
1
2
4
nausea
1
-
1
1
4
7
abdominal pain
-
1
-
1
1
3


Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
21
Dose (mcg/kg)
45
65
100
170
250
ALL
# of patients treated
1
1
3
4
4
13
diarrhea
1
-
1
-
-
2
vomiting
-
-
-
-
2
2
abdominal distension
-
1
-
-
-
1
constipation
-
-
-
1
-
1
dyspepsia
-
-
-
1
-
1
AST increase
-
-
-
-
2
2
Hematologic
 
 
 
 
 
 
anemia
-
-
-
1
-
1
decreased lymphocytes
-
-
-
-
1
1
Total Grade 3 or greater
-
-
2
1
2
5
Orange highlighting indicates that one of the patients experienced a grade 3 or 4 toxicity in this category.  Please 
note that there was only 1 patient who experienced a high grade toxicity of each type.
1 adapted from Clinical Study Report No 1066017 from Roche dated December 2015, “Summary of Adverse Events 
Related to Study Medication, Safety-Evaluable Patients Protocol: BP29387” See pages 175-193 of the report.”
Table 3: Grade 3 or 4 Adverse Events Attributed to LMB-100
Dose (mcg/kg)
45
65
100
170
250
ALL
# of patients treated
1
1
3
4
4
13
Vascular leak (gr 4)
-
-
-
-
1
1
Hyponatremia (gr 3)
-
-
-
-
1
1
Anemia (gr 3)
-
-
-
1
-
1
Decreased lymphocytes (gr 3)
-
-
-
-
1
1
Dyspnea (gr 3)
-
-
-
-
1
1
Infusion-related reaction (gr 3)
-
-
1
-
-
1
Arthritis (gr 3)
-
-
1
-
-
1
1 adapted from Clinical Study Report No 1066017 from Roche dated December 2015, “Summary of Adverse Events 
Related to Study Medication, Safety-Evaluable Patients Protocol: BP29387” See pages 175-193 of the report.
1.2.3.4.2 Anti-Drug Antibodies (ADAs) and LMB-100 Drug Levels
Twelve participants were evaluable for efficacy.  The best confirmed overall response was stable 
disease in 3 participants.  A Roche-developed ELISA test was used to retrospectively assess anti-
drug antibody (ADA) titers.  Four of 13 patients had detectable ADAs at study enrollment while 
the remaining participants did not; however, the remaining 10 participants developed detectable 
ADAs by the end of Cycle 2. (Figure 7, Table 4 and Table 5). All evaluable participants achieved 
expected serum drug levels during the first cycle of treatment. Six of 7 participants without pre-
existing ADAs achieved effective drug levels during the second cycle, while 0 of 2 participants 
with pre-existing ADAs did. One of 3 participants that received a third cycle of treatment also 
achieved effective drug levels during this cycle.  A positive test for ADAs did not definitively 
predict poor blood levels in the subsequent cycle (see patient 1101 in Table 5, who had very good 
LMB-100 blood levels despite the presence of ADA). 


Abbreviated Title: LMB-100 in Mesothelioma
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In summary the data regarding LMB-100 ADA and LMB-100 blood levels show:

Presence of ADA is not predictive of ability to achieve measurable LMB-100 concentration 
in the serum, which is the most important parameter for drug efficacy.

Patients who have presence of pre-existing ADA are able to achieve good LMB-100 blood 
levels during cycle 1 (4/4 patients), but may not do so during cycle 2 (2/2 patients with 
undetectable blood levels) although the numbers are small.

Patients who do not have presence of pre-existing ADA are able to achieve good LMB-
100 blood levels during cycle 1 (7/7 patients) as well as cycle 2 (6/7 patients).

Very few patients have been to determine LMB-100 blood levels during cycle 3 and 
beyond. However, 1/3 patients had good LMB-100 blood levels that were in fact higher 
than those achieved during cycle 1 and 2 despite the presence of ADA. In addition, another 
patient had low but detectable blood levels during cycle 3. More patients need to be treated 
to determine what percent of patients will achieve good blood levels during cycle 3 and 
beyond.
Figure 7: Effect of anti-drug antibodies (ADA) on the ability to achieve good LMB-100 blood 
levels in patients treated with LMB-100.


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Version Date: 02/16/2021
23
Table 4: Effect of ADA on LMB-100 blood levels in patients without pre-existing ADA. 
The table shows patients treated at different dose levels of LMB-100; ADA prior to start of each 
cycle and LMB-100 blood levels as Cmax (ng/ml). In addition, the change in LMB-100 Cmax 
concentration (as percent increase or percent decrease) during cycle 2 and 3 is shown as dC1/dC2 
and dC1/dC3 respectively. Please note that – means the PK assay was not performed.
 
 
Cycle 1
Cycle 2
Cycle 3
Patien
t 
Dose 
(mcg/kg)
ADA 
(Day1)
Cmax 
(ng/ml)
ADA 
(Day1)
Cmax 
(ng/ml)
dC1/dC 
(%)
ADA 
(Day1)
Cmax 
(ng/ml)
dC1/dC 
(%)
1002
65
0
1150
8100
711
-38
-
-
-
1401*
100
0
1790
0
1610
-10
24300
267
-85
1402
100
0
1650
0
1360
-18
8100
0
-100
1101*
170
0
2760
300
3950
43
900
3490
26
1202
170
0
3040
0
1940
-36
-
-
-
1301
170
0
3430
72900
527
-85
-
-
-
1403
170
0
1930
900
1550
-20
-
-
-
1102*
250
0
5480
0
4770
-13
-
-
-
1302
250
0
4340
-
-
-
-
-
-
* Patient’s treatment stopped due to study closure
ADA data are from Roche "Bioanalytical Report (ADA) for Clinical Study BP29387“with ADA time 
point codes translated as specified in the BP29837 Lab Manual Version 1.0. Cmax data were taken from 
the Roche final study report.
Table 5: Effect of ADA on LMB-100 blood levels in patients with pre-existing ADA. 
The table shows patients treated at different dose levels of LMB-100; ADA prior to start of each 
cycle and LMB-100 blood levels as Cmax (ng/ml). In addition, the change in LMB-100 Cmax 
concentration (as percent increase or percent decrease) during cycle 2 and 3 is shown as dC1/dC2 
and dC1/dC3 respectively. Please note that – means the PK assay was not performed.
 
 
Cycle 1
Cycle 2
Patient 
Dose 
(mcg/kg)
ADA 
(Day1)
Cmax 
(ng/ml)
ADA 
(Day1)
Cmax 
(ng/ml)
dC1/dC2 
(%)
1001
45
2700
620
196830
0
-100
1201
100
8100
495
196830
0
-100
1501*
250
2700
3730
196830
-
-
1003
250
900
2960
196830
-
-
* Patient’s treatment stopped due to study closure


Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
24
1.2.3.5
Clinical testing of single agent LMB-100 (Current Study – 16C0127 as of 8/15/17)
1.2.3.5.1 Arms A1 and A2 
Figure 8: Serum Creatinine for Patients 1, 2 and 3 treated at 170 µg/kg
C1
D1
C1
D2
C1
D3
C1
D4
C1
D5
C1
D6
C1
D7
C1
D8
C1
D9
C1
D10
C1
D11
C1
D12
C1
D13
C1
D14
C1
D15
C1
D16
C1
D17
C1
D18
C1
D19
C1
D20
C1
D21
Ser
um 
Cre
atini
ne 
(mg
/dL)
PATIENT 1 0.83
0.9 1.021.041.24 1.3 1.351.351.241.141.181.13
0.99
PATIENT 2 1.06
1.03
1.251.311.662.012.272.752.952.942.67
1.95
PATIENT 3 0.99
1.21
1.211.621.611.861.961.881.881.691.76
0
1
2
3
PATIENT 1
PATIENT 2
PATIENT 3
Serum Creatinine (mg/dL)
Serum Creatinine (mg/dL)
As of December 20, 2016 when Arms A1 and A2 (single agent LMB-100) were closed and Arms 
B1 and B2 (LMB-100 + nab-paclitaxel) were established ten patients were enrolled on the study. 
Out of these 10 patients 7 had peritoneal mesothelioma and 3 pleural mesothelioma; 6 female and 
4 male and median age was 62 years old. 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 (Figure 8). Since increase in serum 
creatinine was a common toxicity pattern at this dose level it was defined as DLT as per protocol 
established criteria (per bullet one under Other Toxicities in section 3.1.1). The protocol was 
subsequently amended (Amendment B dated 08/23/16) 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 (3.3.1) of the protocol 
accordingly as part of Amendment B. 
All subsequent patients were treated at 140 mcg/kg. Patients 001-003 have completed 4 cycles of 
LMB-100 treatment (LMB-100 170 mcg/kg during cycle 1 and LMB-100 140 mcg/kg during cycle 
2-4) and seven additional patients have been enrolled at dose level -1 (140 mcg/kg). No DLT’s 
have been observed at the LMB-100 dose level of 140 mcg/kg. Therefore, the recommended phase 
of single agent LMB-100 is 140 mcg/kg given every 3 weeks.


Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
25
Grade 2 infusion reactions were seen in 5 patients at some point during the treatment with LMB-
100. In 2 patients it was seen during cycle 2 and 3 patients during cycle 3 and cycle 4 of treatment. 
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. 
No serious adverse events were observed.  The most frequently occurring events were 
hypoalbuminemia (11 events), anemia (6), increased creatinine (4), decreased lymphocytes (4), 
hyperglycemia (3), dyspepsia (2) and fever (2).  There were single occurrences of limb edema, 
decreased platelets, weight gain and weight loss.  Most of the events were grade 2 with the 
exception of one grade 3 decreased lymphocytes and three grade 3 hyperglycemia.
Out of 10 patients treated with LMB-100 alone who have been evaluated for tumor response after 
cycle 2, 9 had stable disease and 1 had progressive disease.
1.2.3.5.2 Arm B1 
As of August 15, 2017, 6 patients have been treated at Arm B1’s dose level 1 (i.e. LMB-100: 100 
mcg/kg on days 1, 3 and 5 plus nab-paclitaxel: 100 mg/m2 on days 1 and 8 of a 21-day cycle. Of 
these 6 patients, 1 patient was not evaluable for toxicity since he did not receive day 8 nab-
paclitaxel during cycle 1. Of the 5 patients who were evaluable for toxicity we had one DLT (grade 
4 myositis/CPK elevation). 
1.2.3.5.3 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 was done for the first five 
patients treated on the study and is shown in Table 6 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 6, all 10 patients had good LMB-100 blood levels during cycle 1. However 
only 5 of 10 patients had detectable blood levels during cycle 2. None of the 9 patients who got 
cycle 3 of LMB-100 had good LMB-100 blood levels during cycle 3; and none of 6 patients had 
good LMB-100 blood levels during cycle 4. 
Table 6: 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


Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
26
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)
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
N/A
N/A
5
140
1124
140
BQL
N/A
N/A
N/A
N/A
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
2584
140
1099
140
BQL
140
BQL
10
140
3118
140
2450
140
BQL
140
BQL
* BQL: below assay’s quantifiable limit (2.1 ng/mL); 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 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. Based on the result of the data from the 
first 5 patients, as of Amendment C (dated 03/09/17) LMB-100 will only be administered during 
cycles 1 and 2 in patients enrolled subsequent this amendment (Arms B1 and B2).  Previously 
enrolled subjects will continue to receive 4 cycles of LMB-100 as PK data are not yet complete.
1.2.4
Comparison of toxicity and immunogenicity of LMB-100 to SS1P 
LMB-100 was safely administered to four patients at 170 mcg/kg without DLT.  This is nearly 
four times the maximum tolerated dose (MTD) of SS1P.  Most patients without pre-existing ADAs 
were able to achieve effective drug levels of LMB-100 for 2 cycles, unlike what has been seen 
previously with SS1P (see Figure 2 and Figure 9). These data demonstrate that LMB-100 is both 
less toxic and less immunogenic than SS1P. 


Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
27
Figure 9: The ability to achieve good drug levels during cycle 2 is shown for patients who 
were treated on a phase I trial of single agent SS1P[12] and those treated with LMB-100.
Only 9% of patients treated with SS1P had good blood levels during cycle 2 versus 86% for 
patients treated with LMB-100 (p>0.001 by two tailed Fisher’s exact test).  
1.2.5
Rationale for the study
There is clearly an unmet need to identify improved therapies for patients with malignant 
mesothelioma. LMB-100 is a reduced immunogenicity anti-mesothelin RIT developed in NCI’s 
Laboratory of Molecular Biology in collaboration with Roche.  Mesothelin is expressed in over 
95% of epithelioid subtype of malignant mesothelioma. Limited dose escalation completed to date 
indicates safety and provides preliminary data on immunogenicity. Identification of the 
recommended phase 2 dose (RP2D), now established at 140 mcg/kg and preliminary assessment 
of its monotherapy efficacy will inform future studies of LMB-100 in combination with other 
agents. 
As of Amendment C, we also began to evaluate the efficacy and tolerability of 2 cycles of LMB-
100 at the established RP2D in combination with nab-paclitaxel (Arm B) in order to explore the 
synergy between the agents as addressed in section 1.2.3.3.4.  Initially, we planned to study 2 
escalating dose levels of LMB-100, 100 mcg/kg (dose level 1) and 140 mcg/kg (dose level 2) with 
a stable dose of nab-paclitaxel (100 mg/m2). However, as of Amendment F, it was determined that 
that the highest dose level tested would be dose level 1 based on data from a companion protocol 
(16C0128) in which LMB-100+nab-paclitaxel is used the treatment of patients with pancreatic 
cancer. In this study, 2 of 6 subjects treated with an LMB-100 dose of 100 mcg/kg and a nab-
paclitaxel dose 125 mg/ m2 experienced DLT.  Therefore, we have decided not to evaluate dose 
level 2. Dose de-escalation may occur if more than 1 DLT occurs at the initial dose level,  


Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
28
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria (All Arms)
2.1.1.1
Histologically confirmed epithelial or biphasic mesothelioma not amenable to potentially 
curative surgical resection.  However, patients with biphasic tumors that have a ≥ 50% 
sarcomatoid component will be excluded.  The diagnosis will be confirmed by the 
Laboratory of Pathology, CCR, NCI.  
2.1.1.2
Archival sample or fresh biopsy or tumor effusion must be available for confirmation of 
diagnosis.
2.1.1.3
Patients must have measurable disease per RECIST 1.1. as defined per .  (See Section 
6.3).
2.1.1.4
Patients must have had at least one prior chemotherapy regimen that includes pemetrexed 
and cisplatin or carboplatin. There is no limit to the number of prior chemotherapy 
regimens received.  
2.1.1.5
The last dose of previous therapy must have occurred at least 3 weeks prior to the start of 
study therapy. Palliative radiotherapy is allowed up to 2 weeks before the first LMB-100 
infusion. 
2.1.1.6
Patients for whom no standard curable therapy exists
2.1.1.7
Age ≥ 18 years. Because no dosing or adverse event data are currently available on the 
use of LMB-100 alone or in combination with nab-paclitaxel in patients <18 years of age, 
children are excluded from this study 
2.1.1.8
All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure 
must have resolved to Grade  1, except alopecia (any grade) and < Grade 2 peripheral 
neuropathy.
2.1.1.9
ECOG performance status (PS) 0 or1 (Appendix A)
2.1.1.10 Adequate hematological function: neutrophil count of  1.5  109 cells/L, platelet count 
of  100,000/L (transfusion independent, defined as not receiving platelet transfusions 
within 7 days prior to laboratory sample), hemoglobin  9 g/dL
2.1.1.11 Adequate Liver function: AST and ALT < 2.5 X upper limit of normal, alkaline 
phosphatase < 2.5 X upper limit of normal, unless bone metastasis is present (<5 X upper 
limit of normal) in the absence of liver metastasis.
2.1.1.12 Bilirubin  1.5 mg/dL (excluding Gilbert’s Syndrome, see below).
2.1.1.13 Patients with Gilbert’s syndrome will be eligible for the study. The diagnosis of Gilbert's 
syndrome is suspected in people who have persistent, slightly elevated levels of 
unconjugated bilirubin without any other apparent cause. A diagnosis of Gilbert’s 
syndrome will be based on the exclusion of other diseases based on the following criteria:

Unconjugated hyperbilirubinemia noted on several occasions

No evidence of hemolysis (normal hemoglobin, reticulocyte count, and 
LDH)

Normal liver function tests


Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
29

Absence 
of 
other 
diseases 
associated 
with 
unconjugated 
hyperbilirubinemia
2.1.1.14 Adequate renal function: creatinine < 1.5 mg/dL OR creatinine clearance (by Cockcroft 
Gault formula Appendix B)  50 mL/min.
2.1.1.15 Must have serum albumin > 2.5 mg/dL without intravenous supplementation 
2.1.1.16 Must have left ventricular ejection fraction > 50%
2.1.1.17 Must have an ambulatory oxygen saturation of > 90% on room air
2.1.1.18 The effects of LMB-100 alone or in combination with nab-paclitaxel on the developing 
human fetus are unknown.  For this reason:
2.1.1.18.1 Women of child-bearing potential (defined as a sexually mature woman who (1) has not 
undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy 
[the surgical removal of both ovaries] or (2) has not been naturally postmenopausal for 
at least 24 consecutive months [i.e., has had menses at any time during the preceding 24 
consecutive months]) must:

Either commit to true abstinence* from heterosexual contact (which must be 
reviewed on a monthly basis), or agree to use, and be able to comply with, effective 
contraception without interruption, 28 days prior to starting study therapy 
(including dose interruptions), while on study medication and for 3 months after 
the last dose of study therapy; and

Have a negative serum pregnancy test (β -hCG) result at screening and agree to 
ongoing pregnancy testing during the course of the study, and after the end of study 
therapy.  This applies even if the subject practices true abstinence* from 
heterosexual contact.
2.1.1.18.2 Men must agree to practice true abstinence* or agree to use a condom during sexual 
contact with a pregnant female or a female of childbearing potential while participating 
in the study, during dose interruptions and for 6 months following discontinuation of 
study therapy, even if he has undergone a successful vasectomy.
2.1.1.19 Ability of subject to understand and the willingness to sign a written informed consent 
document.
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the 
subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception].
2.1.2
Exclusion Criteria (All Arms)
2.1.2.1
Known or clinically suspected CNS primary tumors or metastases including 
leptomeningeal metastases. History or clinical evidence of CNS metastases unless they 
have been previously treated, are asymptomatic, and have had no requirement for steroids 
or enzyme-inducing anticonvulsants in the last 14 days.
2.1.2.2
Evidence of significant, uncontrolled concomitant diseases which could affect compliance 
with the protocol or interpretation of results, including significant pulmonary disease other 
than primary cancer, uncontrolled diabetes mellitus, and/or significant cardiovascular 
disease (such as New York Heart Association Class III or IV cardiac disease, myocardial 


Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
30
infarction within the last 6 months, unstable arrhythmias, unstable angina, or clinically 
significant pericardial effusion)
2.1.2.3
Active or uncontrolled infections.
2.1.2.4
HIV or active HBV or HCV infection. 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.
2.1.2.5
Patients with prior pneumonectomy
2.1.2.6
Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that would 
contraindicate the use of an investigational drug
2.1.2.7
Major surgery or significant traumatic injury ≤ 28 days prior to the first LMB-100 infusion 
(excluding biopsies) or anticipation of the need for major surgery during study treatment
2.1.2.8
Dementia or altered mental status that would prohibit informed consent
2.1.2.9
Live attenuated vaccinations 14 days prior to treatment
2.1.2.10 Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with LMB-100, breastfeeding should be 
discontinued if the mother is treated with LMB-100.  These potential risks may also apply 
to other agents used in this study.
2.1.2.11 Known hypersensitivity to any of the components of LMB-100
2.1.2.12 High doses of systemic corticosteroids within 7 days prior to first dosing. High dose is 
considered as  20 mg of dexamethasone a day (or equivalent) for  7 consecutive days.
2.1.3
Exclusion Criteria (Arm B only)
2.1.3.1
Subjects must not have received paclitaxel or nab-paclitaxel within 4 months prior to 
initiation of study therapy
2.1.3.2
Participants with contra-indication and/or history of severe hypersensitivity reactions to 
nab-paclitaxel 
2.2
SCREENING EVALUATION
Note: Screening evaluation testing/procedures are conducted under the separate screening 
protocol, 01-C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural 
Research Program Clinical Protocols)
Screening assessments will be performed within 28 days prior to study enrollment.

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 may be collected if archival tumor 
tissue is not available.

History and physical exam

Vital signs including pulse oximetry


Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
31

ECOG performance status

Urine or serum hCG in women of childbearing potential

ECG

Echocardiogram

Chest X-ray

CT scan of chest, abdomen and/or pelvis and areas of known or suspected disease 
involvement; MRI may also be performed when appropriate

FDG-PET scan

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)

Urinalysis

Viral markers – HBSAg, anti-HCV, anti-HIV
2.3
REGISTRATION PROCEDURES
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  After 
confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to advise 
them of the acceptance of the patient on the protocol prior to the release of any investigational 
agents.  Verification of Registration will be forwarded electronically via e-mail to the research 
team. A recorder is available during non-working hours. 
2.3.1
Treatment Assignment Procedures
Cohorts
Letter
Name
Description
A1
Mesothelioma dose de-
escalation
Up to 18 Subjects with epithelial or biphasic mesothelioma 
enrolled to determine RP2D of LMB-100
A2
Mesothelioma 
dose 
expansion
7- 10 (depending on interim efficacy analysis) additional 
subjects with epithelial or biphasic mesothelioma treated at 
RP2D of LMB-100
B1
Mesothelioma 
with 
no 
recent nab-paclitaxel dose 
de-escalation
Up to 12 subjects with epithelial or biphasic mesothelioma 
who have not been treated with nab-paclitaxel in the past 4 
months enrolled to determine the RP2D of LMB-100 +nab-
paclitaxel


Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
32
B2
Mesothelioma 
with 
no 
recent nab-paclitaxel dose 
expansion
7- 10 (depending on interim efficacy analysis) additional 
subjects with epithelial or biphasic mesothelioma who have 
not been treated with nab-paclitaxel in the past 4 months 
treated at RP2D of LMB-100+nab-paclitaxel
Arms
Letter
Name
Description
A1
LMB-100 dose escalation
De-escalating doses of LMB-100 in up to 18 subjects
A2
LMB-100 dose expansion
Fixed dose of LMB-100 as determined in Arm A1 in up to 16 
subjects
B1
LMB-100+ nab-paclitaxel 
dose escalation
De-escalating doses of LMB-100 + fixed dose of nab-
paclitaxel in up to 12 subjects
B2
LMB-100+ nab-paclitaxel 
dose expansion
Fixed dose of LMB-100 as determined in Arm B1 + fixed dose 
of nab-paclitaxel in up to 16 subjects
Arm Assignment
Subjects in cohort A1 are assigned to arm A1.  Subjects in cohort A2 are directly assigned to arm 
A2.  (Note:  Part A of the study is now closed).
Subjects in cohort B1 are assigned to arm B1.  Subjects in cohort B2 are directly assigned to arm 
B2. 
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is an open-label, single center Phase I study of LMB-100 in patients with advanced 
mesothelioma. Four arms will be assessed: Arms A1 and A2: LMB-100 monotherapy and Arms 
B1 and B2: LMB-100 in combination with nab-paclitaxel.

Arms A1 and A2 (closed as of Amendment C- 03/09/17)
Up to 18 patients will be enrolled to test up to 3 de-escalating doses of LMB-100 using a standard 
3+3 design (Arm A1).  Initially, it was planned that up to 16 patients would be evaluated at the 
RP2D, now determined as 140 mcg/kg in the dose expansion portion of the study using a two-
stage Minimax design (Arm A2). Patients treated at the RP2D during the dose de-escalation 
portion of the study were included in the count of 16 patients.  However, as of amendment C, 10 
subjects have been treated at the RP2D and as noted in section 8, enrollment will be temporarily 
halted after the enrollment of 10 evaluable subjects in order to assess PK and ADA data. As no 
subjects have demonstrated a partial or complete response at this dose, Arms A1 and A2 will no 
longer be enrolling.  All future subjects will be enrolled to Arms B1 and B2. 
Subjects previously enrolled on Arms A1 and A2 will continue to be treated as originally planned, 
receiving LMB-100 intravenously on days 1, 3 and 5 of each 21 day cycle.  A maximum of 4 
cycles of treatment will be administered.


Abbreviated Title: LMB-100 in Mesothelioma
Version Date: 02/16/2021
33

Arms B1 and B2
Up to 12 evaluable patients will be enrolled to test up to 2 de-escalating doses of LMB-100 with a 
constant dose of nab-paclitaxel (Arm B1).  Up to 16 patients will be evaluated at the recommended 
phase 2 dose (RP2D) in the dose expansion portion of the study using a two-stage Minimax design 
(Arm B2). Patients treated at the RP2D during the dose de-escalation portion of the study will be 
included in the count of 16 patients.  
In both portions of Arm B, patients will receive LMB-100 intravenously on days 1, 3 and 5 of each 
21 day cycle for up to 2 cycles and nab-paclitaxel on days 1 and day 8 of each 21 day cycle for up 
to 6 cycles.

All Arms
Pharmacokinetic measurements will be performed with each cycle. Assessment of anti-LMB-100 
antibodies will be performed at the start of each cycle. Response to therapy will be assessed at 
baseline and then following every two cycles by CT scan.  Response will be assessed by RECIST 
1.1 or modified RECIST for MPM. Tumor mesothelin expression will be assessed retrospectively. 
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.
3.1.1
Dose Limiting Toxicity (Dose de-escalation cohorts only)
For the purpose of this study, a DLT will be defined as any of the following events attributed to 
LMB-100 (i.e. related to LMB-100) and occurring within 21 days after the first dose of LMB-100, 
the DLT period:
Hematological toxicities:

Grade 4 neutropenia (i.e. absolute neutrophil count (ANC) <0.5 x 109 cells/L) for a 
minimum duration of 7 days)

Grade 3 and 4 febrile neutropenia (i.e. ANC < 1.0 x109 cells/L with a single 
temperature of >38.3°C or a sustained temperature of ≥38°C for more than one hour

Grade 4 thrombocytopenia (≤25.0 x109 cells/L)

Grade 3 thrombocytopenia associated with bleeding episodes
Grade ≥ 3 non-hematological toxicity with the exception of:

Alopecia (any grade)

Grade 3 nausea and vomiting without appropriate treatment

Grade 3 diarrhea lasting for ≤ 2 days with no fever or dehydration

Infusion-related reactions up to and including Grade 3. They are not considered to 
be DLTs since, based on experience with monoclonal antibodies, IRRs are 
idiosyncratic and not dose-related events. Precautions will be taken if IRRs Grade ≥ 2 
occur (see Section 3.3.2). 

Asymptomatic ≥ Grade 3 lymphopenia, leukopenia, hypoalbuminemia, 
dyselectroletemia resolving within 24 hours, increase in alkaline phosphatase. 


Abbreviated Title: LMB-100 in Mesothelioma
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34

Isolated Grade 3 fever (without signs and/or symptoms of an infection) 
occurring within 48 hours of LMB-100 infusion and resolving within 48 hours 
to ≤ Grade 2 and fully resolved within 1 week
Grade ≥ 4 non-hematological toxicity:

Infusion-related reactions
Other toxicities:

Any other drug related toxicity considered significant enough to be qualified as a 
DLT in the opinion of the principal investigator.

Inability to start cycle 2 within 3 weeks of completing cycle 1 due to drug-related 
adverse events.
If a patient experiences a DLT of any grade, LMB-100 will be discontinued in the patient; however, 
nab-paclitaxel may be continued per protocol.
3.1.2
Dose De-Escalation (Arm A1)
Six patients will initially be entered at dose level 1.  If fewer than 2 patients experience DLT during 
within 21 days after the first dose of LMB-100 at the initial level, this will be the RP2D.  Otherwise, 
dose de-escalation will proceed in cohorts of 3–6 patients. The RP2D is the dose level at which no 
more than 1 of up to 6 patients experience DLT during cycle 1. If a patient did not experience DLT 
and did not finish cycle 1, he or she will not be evaluable for toxicity and will be replaced in the 
dose level to ensure that at least 3 patients in each cohort have been assessed for the full DLT 
period prior to moving to the next dose level. If 2 or more DLTs occur at dose level -2, an 
amendment will be submitted in order to explore dose levels lower than 100 mcg/kg.
Table 7: Arm A1 Dose de-escalation table.
Dose De-escalation Schedule
Dose Level
Dose of LMB-100 in µg/kg 
Level 1
170
Level -1
140
Level -2
100
Table 8: Arm A1 Dose de-escalation will follow the rules outlined below.
Number of Patients with 
DLT
at Dose Level 1
De-escalation Decision Rule
0 or 1 out of 6
This will be the recommended phase 2 dose


Abbreviated Title: LMB-100 in Mesothelioma
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35
Number of Patients with 
DLT
at Dose Level 1
De-escalation Decision Rule
≥ 2 out of 6
Enter 3 patients at the next lower dose level
Number of Patients with 
DLT at Any Other Given 
Dose Level
De-escalation Decision Rule
0 or 1 out of 3
Enter up to 3 more patients at this dose level.

If fewer than 2 out of the 6 patients evaluated at 
this dose level experience DLT, this is the 
recommended phase 2 dose.  

