untitled h1
untitled h2

Abbreviated Title: LMB-100 + Abrx in PDA CC Protocol \#: 16C0128 L Version Date: December 11, 2018 NCT \#: NCT02810418 Title: A Phase I/II Study of Mesothelin-Targeted Immunotoxin LMB-100 Alone or in Combination with Nab-Paclitaxel in Participants with Previously Treated Metastatic and/ or Locally Advanced Pancreatic Ductal Adenocarcinoma and Mesothelin Expressing Solid Tumors NCI Principal Investigator: Christine Alewine, M.D., Ph.D.  
Laboratory of Molecular Biology (LMB), CCR, NCI Building 37, Room 5116 9000 Rockville Pike Phone: 240-760-6146 Email: Christine.alewine@nih.gov Investigational Agents:  
| Drug Name:      | LMB-100 (formerly RO6927005)     | Mesothelin Expression Testing   |
|-----------------|----------------------------------|---------------------------------|
| IND Number:     | 123332                           | NSR device                      |
| Sponsor/Holder: | Center for Cancer Research, NCI, | Center for Cancer Research      |
| NIH             |                                  |                                 |
| Manufacturer:   | F. Hoffman-La Roche Ltd          | NCI Laboratory of Pathology     |
untitled h1
commercial agents

NAB Paclitaxel will be obtained from commercial sources by the NIH CC pharmacy.  
1
untitled h1
precis background

x Pancreatic cancer is the fourth most common cause of cancer death in the United States, claiming more than 40,000 lives each year.  
x Incidence nearly equals mortality with just 6% of participants living five years beyond their diagnosis. Most patients are diagnosed at an advanced stage, but even patients with early stage disease have a long term survival of less than 20%.  
x Mesothelin is specifically a marker of adenocarcinoma in the human disease and is not expressed in preceding pre-malignant stages of tumor development x Expression of mesothelin in pancreatic ductal adenocarcinoma (PDA) has been examined in several published studies and ranges from 86 to 100%
x Recombinant immunotoxins (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-binding domain of PE is replaced by the mesothelin-binding antibody fragment. SS1P was the first mesothelin-targeted RIT tested in patients.  
x LMB-100 contains a newly engineered PE fragment that has improved activity against most pancreatic cancer cell lines in vitro, and is also much less toxic than SS1P in pre-clinical models. The new PE contains modifications specifically designed to reduce immunogenicity of the molecule.  
x Pre-administration of paclitaxel with SS1P was demonstrated to increase the amount of immunotoxin internalized by tumor cells and to reduce levels of shed mesothelin in the intra-tumoral environment so that more immunotoxin could bind tumor cells. The effect is even more pronounced with NAB-paclitaxel in a pancreatic cancer model.  
x Initial clinical testing of LMB-100 was performed by Roche in a multi-center international first in human trial (NCT02317419). The agent was well tolerated and appeared to have decreased immunogenicity compared to SS1P based on preliminary results.  
x In initial and subsequent clinical testing, LMB-100 was found to have half-life of ~60 mins.  
This is shorter then that measured for previous RITs used in the clinical setting.
untitled h1
primary objectives 3/4 arm a1

x To determine the maximum tolerated dose of short infusion LMB-100 in combination *nab-*paclitaxel chemotherapy in participants with advanced pancreatic cancer
¾ Arm B1 (Continuous infusion single agent lead-in):
x To determine the maximum tolerated dose of LMB-100 given in a continuous infusion format over 24 - 96 hours to patients with advanced solid tumors that express mesothelin
¾ Arm B2 (Continuous infusion combination therapy):
x Establish a tolerated dose of LMB-100 given by continuous infusion in combination with nab-paclitaxel chemotherapy in participants with advanced pancreatic cancer
untitled h1
3/4 arm a2 (phase ii

x To determine the objective response rate (PR+CR) according to RECIST 1.1 criteria of short infusion LMB-100 in combination with nab-paclitaxel chemotherapy in participants with advanced pancreatic cancer
untitled h1
eligibility

x Age ≥ 18 years x Histologically confirmed recurrent, metastatic and/or advanced pancreatic ductal adenocarcinoma (Except for Arm B1 [Single Agent Lead-in])
x For Arm B1 (Single Agent Lead-in), ONLY: Histologically confirmed solid tumor malignancy for which no curative therapy exists with at least 25% of tumor cells expressing mesothelin as determined by NCI Laboratory of Pathology. Determination can be made using archival tumor tissue or fresh biopsy.  
x Treatment must include at least one prior chemotherapy regimen x No nab-paclitaxel or paclitaxel treatment in the last four months (Except for Arm B1 [Single Agent Lead-in])
x Adequate organ function x Participants with HIV, active HBV or HCV infections are eligible only for the Arm B1
(Single Agent Lead-in)
untitled h1
design

x This study is a Phase I/II open label study to assess the safety and efficacy of LMB-100 in combination with the standard of care agent nab-paclitaxel in participants metastatic and/or locally advanced pancreatic ductal adenocarcinoma x Subjects will be treated for up to 2 or 3 cycles depending on arm.  
x In Arm A1 (Phase I, short infusion) of the study, up to 3 dose levels will be evaluated. LMB100 will be administered on days 1, 3 and 5 of a 21-day cycle and nab-paclitaxel will be administered on days 1 and 8 x In Arm A2 (Phase II, short infusion), if explored, up to 20 evaluable participants (including those treated at 65 mcg/kg, will be enrolled. Arm A2 will not be explored if 65 mcg/kg is not deemed safe in Arm A1 x In Arm B1 (Continuous infusion, single Agent Lead-in), escalating doses of single agent LMB-100 will be administered. The study drug will be given as a continuous infusion for the 1, 2, 3, or 4 days of a 21-day cycle.  
x Arm B2 (Continuous infusion, combination therapy) will be initiated after completion of both Arm A1 and Arm B1 Single Agent Lead-in. It will test a single dose level of LMB100 based on data from the Lead-in given in combination with nab-paclitaxel. LMB-100 will be given as a continuous infusion for 24 hours on Day 1 of a 14-day cycle. Nabpaclitaxel will also be given on Day 1.  
x The Arm A2 (Phase II, short infusion) portion of the study, if explored, will be conducted in a Simon Minimax two stage phase II design. The first stage will enroll 13 evaluable participants, including the six participants treated at 65 mcg/kg. If 1 or more has a response, then accrual would continue until a total of 20 evaluable participants have been enrolled.  
| TABLE OF CONTENTS                                                                                                                                   |                                                                                                                                                         |                                                                                                                                                  |
|-