If 2 or more out of the 6 patients evaluated at this 
dose level experience DLT, enter 3 patients at 
the next lower dose level.
> 2 out of 3
Enter 3 patients at the next lower dose level.
3.1.3
,Dose De-Escalation (Arm B1)
Dose de-escalation will proceed in cohorts of 6 patients. Before proceeding to the next dose level, 
the last patient enrolled at the previous level must have completed at least one cycle of study 
therapy. The RP2D is the dose level at which no more than 1 of up to 6 patients experience DLT 
during cycle 1, and the dose below that at which at least 2 (of ≤6) patients experience DLT. If a 
patient did not experience DLT and did not finish treatment, he or she will not be evaluable for 
toxicity and will be replaced in the dose. If 2 or more DLTs occur at dose level -1, an amendment 
will be submitted in order to explore LMB-100 dose levels lower than 65 mcg/kg.
Table 9: Arm B1 Dose de-escalation table.
Dose De-escalation Schedule
Dose Level
Dose of LMB-100 in µg/kg 
Nab-paclitaxel in mg/m2
Level -1
65
100
Level 1
100
100


Abbreviated Title: LMB-100 in Mesothelioma
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36
Table 10: Arm B1 dose de-escalation will follow the rules outlined below.
Number of Patients with 
DLT
at a Given Dose Level
De-Escalation Decision Rule
<1 out of 6
This is the recommended phase 2 dose. 
> 2
Enter up to 6 patients at the next lower dose.
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 will be given as an IV solution on Days 1, 3, and 5 (QOD× 3) of every 21 day cycle (up 
to 4 cycles for Arms A1 and A2, up to 2 cycles for Arms B1 and B2).
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
General Instructions
1. LMB-100 drug product should be inspected visually for particulates prior to 
administration.
2. Do not use the solution if there is particulate matter or if it is discolored.
3. Do not shake or freeze the vial contents.
4. Ensure the drug vial content is protected from light during preparation and administration 
(ambient light conditions are acceptable but avoid exposure to direct sunlight).
5. LMB-100 drug product does not contain any preservatives. Vials are for single use only 
and partially used vials must not be reused.  
6. Any unused product should be kept for drug reconciliation.
7. No dilution of LMB-100 drug product into 0.9% saline bags should be performed.
8. Do not administer as IV push or bolus.
9. 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.


Abbreviated Title: LMB-100 in Mesothelioma
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37
3.2.1.2
Specific Instructions 
LMB-100 is diluted with 0.9% NaCl (1:10) in-line immediately prior to administration (see Figure 
10 below). 
The undiluted LMB-100 drug product, filled in a disposable syringe, is administered by 
intravenous syringe infusion using a syringe driver pump.
In order to allow in-line dilution (1:10) immediately prior to administration of neat drug product, 
a side flow with 0.9% NaCl must be applied (as illustrated in Figure 10).  An IV infusion pump 
and syringe driver should be used to control the infusion rate of isotonic 0.9% NaCl solution and 
LMB-100 respectively.  
LMB-100 is administered using peripheral vein access and should not be administered using a 
central venous catheter.
Figure 10: 
Schematic view of the administration set-up.
The LMB-100 drug product should be filtered during withdrawal from the vial 
using a BD filter needle or alternatively, an in-line filter may be used as depicted.  
1. The syringes for administration must be prepared under appropriate aseptic conditions as 
LMB-100 drug product does not contain antimicrobial preservatives. All preparation 
should be conducted under laminar flow hood with safety glasses, lab coat and arm 
protection and a work procedure to minimize particle contamination. 


Abbreviated Title: LMB-100 in Mesothelioma
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38
2. As a measure of precaution, a BD 18G (USA: 19G) blunt filter needle Versapore should 
be used, if no in-line filter is applied, for the withdrawal of the undiluted drug product 
(LMB-100) from the vial into the syringe. 
3. Alternatively, an in-line filter may be used to filter the undiluted drug product (LMB-
100) during syringe infusion before side-flow dilution. For this, an in-line filter (0.2 μm 
pore size) should be positioned between the syringe extension line and the 
injection/infusion valve (see Figure 10). The filtration must occur before in-line dilution 
with 0.9% saline.
4. Withdraw up to 2 mL excess volume of LMB-100 to the intended dosing volume into the 
syringe for priming and purging the syringe extension lines before administration (see step 
8).  
5. The prepared syringe should be stored and transported with a closing cone/stopper.
6. Since LMB-100 drug product does not contain antimicrobial preservatives and to comply 
with the chemical and physical in-use stability, the prepared syringes for infusion should 
be used immediately. If not used immediately, total in-use storage times of prepared 
syringes should not exceed 24 hours to limit microbial growth in case of potential 
accidental contamination.  Storage conditions should generally be at 2°C to 8°C, but 
syringes may be held at room temperature for up to a maximum of 4 hours.  The 
temperature during syringe preparation, storage and drug administration must not exceed 
25 °C.
7. Establish the saline flow first by flushing the lines including the 4-way stopcock and 
extension lines with saline. 
8. Put the filled syringe in the pre-programmed syringe driver, remove the cap and attach the 
infusion set. Follow the syringe driver manual/local instructions regarding how to set up 
and prime/purge the system before the line is attached to the closed 4-way stopcock before 
starting the administration.
9. The end of infusion is defined as the time point at which the syringe driver finishes 
administering the total volume of LMB-100 to be infused. 
10. At the end of the first infusion, the IV line should remain in place for 2 hours. 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. If feasible, the line for drawing blood for PK samples 
(opposite extremity to the one with the infusion line) will remain in place until the 24-hour 
sample is taken.
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 


Abbreviated Title: LMB-100 in Mesothelioma
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39
0.9% NaCl should be done in line, immediately prior to administration of the neat DP. The infusion 
duration should be 30 minutes (± 5 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 3.3.2.
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:
o
Diphenhydramine 25-50 mg PO or IV
o
Ranitidine 150 mg PO
o
Acetaminophen 650 mg PO
o
Dexamethasone 20 mg, PO, 6-12 hours prior to LMB-100 administration, OR
o
Dexamethasone 10 mg, IV, 30 – 60 minutes (+30 minutes) prior to LMB-100 
administration, OR
o
equivalent dose of another corticosteroid as clinically indicated
(See section 3.2.2 for complete instructions on response to IRRs)
Participants who experienced an IRR of Grade 3 or 4 on a previous infusion where dexamethasone 
or another steroid was pre-administered should not receive further LMB-100 and will be 
discontinued from study therapy.
Table 11 - Premedication for LMB-100
Dose (mg)
Route
Acetaminophen
650
Orally
Ranitidine
150
Orally
Diphenhydraminea
25-50
Orally or IV
Dexamethasoneb
10
OR
IV
Dexamethasoneb
20
Orally
a or alternative antihistamine at an adequate dose.
b or equivalent dose of another corticosteroid administered if a >grade 2 IRR occurred on a previous 
infusion despite standard pre-medication.
3.2.2
Nab- paclitaxel (Arms B1 and B2 Only)
Nab-paclitaxel will be administered at a dose of 100 mg/m2, intravenously over 30 minutes on Days 
1 and 8 of each 21 day cycle for up to 6 cycles in the absence of toxicity or disease progression. 


Abbreviated Title: LMB-100 in Mesothelioma
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40
Detailed information about the preparation of the infusion solution and administration of nab-
paclitaxel including information about compatible infusion bags, administration sets, and in line 
filters can be found in the package insert.
3.2.3
Co-administration of Nab-paclitaxel and LMB-100 (Arms B1 and B2 only)
On days when both LMB-100 and nab-paclitaxel are both scheduled to be administered (Day 1 of 
cycles 1 and 2), nab-paclitaxel will be administered first. LMB-100 infusion will be initiated 30 
minutes after completion of the nab-paclitaxel.
3.3
DOSE MODIFICATIONS
3.3.1
For Arm A1 Subjects Treated at 170 mcg/kg only
As discussed in section 1.2.3.5, the three subjects treated at 170 mcg/kg will be subsequently dosed 
at 140 mcg/kg.  Any further adverse events will be managed as per Table 12 below.
3.3.2
For all Subjects
Table 12 below provides a guideline on how to manage certain toxicities which are expected with 
LMB-100 based on preclinical studies and previous clinical experience with molecules in the same 
class
Table 12 - 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


Abbreviated Title: LMB-100 in Mesothelioma
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41
Event
Action to Be Taken
o
Patients experiencing IRR CTCAE Grade 4 or 
anaphylaxis must be permanently discontinued from 
LMB-100 treatment
Vascular leak syndrome
In the event of Grade ≥2 CTCAE vascular 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 each 
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 


Abbreviated Title: LMB-100 in Mesothelioma
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42
Event
Action to Be Taken
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 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
Periodic monitoring of renal function and serum electrolytes
IV fluids 0.9 NaCl may be administered after LMB-100 
infusion if clinically indicated because of increasing serum 
creatinine or decreased urine output.
IRR = infusion related reaction; IV = intravenous; CTCAE = Common Terminology Criteria for 
Adverse Events
3.3.3
Nab-paclitaxel
If nab-paclitaxel is withdrawn prior to cycle 2, LMB-100 may still be continued in the absence of 
progressive disease.
Dose modifications of nab-paclitaxel for myelosuppression and other chemotherapy related 
toxicities will be made as per the NSCLC instructions in the package insert.


Abbreviated Title: LMB-100 in Mesothelioma
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3.4
STUDY CALENDAR
3.4.1
Arms A1 and A2 Calendar
1 cycle =21 days
Screening assessments must occur within 28 days prior to enrollment.  If screening assessments are performed within 3 days prior to 
dosing, the assessments do not need to be repeated on C1D1 unless otherwise indicated (see ECG and pregnancy test below).
Assessments after C1D1 may be performed up to 3 days prior to indicated time unless otherwise indicated.
Dosing cycles after cycle 1 may be delayed for up to two weeks to accommodate schedule conflicts, Federal holidays and inclement 
weather, etc.
Cycle 1
Subsequent Cycles
Post Therapy Follow-up
Procedure
Screening
Day 
1
Day 
3
Day 
5
Day 
8
Day 
15
Day 
1
Day 
3
Day 
5
Day 
8
Day 
15 
Follow-Up 
Visit13
Long-Term 
Follow Up
LMB-100
X
X
X
X
X
X
History and PE
X
X
X
X
X
X
X
X
X
C2 
only
X
Weight
X
X
X
X
X
X
X
X
C2 
only
X
Height
X
Vital signs1
X
X
X
X
X
X
X
X
X
C2 
only
X
Performance Score
X
X
X
Labs2
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
HLA Typing (Class I 
and Class II)
X3
Anti HIV, anti HCV, 
HBSAg
X
Urine or serum hCG in 
women of childbearing 
potential4
X
X5
X
X
Confirmation of dx6
X
NIH 
Advance 
Directives Form
X7


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44
Cycle 1
Subsequent Cycles
Post Therapy Follow-up
Procedure
Screening
Day 
1
Day 
3
Day 
5
Day 
8
Day 
15
Day 
1
Day 
3
Day 
5
Day 
8
Day 
15 
Follow-Up 
Visit13
Long-Term 
Follow Up
Biopsy (optional)
X8
C3 
only9
Correlative 
Research 
Studies 
Please see section 5.2
PK 
Please see section 5.2.1
CT CAP and/or if 
clinically indicated 
MRI +/- gadolinium
X
Every 6 weeks ± 7 days
X10
X14
FDG-PET
X
Every 6 weeks ± 7 days
X10
X14
ECG11
X
X
X
X
X
X
X
X
Echocardiogram
X
Chest X-Ray12
X
X
X
Annual phone call to 
monitor survival and 
additional CA therapy
X
Adverse Events
Monitored continuously
Concomitant 
Medications
Monitored continuously
1
At screening: heart rate, blood pressure, body temperature, pulse oximetry. During the infusions of all study medication in Cycles 1 and 2, 
vital signs (heart rate, blood pressure, body temperature) have to 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. From Cycle 3 onwards, vital 
signs have to be monitored only pre and post infusion if study medication has been tolerated well in previous cycles. 
2
CBC with differential, Acute Care Panel, Hepatic Panel, Mineral Panel, creatine kinase, C-reactive protein, PT, PTT, fibrin degradation products.
3
May be performed after study consent is signed but prior to treatment initiation (baseline)
4
Required in women of childbearing potential; i.e. premenopausal women and women ≤ 2 years after menopause (menopause is defined as 
amenorrhea for > 2 years.
5
Only required if more than 14 days have passed since screening.
6
Please see section 2.2 for tissue requirements
7
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.
8
To be performed at baseline – any time after patient has signed the study consent, but before study therapy initiation.
9
To be performed after the completion of 2 cycles of study therapy.


Abbreviated Title: LMB-100 in Mesothelioma
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45
10
Performed only if patient removed from study therapy for reason other than progressive disease
11
Single 12-lead ECG will be recorded at screening (within 7 days before first dose of study treatment), then pre- and end of LMB-100 infusion 
for first 3 cycles 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.
12
Chest X-rays will be obtained at screening and pre-infusion time on indicated dosing days. In addition, Chest X-ray will be performed when 
clinically indicated during the study treatment period. Chest X-rays will be obtained at the time of the tumor assessments, when convenient
13
The assessments listed refer to those that will be performed if the patient is seen in clinic 4- 6 weeks after the last dose of study drug.  If the 
patient is unable to return to the clinic for the follow up visit, an adverse event assessment will be performed by telephone.
14
Scans performed only in patients who have not had progressive disease.  Scans will continue every 6 weeks until disease progression.


Abbreviated Title: LMB-100 in Mesothelioma
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3.4.2
Arms B1 and B2 Calendar
1 cycle =21 days
Screening assessments must occur within 28 days prior to enrollment.  If screening assessments are performed within 3 days prior to 
dosing, the assessments do not need to be repeated on C1D1 unless otherwise indicated (see ECG and pregnancy test below).
Assessments after C1D1 may be performed up to 3 days prior to indicated time unless otherwise indicated.
Dosing cycles after cycle 1 may be delayed for up to two weeks to accommodate schedule conflicts, Federal holidays and inclement 
weather, etc.
Cycle 1 and cycle 2
Subsequent Cycles
Post Therapy Follow-up
Procedure
Screening
Day 
1
Day 
3
Day 
5
Day 
8
Day 
15
Day 
1
Day 
3
Day 
5
Day 
8
Day 
15 
Follow-Up 
Visit13
Long-Term 
Follow Up
LMB-100
X
X
X
Nab-paclitaxel
X
X
X
X
History and PE
X
X
X
X
X
C1 
only
X
X
X
Weight
X
X
X
X
C1 
only
X
X
X
Height
X
Vital signs1
X
X
X
X
X
C1 
only
X
X
X
Performance Score
X
X
X
Labs2
X
X
X
X
X
C1 
only
X
X
X
Urinalysis
X
X
X
HLA Typing (Class I 
and Class II)
C1 
only 
3
Anti HIV, anti HCV, 
HBSAg
X
Urine or serum hCG in 
women of childbearing 
potential4
X
X5
X
X
Confirmation of dx6
X
NIH 
Advance 
Directives Form
X7


Abbreviated Title: LMB-100 in Mesothelioma
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Cycle 1 and cycle 2
Subsequent Cycles
Post Therapy Follow-up
Procedure
Screening
Day 
1
Day 
3
Day 
5
Day 
8
Day 
15
Day 
1
Day 
3
Day 
5
Day 
8
Day 
15 
Follow-Up 
Visit13
Long-Term 
Follow Up
Biopsy (optional)
X8
C3 
only9
Correlative 
Research 
Studies 
Please see section 5.2.2
PK 
Please see section 5.2.2
CT CAP and/or if 
clinically indicated 
MRI +/- gadolinium
X
Every 6 weeks ± 7 days
X10
X14
FDG-PET
X
Every 6 weeks ± 7 days
X10
X14
ECG11
X
X
X
X
X
X
Echocardiogram
X
Chest X-Ray12
X
C2 
only
C1 
only
Annual phone call to 
monitor survival and 
additional CA therapy
X
Adverse Events
Monitored continuously
Concomitant 
Medications
Monitored continuously
1
At screening: heart rate, blood pressure, body temperature, pulse oximetry. During the infusions of all study medication in Cycles 1 and 2, 
vital signs (heart rate, blood pressure, body temperature) have to 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. From Cycle 3 onwards, vital 
signs have to be monitored only pre and post infusion if study medication has been tolerated well in previous cycles. 
2
CBC with differential, Acute Care Panel, Hepatic Panel, Mineral Panel, creatine kinase, C-reactive protein, PT, PTT, fibrin degradation products.
3
May be performed after study consent is signed but prior to treatment initiation (baseline)
4
Required in women of childbearing potential; i.e. premenopausal women and women ≤ 2 years after menopause (menopause is defined as 
amenorrhea for > 2 years.
5
Only required if more than 14 days have passed since screening.
6
Please see section 2.2 for tissue requirements
7
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.
8
To be performed at baseline – any time after patient has signed the study consent, but before study therapy initiation.


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9
To be performed after the completion of 2 cycles of study therapy.
10
Performed only if patient removed from study therapy for reason other than progressive disease
11
Single 12-lead ECG will be recorded at screening (within 7 days before first dose of study treatment), then pre- and end of LMB-100 infusion 
for the first 2 cycles 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.
12
Chest X-rays will be obtained at screening and pre-infusion time on indicated dosing days. In addition, Chest X-ray will be performed when 
clinically indicated during the study treatment period. Chest X-rays will be obtained at the time of the tumor assessments, when convenient
13
The assessments listed refer to those that will be performed if the patient is seen in clinic 4- 6 weeks after the last dose of study therapy.  If the 
patient is unable to return to the clinic for the follow up visit, an adverse event assessment will be performed by telephone.
14
Scans performed only in patients who have not had progressive disease.  Scans will continue every 6 weeks until disease progression.


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3.5
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
3.5.1
Criteria for removal from protocol therapy
Prior to removal from study, a safety follow up visit as indicated in section 3.5.2 must be 
completed.

Progressive disease

Arm A1 or A2 participant has completed 4 cycles of study therapy

Arm B1 or B2 participant has completed 6 cycles of study therapy

Participant requests to be withdrawn from active therapy

Pregnancy

Unacceptable Toxicity as defined in sections 3.1.1 and 3.3

Investigator discretion
3.5.2
Follow Up
All patients will be asked to return for a follow up visit ~ 4 – 6 weeks after the last dose of the 
study drug (see Study Calendar for assessments). If the subject is unable to return to the NIH, a 
brief assessment for adverse events will be performed by telephone. Subjects who have not had 
progressive disease will continue to have follow-up scans every 6 weeks until disease progression. 
Thereafter, all patients or their physicians will be contacted annually by telephone to assess 
survival status and additional anti-cancer therapy.
3.5.3
Off-Study Criteria

Patient lost to follow-up

Participant requests to be withdrawn from study+

Death
+ Patient will be required to complete follow up visit prior to removal from study therapy for this reason.
3.5.4
Off Protocol Therapy and Off Study Procedure
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office  
ncicentralregistration-l@mail.nih.gov.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1.1
Permitted Therapy
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter (OTC) 
drugs, approved dietary and herbal supplements, nutritional supplements) used by a patient from 


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the screening period until the follow-up visit. If any treatment is given within 4 weeks prior to 
screening this should be reported to the investigator and recorded in the eCRF.
All therapy and/or medication administered to manage adverse events should be recorded on the 
Adverse Event eCRF
4.1.2
Prohibited Therapy
Patients should be treated for all concomitant conditions and adverse events according to accepted 
standards of medical care at the discretion of the investigator. The following treatments are not 
permitted during the study:

Any other investigational therapy

Cytotoxic chemotherapy agents other than study agents

Radiotherapy. Note: palliative 8Gy radiotherapy is allowed.

Immunosuppressive therapy and chronically administered glucocorticoids (high dose is 
considered as  20 mg of dexamethasone a day [or equivalent)] for  7 consecutive days)

Other systemic anti-neoplastic agents and targeted therapies
If any anti-neoplastic or investigational therapies listed above are needed, the patient will be 
considered to have evidence of progressive neoplastic disease and have experienced treatment 
failure with study treatment and should be withdrawn from study treatment.
All concomitant treatments must be documented in the eCRF.
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 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.


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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:
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 Dr. Jon Inglefield in Frederick 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 collected before first dose of LMB-100 administration during each cycle in which 
LMB-100 is administered (See 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.  


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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 Dr. Jon Inglefield in Frederick 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
5.1.2.4
Sample Storage
Samples will be stored in the CPP until shipment to the Leidos Biomedical Inc. Lab in Frederick. 
5.1.3
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.
5.1.3.1
Sample Collection 
Samples will be obtained as follows:

Arms A1 and A2 - prior to the first LMB-100 dose of each cycle and at the end of treatment

Arms B1 and B2 -prior to the first LMB-100 dose of cycles 1 and 2, prior to the first nab-
paclitaxel administration during cycles 3 – 6, 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 (tiger 
top tube) labeled as follows:
- Subject ID Number 
- Study Number 
- Time and date of collection
5.1.3.2
Sample Processing
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.


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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.
5.1.3.3
 Sample Storage
All serum samples will be stored by Dr. Figg’s Clinical Pharmacology Program.
5.1.4
Retrospective Analysis of Mesothelin Expression in tumor tissue
IHC analysis will be performed by the Laboratory of Pathology at NCI to determine mesothelin 
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 or after 
cycle 2 may be used for this purpose. Specimens will be used to correlate treatment with response 
with mesothelin expression in an exploratory analysis. 
5.1.4.1
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 2). 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.
5.1.5
Cytokines for identification of mechanism for PE-mediated capillary leak syndrome
PE-based RITs cause dose-limiting CLS. At low doses CLS manifests as mild and transient weight 
gain, hypoalbuminemia, and peripheral or facial edema.  At higher doses it can cause life-
threatening cardiopulmonary compromise. Previous studies in rats have indicated that pathological 
changes indicative of CLS onset occur within just two hours of toxin administration and even when 
the PE fragment lacks a targeting domain.[32] In vitro studies with cultured endothelial cells have 
demonstrated that super-physiologic doses of PE-based RITs cannot induce endothelial cell 
toxicity unless the cells express the RIT target.[33] Together these data suggest the hypothesis that 
PE-based RITs cause CLS by triggering release of vasoactive cytokines by specific immune 
cells rather than through direct damage to endothelial cells. 
5.1.5.1
Specimen collection 
To test this hypothesis, we will collect additional serum from participants during each of LMB-
100 therapy on:

Days 1, 3, and 5 (Pre-dose)

Day 8


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in 4 mL red SST tubes  
5.1.5.2
Sample processing
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
Cytokine levels will be retrospectively assessed.
5.1.6
Gene expression-based characterization of the immune landscape before and after 
treatment with LMB-100
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. We will evaluate tumor biopsies before and after treatment with 
LMB-100 (using samples referenced in section above) 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 also 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. 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 also markers expressed by tumor cells 
and tumor stroma. To cover those target transcripts, a combination of a commercially available 
pre-designed probe set (GX Human Immunology v2, NanoString Technologies) will be used in 
combination with a custom-designed code set of thirty additional targets (Panel Plus, NanoString 
Technologies). Hybridization complexes will be quantified using a NanoString nCounter Analysis 
System, at the Genomics Core Facility of the Center for Cancer Research, NCI.  
Results obtained by this approach will be correlated with data obtained from 
immunohistochemistry of tumor biopsies as well as with data from analysis of peripheral blood 


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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.
5.1.7
Mapping T cell epitopes in LMB-100.
Identification and investigation of T cell epitopes in therapeutic proteins is important for 
understanding of the immunogenicity response against LMB-100. Identification of those T cell 
epitopes will allow us to engineer the next generation of immunotoxin which will be less 
immunogenic because it will have less T cell epitopes. 
Method: For T cell epitope mapping we isolate PBMC from patients that were previously treated 
with the immunotoxin and had neutralizing antibodies. PBMC are frozen at a concentration of 1.5 
x107 cells/ml/vial. Cells are viably frozen in the following freezing media: RPMI, 10% human AB 
serum, 1% P/S (antibiotic) and 7.5% DMSO.   
The PBMC are stimulated with the whole protein and the activated T cells are expanded using 
human IL2 which is a lymphocyte stimulator. Next, the in vitro expanded PBMC are re- stimulated 
with a peptide library spanning the sequence of the Fab portion of the immunotoxin. The T cell 
activation is detected by monitoring secretion of IL2 using IL2 ELISpot.
An illustration of the method, the controls and threshold determination were previously described 
in Mazor et al 2012.[20] 
5.1.7.1
Sample collection
Samples will be collected at baseline and at the end of treatment in eight 8 mL whole blood tubes 
(black and blue).” [BD Vacutainer® CPT (REF 362761)]
5.1.7.2
Sample processing
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
PBMCs will be processed within 6 hours post-collection using Ficoll- Hypaque density-gradient 
separation according to manufacturer’s instructions.  Collect the buffy coat and wash three times 
with Dulbecco's PBS without Ca and Mg. Cryopreserve in liquid nitrogen at a concentration of 1.5 
x 107 cells/mL in RPMI1640 supplemented with 5% human AB serum and 7.5% DMSO.
5.1.7.3
Sample storage
Samples will be stored in by the Clinical Pharmacology Program; analyses will be performed in 
the laboratory of Dr. Raffit Hassan. 


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5.1.8
Assessment of Myeloid Derived Suppressor Cells (MDSC) in Subjects with Mesothelioma
5.1.8.1
Sample collection
Samples will be collected at baseline prior to first dose of LMB-100 and the end of cycle 2 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 (30 mL) will be drawn into three 10 mL 
sodium heparin (green top) tubes.
The tube should be labeled with the following information:
- Subject ID Number 
- Study Number  
- Time and date of collection 
-Specimen type: peripheral blood
5.1.8.2
Sample processing
The samples will be sent to NIH flow lab located at 3S240, South part of Building 10.
All specimens for flow cytometry will be scheduled in advance by contacting Dr. Stetler-
Stevenson stetler@mail.nih.gov and/or Dr. Yuan yuanc@mail.nih.gov by email. Peripheral blood 
samples should arrive no later than 1 pm to the flow cytometry laboratory on the day scheduled.
Specimens are received in the laboratory via escort or via delivery by someone from the clinical 
team. Specimens for delivery AFTER HOURS ONLY may also be placed in the secure specimen 
drop box located in Laboratory of Pathology 3N hallway. Peripheral blood specimens are collected 
in sodium heparin tubes, and are stored at room temperature until delivery. 
The specimens should be delivered as soon as possible after collection, and cannot be evaluated if 
> 48 hours old.  
Upon receipt in the flow lab, the sample will be checked for correct labeling with appropriate 
patient identifiers and specimen type (e.g. peripheral blood). 


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5.2
SAMPLE COLLECTION SCHEDULE
5.2.1
Arms A1 and A2 sample collection schedule
PK
(5.1.1)
ADA
(5.1.2)
Serum 
mesothelin and 
MPF
(5.1.3)
PE 
mediated 
CLS 
(Cytokines)
(5.1.5)
T-cell 
epitopes
(5.1.7)
MDSC 
Assessment
(5.1.8)
Tumor 
Samplea
(5.1.4,5.1.6)
Cycle
Day
2 
mL 
K2EDTA 
tube
2 
mL 
K2EDTA 
tube
2 mL blood in 
3.5 mL tiger top 
tube
4 mL red SST 
tube
Eight 8 mL 
whole blood 
tubes
Three 
10 
mL 
sodium 
heparin 
(green top) tubes
NA
Screening
Screening 
period ± 3 
days
 
 
 
Xa
1
Pre-dose, EOI, 1, 2, 
3, 4, and 6 hours 
after 
start 
of 
infusion
Pre-dose
X
Pre-dose
Xb
Xb
Xc
3
Pre-dose
5
Pre-dose, EOI, 1, 2, 
3, 4, and 6 hours 
after 
start 
of 
infusion
Pre-dose
1
8
X


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PK
(5.1.1)
ADA
(5.1.2)
Serum 
mesothelin and 
MPF
(5.1.3)
PE 
mediated 
CLS 
(Cytokines)
(5.1.5)
T-cell 
epitopes
(5.1.7)
MDSC 
Assessment
(5.1.8)
Tumor 
Samplea
(5.1.4,5.1.6)
Cycle
Day
2 
mL 
K2EDTA 
tube
2 
mL 
K2EDTA 
tube
2 mL blood in 
3.5 mL tiger top 
tube
4 mL red SST 
tube
Eight 8 mL 
whole blood 
tubes
Three 
10 
mL 
sodium 
heparin 
(green top) tubes
NA
1
Pre-dose, EOI, 1, 2, 
3, 4, and 6 hours 
after 
start 
of 
infusion
Pre-dose
X
Pre-dose
3
Pre-dose
5
Pre-dose, EOI
Pre-dose
2
8
X
1
Pre-dose and EOI
Pre-dose
X
Pre-dose
X 
(end of cycle 2)
Xc
3
Pre-dose
5
Pre-dose and EOI
Pre-dose
3 & 4
8
X
At time of 
Progression
 
 
X
 
End 
of 
Treatment
X
X
X


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PK
(5.1.1)
ADA
(5.1.2)
Serum 
mesothelin and 
MPF
(5.1.3)
PE 
mediated 
CLS 
(Cytokines)
(5.1.5)
T-cell 
epitopes
(5.1.7)
MDSC 
Assessment
(5.1.8)
Tumor 
Samplea
(5.1.4,5.1.6)
Cycle
Day
2 
mL 
K2EDTA 
tube
2 
mL 
K2EDTA 
tube
2 mL blood in 
3.5 mL tiger top 
tube
4 mL red SST 
tube
Eight 8 mL 
whole blood 
tubes
Three 
10 
mL 
sodium 
heparin 
(green top) tubes
NA
Follow-up 
Visit 
 
 
X
 
 
ADA =anti-drug antibody; EOI =End of infusion; PK =pharmacokinetic; MDSC= myeloid derived suppressor cell
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.
May be collected prior to day 1 at any time after the consent is signed (baseline).
c.
Optional biopsies – collected at baseline (biopsy if collected at screening can be used as baseline sample) and at any time after the completion 
of 2 cycles of therapy.


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5.2.2
Arms B1 and B2 Sample Collection Schedule
PK
(5.1.1)
ADA
(5.1.2)
Serum 
mesothelin and 
MPF
(5.1.3)
PE 
mediated 
CLS 
(Cytokines)
(5.1.5)
T-cell 
epitopes
(5.1.7)
MDSC 
Assessment
(5.1.8)
Tumor 
Samplea
(5.1.4,5.1.6)
Cycle
Day
2 
mL 
K2EDTA 
tube
2 
mL 
K2EDTA 
tube
2 mL blood in 
3.5 mL tiger top 
tube
4 mL red SST 
tube
Eight 8 mL 
whole blood 
tubes
Three 
10 
mL 
sodium 
heparin 
(green top) tubes
NA
Screening
Screening 
period ± 3 
days
 
 
 
Xa
1
Pre-dose, EOI, 1, 2, 
3, 4, and 6 hours 
after 
start 
of 
infusion
Pre-dose
X
Pre-dose
Xb
Xb
Xc
3
Pre-dose
5
Pre-dose, EOI, 1, 2, 
3, 4, and 6 hours 
after 
start 
of 
infusion
Pre-dose
1
8
X
1
Pre-dose, EOI, 1, 2, 
3, 4, and 6 hours 
after 
start 
of 
infusion
Pre-dose
X
Pre-dose
2
3
Pre-dose


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PK
(5.1.1)
ADA
(5.1.2)
Serum 
mesothelin and 
MPF
(5.1.3)
PE 
mediated 
CLS 
(Cytokines)
(5.1.5)
T-cell 
epitopes
(5.1.7)
MDSC 
Assessment
(5.1.8)
Tumor 
Samplea
(5.1.4,5.1.6)
Cycle
Day
2 
mL 
K2EDTA 
tube
2 
mL 
K2EDTA 
tube
2 mL blood in 
3.5 mL tiger top 
tube
4 mL red SST 
tube
Eight 8 mL 
whole blood 
tubes
Three 
10 
mL 
sodium 
heparin 
(green top) tubes
NA
5
Pre-dose, EOI
Pre-dose
8
X
1
X
X 
(end of cycle 2)
Xc
3
5
3 -6
8
At time of 
Progression
 
 
X
 
End 
of 
Treatment
X
X
X
Follow-up 
Visit 
 
 
X
 
 


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ADA =anti-drug antibody; EOI =End of infusion; PK =pharmacokinetic; MDSC= myeloid derived suppressor cell
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.
May be collected prior to day 1 at any time after the consent is signed (baseline).
c.
Optional biopsies – collected at baseline (biopsy if collected at screening can be used as baseline sample) and at any time after the completion 
of 2 cycles of therapy.


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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 the Labmatrix utilized by the CPP. . This is a secure program, with access to t 
Labmatrix limited to defined CPP 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 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°C or -80°C 
according to stability requirements. These freezers are located onsite in the CPP and offsite at NCI 
Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to 
be accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused samples 
must be returned to the CPP. 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 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 


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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
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)
5.3.4
NIH Flow Cytometry Laboratory
Specimens received in the flow cytometry laboratory are accessible only to the flow cytometry 
laboratory team, as the laboratory door is locked and key access is only provided to the flow 
cytometry laboratory members.  Additionally, the flow cytometry laboratory is set behind a set of 
double doors that are accessible only by badge/key card access.
5.3.5
Protocol Completion/Sample Destruction
All specimens obtained in the protocol are used as defined in the protocol. Any specimens 
remaining at the completion of the protocol will be stored in the conditions described above. The 
study will remain open as long as sample or data analysis continues. Samples from consenting 
subjects will be stored until they are no longer of scientific value or until a subject withdraws 
consent for their continued use, at which time they will be destroyed. Once primary research 
objectives for the protocol are achieved, intramural researchers can request access to remaining 
samples, provided they have an IRB-approved protocol and patient consent or an exemption from 
OHSRP. 
The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be 
made per the requirements of section 7.2.1.


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6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
Study data will be recorded and stored in the C3D and Labmatrix databases. The PI will be 
responsible for overseeing entry of data into an in-house password protected electronic system 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 30 days after the study 
intervention was last administered.  Beyond 30 days after the last intervention, only adverse events 
which are serious and related to the study intervention need to be recorded. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.  
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:
_X_ Coded, linked data in an NIH-funded or approved public repository.  
_X_ Coded, linked data in BTRIS 


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_X_ 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:
_X_ An NIH-funded or approved public repository.  Insert name or names:__clinicaltrials.gov__.
_X_ BTRIS (automatic for activities in the Clinical Center)
_X_ Approved outside collaborators under appropriate individual agreements.
_X_ Publication and/or public presentations.
When will the data be shared?
_X_ Before publication.
_X_ 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 6 weeks (2 
cycles).  In addition to a baseline scan, confirmatory scans should also be obtained no less than 4 
weeks following initial documentation of objective response.
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)[34] 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)[35] 
should be used as described in section 6.3.3. 
6.3.1
Definitions
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with LMB-100.
The dose determining population will consist of all patients evaluable for DLT. Patients are 
evaluable for DLT if they are evaluable for toxicity and discontinued earlier due to DLT or 
completed the DLT observation period and have undergone safety evaluations.


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Evaluable for pharmacokinetic analysis: All patients that are evaluable for toxicity will be included 
in the PK analysis population. Patients will be excluded from the PK analysis population if they 
significantly violate the inclusion or exclusion criteria, deviate from the protocol, or if data are 
unavailable or incomplete which may influence the PK analysis. Excluded cases will be 
documented with the reason for exclusion.
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.  These patients will have their response classified according 
to the definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.)
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
6.3.2
Peritoneal Mesothelioma
6.3.2.1
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: as >10 mm
o
Scan slice thickness >5 mm: double the slice thickness 

With calipers on clinical exam: >10 mm.  
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters)
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable.
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions.


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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. 
6.3.2.2
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 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 


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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.[36-38]  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.[39]
Cytology, Histology:  These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment 
of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 


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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.
6.3.2.3
RECIST version 1.1 Response Criteria
6.3.2.3.1 Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum 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.
6.3.2.3.2 Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis).
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 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).
6.3.2.3.3 Evaluation of Best Overall Response


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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.
**
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*


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n-Target Lesions
New Lesions
Overall Response
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as 
an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised
6.3.3
Pleural Mesothelioma
Malignant pleural mesothelioma (MPM) lesions are difficult to measure reliably.[35] Therefore modified 
criteria were defined in 2004 adjusting target lesion measurements to the specific needs of this disease.
6.3.3.1
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 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. 
6.3.3.2
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.


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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.
6.3.4
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 or death, whichever occurs first.


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6.3.6
Objective Response Rate
Objective response rate (ORR) is defined as the proportion of patients with partial response or 
complete response.
6.3.7
Disease Control Rate
Disease control rate (DCR) is defined as the proportion of patients with stable disease, partial 
response or complete response
6.3.8
Overall Survival
Overall survival (OS) is defined as the duration of time from start of treatment to time of death
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 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
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.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING /IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that 
meet the definition of an unanticipated problem will need to be reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here. 
7.3
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


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7.4
NIH REQUIRED 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 within the appropriate timelines.. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
7.4.2
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 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.
Note: The protocol is no longer SMC review as of 9/17/2018 as no patients have been on study 
therapy since the time of the next scheduled review.
8
SPONSOR SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:

Death,

A life-threatening adverse event (see section 8.1.3)

Inpatient hospitalization or prolongation of existing hospitalization 


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o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.

Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions

A congenital anomaly/birth defect

Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.
8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  

Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.

Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity and 
relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 


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occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:

Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician listed on the Form FDA 1572 as the site 
principal investigator or sub-investigator.

Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.

Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form.  
All SAE reporting must include the elements described in section 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
REPORTING PREGNANCY 
8.4.1
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 becomes known. 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 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.


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8.4.2
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 3 
months after the last dose of LMB-100 or 6 months after the last dose of nab-paclitaxel, whichever 
occurs later.
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 the later or 3 months after 
the last dose of LMB-100 or 6 months after the last dose of nab-paclitaxel should, if possible, be 
followed up and documented.
8.5
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, 
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.
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  
The primary objective of this phase I trial is to assess the safety and tolerability of LMB-100 with 
(Arms A1 and A2) and without (Arms B1 and B2) nab-paclitaxel in patients with malignant 
mesothelioma.  Additional objectives are to determine the response rate at the RP2D, to 
retrospectively explore and describe the pharmacokinetic characteristics, including the number of 
effective cycles of LMB-100 therapy that can be given before the development of anti-LMB-100 
neutralizing antibodies limits patient drug exposure.


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10.1 ARMS A1 AND A2
The dose de-escalation study Arm A1 builds upon and extends the findings from the closed phase 
I trial of LMB-100 (NCT02317419) in which 0/4 patients treated at170 mcg/kg experienced a DLT 
and 2/4 patients treated at 250 mcg/kg experienced a DLT. As a result of these prior findings, it 
was planned that 6 patients would be treated at 170 mcg/kg (Table 7). If 0 or 1/6 patients have a 
DLT, then 170 mcg/kg would be declared the RP2D. If 2 or more of the 6 patients have a DLT, 
then 3 to 6 patients would be treated at 140 mcg/kg following the usual 3+3 design. 0 or 1 DLT in 
6 patients at 140 mcg/kg will result in this level being the RP2D. Otherwise, dose levels of 100 
mcg/kg or lower would be explored. Dose de-escalation below 140 was deemed unlikely given the 
available monotherapy data with LMB-100 (Table 1). It was considered likely that accrual to this 
phase would not need to exceed 12 patients. Patients treated at the RP2D in Arm A1 were to be 
included in the efficacy analyses at the RP2D. 
For patients with malignant mesothelioma, low response rates are currently obtained with existing 
treatments. The goal of the dose expansion cohort would be to determine if using LMB-100 would 
rule out a 5% response rate and target a rate of 30%. The study will be conducted using a two-
stage Minimax phase II trial design in order to rule out an unacceptably low 5% PR+CR rate 
(p0=0.05) in favor of an improved PR+CR response rate of 30% (p1=0.30). Both PR and CR will 
be considered a ‘response’ for purposes of this study. With alpha=0.10 (probability of accepting a 
poor treatment=0.10) and beta = 0.10 (probability of rejecting a good treatment=0.10), this cohort 
was to have initially enrolled 13 evaluable patients and if 0 of the 13 have a response, then no 
further patients would be accrued. If 1 or more of the first 13 patients had a response, then accrual 
would continue until a total of 16 patients were enrolled. As it may take several weeks to determine 
if a patient has experienced a response, a temporary pause in the accrual to the trial may be 
necessary to ensure that enrollment to the second stage is warranted. If there were 1 to 2 responses 
in 16 patients, this would be an uninterestingly low response rate. If there were 3 or more responses 
in 16 patients (18.8%), 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 51.3%. 
After the enrollment of 10 evaluable patients the pharmacokinetic and anti-drug antibody level 
(ADA) data underwent an interim analysis.  Dr. William Figg, who has expertise in 
pharmacokinetics, in conjunction with the NCI CCR leadership committee analyzed the PK 
data.  Since the thresholds for ADA and its influence on pharmacokinetics are unclear, pre-
specified criteria for making changes to the protocol were not established.  The objective of the 
assessment was to make recommendations as to whether a therapeutic threshold has been reached 
and what, if any adjustments should be made with regard to the eligibility criteria and/or study 
plan. No adjustments were recommended as a result of the interim analysis.
With Amendment B, it was determined that the 170 mcg/kg dose would no longer be explored 
after DLT occurred in 3 of the first 3 subjects evaluated.  The three existing patients were re-treated 
at the 140 mcg/kg dose and an additional 7 subjects were enrolled to be treated at 140 mcg/kg.  Of 
10 subjects, none experienced partial or complete response.  Therefore, as of Amendment C, it is 
determined that patients will no longer be treated with LMB-100 monotherapy and all future 
subjects are to be enrolled on Arms B1 and B2.


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10.2 ARMS B1 AND B2
The dose de-escalation study (Arm B1) plans to evaluate up to two dose levels of LMB-100 in 
combination with nab-paclitaxel.  Once the RP2D has been determined, a dose expansion cohort 
(Arm B2) will be treated at the RP2D using the design discussed below.  Patients treated at the 
RP2D in Arm B1 will be included in the efficacy analyses at the RP2D.
For patients with malignant mesothelioma, low response rates are currently obtained with existing 
treatments. The goal of the dose expansion cohort would be to determine if using LMB-100 would 
rule out a 5% response rate and target a rate of 30%. The study will be conducted using a two-
stage Minimax phase II trial design in order to rule out an unacceptably low 5% PR+CR rate 
(p0=0.05) in favor of an improved PR+CR response rate of 30% (p1=0.30). Both PR and CR will 
be considered a ‘response’ for purposes of this study. With alpha=0.10 (probability of accepting a 
poor treatment=0.10) and beta = 0.10 (probability of rejecting a good treatment=0.10), this cohort 
will initially enroll 13 evaluable patients and if 0 of the 13 have a response, then no further patients 
will be accrued. If 1 or more of the first 13 patients has a response, then accrual would continue 
until a total of 16 patients have been enrolled. As it may take several weeks to determine if a patient 
has experienced a response, a temporary pause in the accrual to the trial may be necessary to ensure 
that enrollment to the second stage is warranted. If there are 1 to 2 responses in 16 patients, this 
would be an uninterestingly low response rate. If there were 3 or more responses in 16 patients 
(18.8%), 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 51.3%. 
10.3 JUSTIFICATION OF ACCRUAL CEILING
The Arm B1 dose de-escalation cohorts may require up to 12 patients, and the expansion portion 
(Arm B2) may require up to 16 evaluable patients. However, with 6 patients from the Arm B1 
dose de-escalation cohorts potentially being included in the analysis at the RP2D, up to 22 
individual patients may be required. In order to allow for a small number of inevaluable patients 
in Arms B1 and B2 and adding the 10 patients already enrolled on the completed Arms A1 and 
A2, the accrual ceiling will be set at 34 patients. If 1-2 patients per month enroll on this trial, 
accrual would be expected to be completed in approximately 2.5 years.
11 COLLABORATIVE AGREEMENTS
11.1 CLINICAL TRIAL AGREEMENT
A Clinical Trial Agreement (CTA #01059-17) in place between the National Cancer Institute and 
Celgene for the provision of the nab-paclitaxel.
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). The rationale to include MSLN- positive tumors of epithelial cell origin is 
based on preclinical models demonstrating promising anti-tumor efficacy. In addition, molecular 
pathology data demonstrated a high prevalence of mesothelin protein in these tumors. The 


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rationale to evaluate LMB-100 +/- nab-paclitaxel in advanced/metastatic mesothelioma is to 
preliminarily assess the safety and the anti-tumor activity of LMB-100 in this indication.
12.2 PARTICIPATION OF CHILDREN
There are no dosing or adverse event data are currently available on the use of LMB-100 with or 
without nab-paclitaxel 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 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, chest X-rays, 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 Radiation Risks
Subjects in this study may undergo up to 2 CT guided research biopsies which will result in 
exposure to approximately 1.5 rem.  This amount is below the guideline of 5 rem per year allowed 
for adult research subjects by the NIH Radiation Safety Committee.
12.5 RISKS/BENEFITS ANALYSIS
Patients with advanced and/or metastatic 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. 


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Therefore, LMB-100 +/- nab-paclitaxel 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 cancer 
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 
+/- nab-paclitaxel.
12.6 CONSENT PROCESS AND DOCUMENTATION
All patients will be thoroughly screened by the physician and the research nurse prior to 
completing the consent. During the initial consultation, the patient and family or friends, if present, 
will be presented with a forthright and detailed overview of the treatment option available to them 
at the NIH. The experimental nature of the treatment, its objectives, its theoretical advantages and 
disadvantages will be presented. The Informed Consent document is given to the patient and they 
are asked to review it, make notes and ask questions prior to agreeing to participate in this protocol. 
The patient is reassured that participation on this trial is entirely voluntary and that he/she can 
withdraw or decide against treatment at any time without adverse consequences. The physician 
assures the patient that if alternative therapy or no therapy at all is preferred, we will do all that we 
can to facilitate consultation with the appropriate referral organizations. The Informed Consent 
document may be obtained from the patient by the principal investigator, associate investigators, 
or the medical staff fellow under the supervision of the principal investigator.
Consent for the optional biopsies on this study will be obtained at the time of the procedure, using 
the procedure consent.  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 Telephone re-consent procedure
Re-consent on this study may be obtained via telephone. Telephone consent will be obtained per 
OHSRP/IRBO and CCR policies and procedures.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 


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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.
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 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 the NCI CCR. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by clinical 
sites and by NCI CCR research staff will be secured and password protected. At the end of the 
study, all study databases will be archived at the NCI CCR
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 


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objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants.
14 PHARMACEUTICAL INFORMATION  
14.1 LMB-100 (IND # 152907)
14.1.1 Source 
LMB-100 was transferred to the NIH CC Pharmacy by Roche, the drug manufacturer.  For this 
trial, the drug will be supplied by the NIH CC Pharmacy. 
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 three 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 1.2.3.3.3). 
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.[12]


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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 Vascular Leak Syndrome
LMB-100 administration may cause VLS characterized by hypotension, hypoalbuminemia, edema, 
weight gain, and hemoconcentration. Clinical trials with SS1P monotherapy have led to the 
development of reversible VLS. Patients will be monitored with frequent assessments of chest x-
rays, weight, edema, blood pressure, and serum albumin levels prior to and during treatment. 
Patients who develop symptoms of VLS should be closely monitored and receive standard 
symptomatic treatments.
14.1.2.5 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.
14.1.2.6 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 
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.
14.1.2.7 Pregnancy
No studies assessing the reproductive and developmental toxicity of LMB-100 have been 
conducted to date. It is not known whether LMB-100 can cross the placenta or cause harm to the 
fetus when administered to pregnant women or whether it affects reproductive capacity. LMB-100 
should not be administered to pregnant women.
Use of effective contraceptive methods is recommended in all patients receiving LMB-100, 
including up to 4 months and 2 months following the last LMB-100 dose for women and men, 
respectively. 


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14.1.3 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.
14.1.4 Stability and Storage 
Chemical and physical in-use stability for undiluted LMB-100 drug product in syringes has been 
demonstrated for 24 hours at 2-8 °C and 24 hours at ambient temperature.
Storage conditions should generally be at 2-8C, but syringes may be held at room temperature for 
up to a maximum of 4 hours.
14.1.5 Administration procedures
Please refer to section 3.2.1
14.1.6 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.
14.1.6.1 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 
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.


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14.1.6.2 Molecular Weight: approximately 73 kDa
14.1.6.3 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.
14.2 NAB-PACLITAXEL
Please refer to package insert for additional information.
14.2.1 Source 
As of Amendment E, the study drug nab-paclitaxel will be provided under a Clinical Trial 
Agreement with the manufacturer, Celgene.. Commercially purchased nab-paclitaxel may be used 
until the Celgene supply is in place.
14.2.2 Toxicity 
The most common clinically significant adverse reactions reported with nab-paclitaxel in patients 
with pancreatic cancer include: neutropenia, anemia, thrombocytopenia, pancytopenia peripheral 
neuropathy, cardiac failure, tachycardia, dyspnea, pneumonitis, nausea, vomiting, diarrhea 
abdominal pain, intestinal obstruction, colitisarthralgia/myalgia, renal failure, increased alanine 
aminotransferase, increased aspartate aminotransferase, increased bilirubin, and increased 
creatinine.
Hypersensitivity reactions including fatal anaphylactic reactions have rarely been reported with 
nab-paclitaxel. If a hypersensitivity reaction occurs, nab-paclitaxel should be discontinued 
immediately, symptomatic treatment should be initiated, and the participant should not be 
rechallenged with paclitaxel.


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Bone marrow suppression (primarily neutropenia) occurs frequently with nab-paclitaxel. Frequent 
monitoring of blood cell counts should be performed. Participants should not be retreated with 
subsequent cycles of nab-paclitaxel until neutrophils recover to  1500 cells/mm2 and platelets to 
 100,000 cells.
Sensory neuropathy occurs frequently with nab-paclitaxel, though generally not severe. The 
occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose reduction. 
Sepsis was reported in 5% of participants with or without neutropenia who received nab- 
paclitaxel.[40] Complications due to underlying pancreatic cancer, especially biliary obstruction 
or presence of biliary stent, were identified as significant contributing factors.
Pneumonitis occurred in 4% of participants using nab-paclitaxel. Closely monitor all participants 
for signs and symptoms of pneumonitis. After ruling out infectious etiology and upon making a 
diagnosis of pneumonitis, permanently discontinue treatment with nab-paclitaxel and promptly 
initiate appropriate treatment with supportive measures.
Hepatic impairment may increase the toxicity of nab-paclitaxel, particularly myelosuppression. 
Administration of nab-paclitaxel in participants with hepatic impairment should be performed with 
caution.
Congestive heart failure and left ventricular dysfunction have rarely been observed in participants 
receiving nab-paclitaxel. Most of these participants were previously exposed to cardiotoxic 
medicinal products such as anthracyclines or had underlying cardiac history. Participants receiving 
nab-paclitaxel should be vigilantly monitored for the occurrence of cardiac events.
Nausea, vomiting, and diarrhea following administration of nab-paclitaxel may be treated with 
commonly used anti-emetics and constipating agents.
In the very elderly ( ≥ 75 years) who received nab-paclitaxel, there was a higher incidence of serious 
adverse reactions and adverse reactions that led to discontinuation including hematologic toxicities, 
peripheral neuropathy, decreased appetite, and dehydration. Participants 75 years or older should 
be carefully assessed for their ability to tolerate nab-paclitaxel with special consideration to 
performance status, co-morbidities, and increased risk of infections.
14.2.3 Formulation and preparation 
Formulation
ABRAXANE is supplied as a lyophilized powder containing 100 mg of paclitaxel formulated as 
albumin-bound particles in single-use vial for reconstitution.
Preparation
1.
Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, 
USP.
2.
Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 
minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF 
THE VIAL.


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3.
DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized 
cake as this will result in foaming.
4.
Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure 
proper wetting of the lyophilized cake/powder.
5.
Gently swirl and/or invert the vial slowly for at least 2 minutes until
complete dissolution of any cake/powder occurs. Avoid generation of foam.
6.
If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides.
Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel.
Calculate the exact total dosing volume of 5 mg/mL suspension required for the participant: 
Dosing volume (mL) = Total dose (mg)/5 (mg/mL)
The reconstituted suspension should be milky and homogenous without visible particulates. If 
particulates or settling are visible, the vial should be gently inverted again to ensure complete 
resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. 
Discard any unused portion.
Inject the appropriate amount of reconstituted ABRAXANE® into an empty, sterile IV bag 
(plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type IV bag). The use of 
specialized DEHP-free solution containers or administration sets is not necessary to prepare or 
administer ABRAXANE infusions. The use of an in-line filter is not recommended.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior 
to administration whenever solution and container permit.
14.2.4 Stability and Storage 
Unopened vials of ABRAXANE are stable until the date indicated on the package when stored 
between 20°C to 25°C (68°F to 77°F), in the original package. Neither freezing nor refrigeration 
adversely affects the stability of the product.  Product should be retained in the original packaging 
to protect from bright light.
Stability of Reconstituted Suspension in the Vial
Reconstituted ABRAXANE should be used immediately, but may be refrigerated at 2°C to 8°C 
(36°F to 46°F) for a maximum of 24 hours if necessary. If not used immediately, each vial of 
reconstituted suspension should be replaced in the original carton to protect it from bright light. 
Discard any unused portion.
Stability of Reconstituted Suspension in the Infusion Bag
The suspension for infusion when prepared as recommended in an infusion bag should be used 
immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) and protected from bright light 
for a maximum of 24 hours..


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14.2.5 Administration procedures
Please see section 3.2.2.
14.2.6 Incompatibilities  
Please refer to the package insert.


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H, Ernstoff MS: Phase I/Ii Study of Murine Monoclonal Antibody-Ricin-a Chain 
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Mazor R, Vassall AN, Eberle JA, Beers R, Weldon JE, Venzon DJ, Tsang KY, Benhar I, 
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Weldon JE, Xiang L, Zhang J, Beers R, Walker DA, Onda M, Hassan R, Pastan I: A 
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Kuan CT, Pai LH, Pastan I: Immunotoxins containing Pseudomonas exotoxin that 
target LeY damage human endothelial cells in an antibody-specific mode: relevance 


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European Medicines Agency, Committee for Medicinal Products for Human Use 
(CHMP). 
Summary 
of 
opinion 
– 
ABRAXANE 
(available 
online 
at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/11/W 
C500155476.pdf ).


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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 – COCKCROFT-GAULT FORMULA FOR CALCULATION OF CREATININE 
CLEARANCE

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/01/2020
Page 1 of 13
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:
Raffit Hassan, M.D.
STUDY TITLE:
A Phase I Study of the Mesothelin-Targeted Immunotoxin 
LMB-100 with or without Nab-Paclitaxel (Abraxane) in 
Patients with Malignant Mesothelioma
STUDY SITE:
NIH Clinical Center
Cohort: 
Part A -LMB-100 monotherapy 
Consent Version:
03/01/2020
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?
In this study, we will determine a safe dose of LMB-100 in patients with advanced mesothelioma 
with or without nab-paclitaxel. LMB-100 is an investigational agent, meaning that it has not been 
approved by the US Food and Drug Administration. It is a type of manufactured protein which is 
similar to protein normally produced by your body in response to a specific foreign substance.  
LMB-100 is attracted to the mesothelin protein, which is present in a lot of different tumors, 


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
including mesothelioma, but is found in only a very small number of normal tissues.  After binding 
to the mesothelin on tumors, LMB-100 can then attack and kill cancer cells. Nab-paclitaxel is an 
FDA approved agent used in the treatment of breast cancer, non-small cell lung cancer and 
pancreatic cancer.  Its use in this study is investigational as it has not been approved in the 
treatment of mesothelioma.  Part A of the study included two groups of patients (Arms A1 and 
A2) who were assigned to receive LMB-100 alone.  In part B, two other groups (Arms B1 and B2) 
will be assigned to receive LMB-100 with nab-paclitaxel. You are participating in either Arm A1 
or A2 depending on when you were enrolled on the study.. 
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being asked to take part in this study because you have pleural or peritoneal mesothelioma 
that has not responded to prior platinum based therapy.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 34 participants will be enrolled in the study, 10 in part A and the remainder in part B.
DESCRIPTION OF RESEARCH STUDY
The first 3 participants were enrolled in the phase 1 portion of part A (Arm A1) at the highest dose 
of LMB-100 that we will test.  As there were intolerable side effects in more than 1 subject at this 
dose, the next lowest dose was given in the next 7 subjects enrolled and the 3 original subjects 
received the lower dose during their next treatment cycles.  Of these 10 participants; 9 had stable 
disease, meaning the tumor did not change in size, while in 1 subject the tumors grew.  There were 
no intolerable side effects at this dose. No additional patients will be enrolled in part A, but you 
will continue to receive LMB-100 alone if your disease has not worsened.  Please note that based 
on the information from ongoing clinical trials of LMB-100, giving LMB-100 alone for more than 
2 cycles provides no additional clinical benefit as we are unable to detect LMB-100 in the majority 
of participants beyond cycle 2.
You will receive LMB-100 through an IV catheter (a tube inserted in a vein, usually in your arm) 
on day 1, day 3 and day 5 of each 21-day cycle.  You will receive LMB-100 for up to 4 cycles or 
until your disease worsens or you have intolerable side effects, whichever happens first. We will 
continue to follow you after you have finished taking the study drug to keep track of your disease 
status (progression), your survival status or whether you have taken any additional cancer therapy.  
The specific procedures you will have are described below.
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY?  
Before you begin the study
Before beginning the study, you will need to undergo tests and/or procedures to help your doctor 
verify whether you can participate. This is called screening. Most of the exams, tests, and 
procedures you will have are part of the usual approach for your cancer. However, there are some 
extra procedures that you will need to have if you take part in this study.  If you have already 
undergone some of these examinations very recently, your doctor may decide not to repeat them. 
Briefly, these tests, which are performed under a separate consent, include:
Confirmation of diagnosis (You must provide a sample tumor tissue for an evaluation from 
the NCI Laboratory of Pathology.  The tissue may be from a previous surgery, biopsy or 


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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collection from a tumor effusion (fluid around the tumor).  If none is available, we will ask 
you to have a biopsy or a collection of effusion material to provide a fresh sample).  Please 
see page 7, Tumor Biopsies and Effusions for a description of the procedure.
Medical history and physical examination
Routine blood and urine tests including pregnancy test in women who can have children.  
Pregnant women will not be allowed on study.
Scans and x-rays
Electrocardiogram (ECG)
Echocardiogram
Tests for viruses (hepatitis and HIV)
During the study
Once it is determined that you are eligible and you have signed the consent for the study, you will 
receive IV infusions of LMB-100 as described above. Each infusion will last about 30 minutes, 
but it might take longer if your study doctor decides it is needed for your safety.  You will be 
monitored for side effects for 2 hours after the first infusion, and for 30 minutes after all other 
infusions if no side effects occurred previously. We will give you standard pre-medications that 
include an antihistamine (such a Benadryl), acetaminophen (Tylenol), ranitidine (Zantac) and 
dexamethasone, a steroid to help prevent infusion related side effects. 
While you are taking study medication, we will perform a number of tests and examinations for 
safety and to test the effect of the study therapy.
These include routine blood and urine tests that will be done 4 – 5 times per cycle, a chest X-ray 
on day 1 of each cycle, scans that will be performed approximately every 6 weeks, and ECGs that 
will be done just before each infusion.
We will also perform tests for research studies to find out how your body handles the drug (PKs), 
the types of immune cells present in your disease, how your body reacts to the drug and how certain 
side effects of the LMB-100 might be caused. Most of the sampling for these research tests will 
be done before your first dose of study drug, on the days you take the study drug (just before or 
just after you get the study drug) or at the end of treatment. In addition, a blood sample will be 
collected at the end of cycle 2 and on day 8 of each cycle. Exceptions to this are:
PK studies on days 1 and 5 of cycle 1 and on day 1of cycle 2.  These samples will be drawn 
before your infusion and periodically for up to 6 hours after the start of infusion.  
Optional biopsies which may be collected before the first dose of LMB-100 (if you have 
not given a biopsy at screening) and after you have completed two cycles of therapy.  The 
biopsies to be performed are exclusively for research purposes and will not benefit you.  It 
might help other people in the future.  You will be given the opportunity to decide whether 
you want to have these sample collected at the time of each biopsy. All tissue will be 
reviewed by the NCI Laboratory of Pathology.


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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When you are finished taking the drugs
Approximately 4 – 6 weeks after you have had your last dose of study drug, you will be asked to 
return to the NIH for a follow up visit to have the following tests:
Medical history and physical exam
Routine blood and urine tests
Scans if your disease has not worsened since the beginning of the study
ECG
If after this visit, your disease remains stable or improves, you will continue to be scanned every 
6 weeks until your disease worsens.
About once a year, regardless of whether your disease has gotten worse, we will contact you or 
your physician by telephone to ask about any other cancer therapies you may have started and 
about your survival status.
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a woman 
who can become pregnant, or are the partner of a woman who can become pregnant, you will need 
to practice an effective form of birth control before starting study treatment, during study 
treatment, and for 3 months after you finish study.  In addition, male subjects should not donate 
sperm during the study and for 3 months after the last dose of study therapy.  If you think that you 
or your partner is pregnant, you should tell your study doctor or nurse at once.  
Effective forms of birth control include: 
•
abstinence 
intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
vasectomy
RISKS OR DISCOMFORTS OF PARTICIPATION
Risks and Possible Undesirable Effects of LMB-100
Prior to this study LMB-100 has only been given to 15 subjects; therefore, we do not know all of 
the possible side effects.  However, below is a list of the most common and most serious side 
effects occurring on the earlier study, some occurring at higher doses than will be used in this 
study.
The most common side effects (some were serious) were:
Low levels of the blood protein albumin which may lead to swelling, muscle weakness or 
loss of appetite


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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Tiredness
Swelling of the arms and legs
Nausea
Fever
Decreased appetite
Shortness of breath
Pain in muscles 
Less common, but serious side effects included:
Fluid in the organs which may cause low blood pressure, shortness of breath, swelling of 
ankles
Abnormal heartbeat
Reactions during or following the infusion of the drug which may cause fever, chills, rash 
or low blood pressure
Pain in joints
Kidney damage which may cause swelling, may require dialysis
Other possible side effects
Other possible side effects discussed below are based on side effects that occurred when testing a 
similar agent, SS1P and in animal studies of LMB-100.  It is possible that there may be other 
unexpected side-effects that occur in addition to those listed below.
LMB-100 may cause inflammation to membranes causing chest pain, shortness of breath, low 
blood pressure, and heart failure.  In animals, some mild kidney toxicity was seen, characterized 
by increased enzymes and protein in the urine. This will be checked for with regular blood and 
urine tests.
As with other drugs similar to LMB-100, there is a chance that the drug could cause the body to 
produce an unwanted response called ‘Anti-drug antibodies’ (ADAs).  These might not cause 
problems however there is a chance they could lead to a severe anti-drug response in the body.  
ADA levels will be measured during the study to monitor any changes.
There may also be pain and swelling at the infusion site.
It is important that you contact your doctor as soon as you experience any side effects whether you 
think the treatment has caused them or not.  You must also tell your doctor if you have started any 
new medication or had a change to your existing medication.  This includes medications available 
without a prescription (over the counter) and alternative medicines.  If you have any questions or 
concerns about any of the information provided above, about the possible side effects of treatment, 
or the possible consequences of treatment for those side effects, please ask the principal 
investigator or the research staff for more information. 


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The most important symptoms you need to report to your doctor immediately are:
o
possible infusion or allergic reactions (symptoms that start during or within a few 
hours of the infusion, e.g., wheezing, tightness in the throat or chest, rash, and facial 
swelling)
o
chest pain
o
shortness of breath
o
palpitations (fast heart beat)
o
bleeding and high fever
o
impaired brain function (e.g., dizziness, blurred vision, confusion)
If you experience any severe or dangerous side effect, you should:
1. Seek professional medical help immediately.
2. Call your study doctor.
3. If necessary, go to the nearest emergency room.
Risks from pre-medications
Acetaminophen 
Acetaminophen is considered to be safe and effective in the recommended doses. However, when 
taken incorrectly acetaminophen can cause liver damage. Your risk of liver damage may be 
increased if you drink more than three alcoholic drinks every day, take more than the recommended 
dose (overdose), or if you take any additional drugs that also contain acetaminophen at the same 
time.
Diphenhydramine
Drowsiness, dizziness, constipation, stomach upset, blurred vision, or dry mouth/nose/throat may 
occur when taking diphenhydramine.
Ranitidine:  
It can cause constipation, diarrhea, headache, nausea or upset stomach.  Rare serious side effects 
include severe allergic reaction with rash, hives, itching, difficulty breathing; confusion, dark 
urine, depression, fast or slow heartbeat, unusual bruising or bleeding, yellowing of the eyes or 
skin (indicating liver damage).
Dexamethasone:  
Stomach upset, headache, dizziness, changes in your period, trouble sleeping, increased appetite, 
or weight gain may occur. Rarely patients using dexamethasone have experienced increased 
infection, bone/joint pain, thirst, increased urination, irregular heartbeat, eye pain, vision problems, 
black stools, vomit that looks like coffee grounds, puffy face, swelling of the feet and ankles, 
pain/redness/swelling of the arms or legs, tiredness, mood changes, unusual hair/skin growth, 
muscle cramps, weakness, easy bruising/bleeding, slow wound healing, thinning skin and seizures.


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Risks from Study Procedures
The following study procedures and treatments may have risks and cause discomfort while you 
participate on this study:
Blood draws
There is the risk of slight pain, bruising or infection when your blood is drawn.  Drawing blood 
may cause some people to faint. 
ECGs
The glue used to keep the electrodes in place during the ECG may irritate your skin and cause 
redness. 
Tumor Biopsies and Effusions 
Tumor biopsies and tumor effusions: local anesthesia of the skin will be given prior to any tumor 
biopsy or effusion collection, in order to prevent painful sensations.  However, you may still 
experience pain or discomfort at the biopsy site.  Irritation, redness, swelling and/or bleeding may 
also occur.  There is a risk of abnormal healing, fever, infection or of an allergic reaction to the 
anesthetic agent used to anesthetize the skin at the biopsy site.  Once the sample has been obtained, 
a stitch may be used to close the wound and facilitate healing. 
In some cases, we may use CT scans to help guide us during your biopsy.  This introduces the 
added risk of research radiation.  This research study may involve exposure to radiation from up 
to 2 CT guided tumor biopsies.  This radiation exposure is not required for your medical care and 
is for research purposes only. The amount of radiation you will receive in this study is 1.5 rem 
which is below the guideline of 5 rem per year allowed for research subjects by the NIH Radiation 
Safety Committee.  The average person in the United States receives a radiation exposure of 0.3 
rem per year from natural sources, such as the sun, outer space, and the earth's air and soil.  If you 
would like more information about radiation, please ask the investigator for a copy of the pamphlet, 
An Introduction to Radiation for NIH Research Subjects.
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe.  There may be a very 
slight increase in the risk of cancer. 
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body. 
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
The aim of this study is to find a safe dose for this experimental treatment.  We do not know if you 
will receive personal, medical benefit from taking part in this study.  These potential benefits could 
include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by 
the cancer.  Because there is not much information about the drug’s effect on your cancer, we do 


PATIENT IDENTIFICATION
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not know if you will benefit from taking part in this study, although the knowledge gained from 
this study may help others in the future who have cancer.  
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
Instead of being in 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 
Your doctor may decide to stop your therapy for the following reasons:
if he/she believes that it is in your best interest
if your disease comes back during treatment
if you become pregnant
if you have side effects from the treatment that your doctor thinks are too severe
if new information shows that another treatment would be better for you
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to collaborators or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed.
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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The National Institutes of Health and the research team for this study have developed a drug being 
used in this study.  This means it is possible that the results of this study could lead to payments 
to NIH scientists and to the NIH. By law, government scientists are required to receive such 
payments for their inventions. You will not receive any money from the development of LMB-
100. 
Celgene is providing the nab-paclitaxel for this study to NIH without charge.  No NIH employee 
involved in this study receives any payment or other benefits from Celgene.
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 
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 it 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 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.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. The amount and form 


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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of these payments are determined by the NCI Travel and Lodging Reimbursement Policy.   You 
will be given a summary of the policy which provides more information.
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 are 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.
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 NIH 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 Celgene, the pharmaceutical company who produces nab-
paclitaxel 
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. 


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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); 
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.


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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.


PATIENT IDENTIFICATION
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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: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
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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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:
Raffit Hassan, M.D.
STUDY TITLE:
A Phase I Study of the Mesothelin-Targeted Immunotoxin 
LMB-100 with or without Nab-Paclitaxel (Abraxane) in 
Patients with Malignant Mesothelioma
STUDY SITE:
NIH Clinical Center
Cohort: 
Part B -LMB-100 combination therapy 
Consent Version:
03/01/2020
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?
In this study, we will determine a safe dose of LMB-100 in patients with advanced mesothelioma 
with or without nab-paclitaxel. LMB-100 is an investigational agent, meaning that it has not been 
approved by the US Food and Drug Administration. It is a type of manufactured protein which is 
similar to protein normally produced by your body in response to a specific foreign substance.  
LMB-100 is attracted to the mesothelin protein, which is present in a lot of different tumors, 


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including mesothelioma, but is found in only a very small number of normal tissues.  After binding 
to the mesothelin on tumors, LMB-100 can then attack and kill cancer cells. Nab-paclitaxel is an 
FDA approved agent used in the treatment of breast cancer, non-small cell lung cancer and 
pancreatic cancer.  Its use in this study is investigational as it has not been approved in the 
treatment of mesothelioma.  Part A of the study included two groups of patients (Arms A1 and 
A2) who were assigned to receive LMB-100 alone.  In part B, two other groups (Arms B1 and B2) 
will be assigned to receive LMB-100 with nab-paclitaxel. You will participate in either Arm B1 
or B2 depending on when you enroll in the study. 
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being asked to take part in this study because you have pleural or peritoneal mesothelioma 
that has not responded to prior platinum based therapy.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 34 participants will be enrolled in the study, the first 10 in part A and the remainder in Part 
B.
DESCRIPTION OF RESEARCH STUDY
In Part A of the study a safe dose of LMB-100 alone has been established; however, 9 of 10 
subjects who were evaluated had their tumors remain stable, while 1 subject’s tumor grew.  
Therefore, we will enroll Part B to determine a safe dose of LMB-100 in combination with nab-
paclitaxel.  
The first 6 participants will be enrolled in the phase 1 portion of part B (Arm B1) at  a slightly 
lower dose of LMB-100 than the safe dose of part A in combination with a nab-paclitaxel.  If it is 
found to be safe, 10 additional participants will be enrolled (Arm B2) so that we may begin to 
determine whether the study therapy can shrink tumors. If there are too many intolerable side 
effects, we will test a lower dose of LMB-100 in combination with nab-paclitaxel in the next 6 
participants and the enroll an additional 10 patients at that dose level.  
You will receive LMB-100 through an IV catheter (a tube inserted in a vein, usually in your arm) 
on day 1, day 3 and day 5 of each 21-day cycle.  You will receive LMB-100 for up to 2 cycles or 
until your disease worsens or you have intolerable side effects, whichever happens first.  You will 
receive nab-paclitaxel through an IV on day 1 and day 8 of each 21-day cycle for up to 6 cycles or 
until your disease worsens or you have intolerable side effects caused, whichever happens first. 
We will continue to follow you after you have finished taking the study drug to keep track of your 
disease status (progression), your survival status or whether you have taken any additional cancer 
therapy.  The specific procedures you will have are described below.
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY?  
Before you begin the study
Before beginning the study, you will need to undergo tests and/or procedures to help your doctor 
verify whether you can participate. This is called screening. Most of the exams, tests, and 
procedures you will have are part of the usual approach for your cancer. However, there are some 
extra procedures that you will need to have if you take part in this study.  If you have already 


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undergone some of these examinations very recently, your doctor may decide not to repeat them. 
Briefly, these tests, which are performed under a separate consent, include:
Confirmation of diagnosis (You must provide a sample tumor tissue for an evaluation by 
the NCI Laboratory of Pathology.  The tissue may be from a previous surgery, biopsy or 
collection from a tumor effusion (fluid around the tumor).  If none is available, we will ask 
you to have a biopsy or a collection of effusion material to provide a fresh sample).  Please 
see page 10, Tumor Biopsies and Effusions for a description of the procedure.
Medical history and physical examination
Routine blood and urine tests including pregnancy test in women who can have children.  
Pregnant women will not be allowed on study.
Scans and x-rays
Electrocardiogram (ECG)
Echocardiogram
Tests for viruses (hepatitis and HIV)
During the study
Once it is determined that you are eligible and you have signed the consent for the study, you will 
receive IV infusions of LMB-100 and nab-paclitaxel. as described above. Each infusion will last 
about 30 minutes, but it might take longer if your study doctor decides it is needed for your safety.  
Each nab-paclitaxel infusion also lasts about 30 minutes. On day 1 of each cycle, when both 
medications are given, you will receive the LMB-100 about 30 minutes after you have completed 
the nab-paclitaxel infusion.  You will be monitored for side effects for 2 hours after the first 
infusion, and for 30 minutes after all other infusions if no side effects occurred previously.  We 
will give you standard pre-medications that include an antihistamine (such a Benadryl), 
acetaminophen (Tylenol), ranitidine (Zantac) and dexamethasone, a steroid to help prevent 
infusion related side effects. 
While you are taking study medication, we will perform a number of tests and examinations for 
safety and to test the effect of the study therapy.
These include routine blood and urine tests that will be done 4 – 5 times per cycle, a chest X-ray 
on day 1 of each cycle, scans that will be performed approximately every 6 weeks, and ECGs that 
will be done just before each infusion.
We will also perform tests for research studies to find out how your body handles the drug (PKs), 
the types of immune cells present in your disease, how your body reacts to the drug and how certain 
side effects of the LMB-100 might be caused. Most of the sampling for these research tests will 
be done before your first dose of study drug, on the days you take the study drug (just before or 
just after you get the study drug) or at the end of treatment. In addition, a blood sample will be 
collected at the end of cycle 2 and on day 8 of the first two cycles. Exceptions to this are:
PK studies will be performed on days 1 and 5 of cycles 1 and 2.  Except for the cycle 2 day 
5 sample, which will only be drawn immediately before and after the LMB-100 infusion, 
these samples will be drawn before your infusion and periodically for up to 6 hours after 
the start of infusion.  


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Optional biopsies which may be collected before the first dose of LMB-100 (if you have 
not given a biopsy at screening) and after you have completed two cycles of therapy.  The 
biopsies to be performed are exclusively for research purposes and will not benefit you.  It 
might help other people in the future.  You will be given the opportunity to decide whether 
you want to have these sample collected at the time of each biopsy. All tissue will be 
reviewed by the NCI Laboratory of Pathology.
When you are finished taking the drugs
Approximately 4 – 6 weeks after you have had your last dose of study drug, you will be asked to 
return to the NIH for a follow up visit to have the following tests:
Medical history and physical exam
Routine blood and urine tests
Scans if your disease has not worsened since the beginning of the study
ECG
If after this visit, your disease remains stable or improves, you will continue to be scanned every 
6 weeks until your disease worsens.
About once a year, regardless of whether your disease has gotten worse, we will contact you or 
your physician by telephone to ask about any other cancer therapies you may have started and 
about your survival status.
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a woman 
who can become pregnant, you will need to practice an effective form of birth control before 
starting study treatment, during study treatment, and for 3 months after you finish study therapy.  
If you become pregnant while receiving study medication or within 28 days after taking your last 
dose of study medication, you must tell the study doctor right away.  If this happens, study 
medication will be discontinued.  The study doctor will follow you and your pregnancy to 
completion. 
If you are the male partner of a woman who can become pregnant you will need to practice an 
effective form of birth control in addition to using a condom and refrain from donating sperm 
before starting study treatment, during study treatment, and for 6 months after you finish study 
therapy. You should also refrain from sperm donation during this time period.  If your partner 
becomes pregnant while you are receiving study medication or within 6 months after you took 
your last dose of study medication, you must tell the study doctor right away.
Effective forms of birth control include: 
•
abstinence from heterosexual contact
intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation


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•
vasectomy
RISKS OR DISCOMFORTS OF PARTICIPATION
Risks and Possible Undesirable Effects of LMB-100
Prior to this study LMB-100 has only been given to 15 subjects; therefore, we do not know all of 
the possible side effects.  However, below is a list of the most common and most serious side 
effects occurring on the earlier study, some occurring at higher doses than will be used in this 
study.
The most common side effects (some were serious) were:
Low levels of the blood protein albumin which may lead to swelling, muscle weakness or 
loss of appetite
Tiredness
Swelling of the arms and legs
Nausea
Fever
Decreased appetite
Shortness of breath
Pain in muscles 
Less common, but serious side effects included:
Fluid in the organs which may cause low blood pressure, shortness of breath, swelling of 
ankles
Abnormal heartbeat
Reactions during or following the infusion of the drug which may cause fever, chills, rash 
or low blood pressure
Pain in joints
Kidney damage which may cause swelling, may require dialysis
Other possible side effects
Other possible side effects discussed below are based on side effects that occurred when testing a 
similar agent, SS1P and in animal studies of LMB-100.  It is possible that there may be other 
unexpected side-effects that occur in addition to those listed below.
LMB-100 may cause inflammation to membranes causing chest pain, shortness of breath, low 
blood pressure, and heart failure.  In animals, some mild kidney toxicity was seen, characterized 
by increased enzymes and protein in the urine. This will be checked for with regular blood and 
urine tests.
As with other drugs similar to LMB-100, there is a chance that the drug could cause the body to 
produce an unwanted response called ‘Anti-drug antibodies’ (ADAs).  These might not cause 
problems however there is a chance they could lead to a severe anti-drug response in the body.  
ADA levels will be measured during the study to monitor any changes.


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There may also be pain and swelling at the infusion site.
It is important that you contact your doctor as soon as you experience any side effects whether you 
think the treatment has caused them or not.  You must also tell your doctor if you have started any 
new medication or had a change to your existing medication.  This includes medications available 
without a prescription (over the counter) and alternative medicines.  If you have any questions or 
concerns about any of the information provided above, about the possible side effects of treatment, 
or the possible consequences of treatment for those side effects, please ask the principal 
investigator or the research staff for more information. 
The most important symptoms you need to report to your doctor immediately are:
o
possible infusion or allergic reactions (symptoms that start during or within a few 
hours of the infusion, e.g., wheezing, tightness in the throat or chest, rash, and facial 
swelling)
o
chest pain
o
shortness of breath
o
palpitations (fast heart beat)
o
bleeding and high fever
o
impaired brain function (e.g., dizziness, blurred vision, confusion)
If you experience any severe or dangerous side effect, you should:
1. Seek professional medical help immediately.
2. Call your study doctor.
3. If necessary, go to the nearest emergency room.
Risks of nab-paclitaxel
VERY COMMON, SOME MAY BE SERIOUS
In 100 people receiving nab-paclitaxel, more than 9 and up to 100 may have:
anemia (a decrease in the number of 
red blood cells which may make you 
feel weak or tired) 
low number of white blood cells with 
or without fever (that may make it 
easier get infections)
a decrease in the number platelets, the 
cells that help your blood to clot 
(which may lead to unusual bleeding 
or bruising under the skin)
 constipation 
diarrhea 
nausea
vomiting
pain (including muscle, joints, bone, 
and chest pain)
swelling caused by fluid held in the 
tissues, especially of the ankles, feet or 
fingers 
fever  
chills  
decreased appetite 
change in taste  
weight loss  
difficulty sleeping  
depression 
cough  
shortness of breath  


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VERY COMMON, SOME MAY BE SERIOUS
In 100 people receiving nab-paclitaxel, more than 9 and up to 100 may have:
stomach pain
pain, swelling or sores on the inside of 
the mouth
neuropathy, a disorder of the nerves 
which can cause tingling or numbness, 
with weakness, or decreased sensation 
or movement
dizziness 
headache  
feeling tired or weak    
hair loss  
rash, possibly red, bumpy or 
generalized  
itchiness  
changes in nails, including 
discoloration or separation from 
nailbed  
abnormal liver function test results 
dehydration (loss of water and 
minerals in the body)  
nose bleed
decreased potassium levels in the 
blood
COMMON, SOME MAY BE SERIOUS
In 100 people receiving nab-paclitaxel, from 1 to 9 may have:
a severe reduction of red or white blood 
cells and platelets (at nearly the same 
time) which can cause weakness, 
bruising, or make infections more likely  
infections, including pneumonia or of 
the lung, mouth, gallbladder, urinary 
tract, nail, or hair follicle  
a very severe infection of the blood 
which may include a decrease in blood 
pressure 
inflammation of the lung passages  
thickening, inflammation or scarring in 
the lungs which may cause 
breathlessness, cough  
inflammation of the bowel causing 
abdominal pain or diarrhea  
blockage of the intestine  
trouble swallowing  
indigestion or upset stomach 
abnormal chemistry or electrolyte blood 
test results  
abnormal kidney function test results 
nasal congestion  
mouth or throat pain 
dry mouth, nose, and throat  
coughing up blood or bloody sputum  
blood clot in the lungs or in deep vein  
fluid in the chest cavity  
red or flushed skin 
dry skin 
hand-foot syndrome, involving 
reddening, swelling, numbness and 
peeling of palms and soles of feet  
high blood pressure
low blood pressure  
a decrease in the heart’s ability to pump 
blood to all parts of the body and 
possibly heart failure 
faster heart beat  
watery eyes  
changes in vision or blurry vision 
infusion site reactions (described as 
discomfort, bleeding or 
bruising/swelling at the needle site, and 


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COMMON, SOME MAY BE SERIOUS
In 100 people receiving nab-paclitaxel, from 1 to 9 may have:
acute kidney failure 
blood in the urine  
lack of muscle coordination  
muscle weakness  
anxiety 
in some instances infection or leaking 
of IV fluid outside of blood vessel into 
the surrounding tissue)  
localized swelling due to buildup of 
lymph fluid
UNCOMMON, SOME MAY BE SERIOUS
In 100 people receiving nab-paclitaxel, fewer than 1 may have:
irregular or slow heart beat  
stopping of the heart 
allergic reaction (may include skin inflammation, rash, trouble breathing, trouble 
speaking, fever), sometimes fatal 
syndrome involving abnormal blood clotting, with decreased platelets, bruising 
(including tiny red or purple spots under the skin) and possibly leading to blood clots  
edema/swelling and cyst formation of the macular area of the retina  
irritation and redness of the thin membrane covering the eye  
inflammation of the cornea 
too much fluid in the body 
feeling unwell  
sleepiness  
scaly or peeling skin 
potentially life threatening allergic reaction of the skin and oral mucous membranes 
(may include lesions in the mouth, itching and blistering skin) 
hives  
a loss of nerve function in the muscles of the face 
Additional side effects observed during post-marketing surveillance of nab-paclitaxel, not 
otherwise noted above include: 
•
lack of movement in the vocal cords with possible voice changes 
•
skin sensitivity to sunlight 
•
potentially life threatening allergic reaction [may include skin rash with skin blistering]  
•
skin or tissue damage from prior radiation therapy can become damaged again, when a 
person receives chemotherapy after having had radiation therapy. This is referred to 
as radiation recall and may involve redness, peeling, pain, and swelling. Skin changes 
have been noted to range from mild redness to tissue death. Radiation recall 


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may also occur in the lungs and other internal organs. 
Elderly
In subjects  65 years old with metastatic breast cancer who received nab-paclitaxel monotherapy, 
a higher incidence of nose bleed, diarrhea, dehydration (loss of water and minerals in the body), 
feeling tired or weak and swelling caused by fluid held in the tissues, especially of the ankles, feet 
or fingers has been reported.
Birth Defects
Nab-paclitaxel may cause serious birth defects. Please refer to the section about birth control for 
more information on how to protect yourself if you are a female who is able to get pregnant or a 
male patient who has a partner who is able to get pregnant. Nab-paclitaxel can cause irreversible 
infertility in male patients. Male patients should seek advice on conservation of sperm prior to 
treatment.
Risks from pre-medications
Acetaminophen 
Acetaminophen is considered to be safe and effective in the recommended doses. However, when 
taken incorrectly acetaminophen can cause liver damage. Your risk of liver damage may be 
increased if you drink more than three alcoholic drinks every day, take more than the recommended 
dose (overdose), or if you take any additional drugs that also contain acetaminophen at the same 
time.
Diphenhydramine
Drowsiness, dizziness, constipation, stomach upset, blurred vision, or dry mouth/nose/throat may 
occur when taking diphenhydramine.
Ranitidine:  
It can cause constipation, diarrhea, headache, nausea or upset stomach.  Rare serious side effects 
include severe allergic reaction with rash, hives, itching, difficulty breathing; confusion, dark 
urine, depression, fast or slow heartbeat, unusual bruising or bleeding, yellowing of the eyes or 
skin (indicating liver damage).
Dexamethasone:  
Stomach upset, headache, dizziness, changes in your period, trouble sleeping, increased appetite, 
or weight gain may occur. Rarely patients using dexamethasone have experienced increased 
infection, bone/joint pain, thirst, increased urination, irregular heartbeat, eye pain, vision problems, 
black stools, vomit that looks like coffee grounds, puffy face, swelling of the feet and ankles, 
pain/redness/swelling of the arms or legs, tiredness, mood changes, unusual hair/skin growth, 
muscle cramps, weakness, easy bruising/bleeding, slow wound healing, thinning skin and seizures.
Risks from Study Procedures
The following study procedures and treatments may have risks and cause discomfort while you 
participate on this study:


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Blood draws
There is the risk of slight pain, bruising or infection when your blood is drawn.  Drawing blood 
may cause some people to faint. 
ECGs
The glue used to keep the electrodes in place during the ECG may irritate your skin and cause 
redness. 
Tumor Biopsies and Effusions 
Tumor biopsies and tumor effusions: local anesthesia of the skin will be given prior to any tumor 
biopsy or effusion collection, in order to prevent painful sensations.  However, you may still 
experience pain or discomfort at the biopsy site.  Irritation, redness, swelling and/or bleeding may 
also occur.  There is a risk of abnormal healing, fever, infection or of an allergic reaction to the 
anesthetic agent used to anesthetize the skin at the biopsy site.  Once the sample has been obtained, 
a stitch may be used to close the wound and facilitate healing. 
In some cases, we may use CT scans to help guide us during your biopsy.  This introduces the 
added risk of research radiation.  This research study may involve exposure to radiation from up 
to 2 CT guided tumor biopsies.  This radiation exposure is not required for your medical care and 
is for research purposes only. The amount of radiation you will receive in this study is 1.5 rem 
which is below the guideline of 5 rem per year allowed for research subjects by the NIH Radiation 
Safety Committee.  The average person in the United States receives a radiation exposure of 0.3 
rem per year from natural sources, such as the sun, outer space, and the earth's air and soil.  If you 
would like more information about radiation, please ask the investigator for a copy of the pamphlet, 
An Introduction to Radiation for NIH Research Subjects.
While there is no direct evidence that the amount of exposure received from 
participating in this study is harmful, there is indirect evidence it may not be 
completely safe.  There may be a very slight increase in the risk of cancer. 
Please tell your doctor if you have had any radiation exposure in the past year, either 
from other research studies or from medical tests or care, so we can make sure that 
you will not receive too much radiation. Radiation exposure includes x-rays taken in 
radiology departments, cardiac catheterization, and fluoroscopy as well as nuclear 
medicine scans in which radioactive materials were injected into your body. 
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
The aim of this study is to find a safe dose for this experimental treatment.  We do not know if you 
will receive personal, medical benefit from taking part in this study.  These potential benefits could 
include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by 
the cancer.  Because there is not much information about the drug’s effect on your cancer, we do 
not know if you will benefit from taking part in this study, although the knowledge gained from 
this study may help others in the future who have cancer.  


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WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
Instead of being in 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 
Your doctor may decide to stop your therapy for the following reasons:
if he/she believes that it is in your best interest
if your disease comes back during treatment
if you become pregnant
if you have side effects from the treatment that your doctor thinks are too severe
if new information shows that another treatment would be better for you
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to collaborators or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed.
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 
The National Institutes of Health and the research team for this study have developed a drug being 
used in this study.  This means it is possible that the results of this study could lead to payments 


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to NIH scientists and to the NIH. By law, government scientists are required to receive such 
payments for their inventions. You will not receive any money from the development of LMB-
100. 
Celgene is providing nab-paclitaxel for this study to NIH without charge.  No NIH investigator 
involved in this study receives payments or other benefits from any company whose drug, product 
or device is being tested.  However, there are some non-NIH collaborators on this study who may 
receive payments or benefits, limited by the rules of their workplace.
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 
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 it 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 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.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. The amount and form 


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 03/01/2020
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CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy.   You 
will be given a summary of the policy which provides more information.
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 are 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.
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 NIH 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 Celgene, the pharmaceutical company who produces nab-
paclitaxel 
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. 


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 03/01/2020
Page 14 of 16
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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); 
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.


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 03/01/2020
Page 15 of 16
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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.


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (2)
Version Date: 03/01/2020
Page 16 of 16
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: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
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:
.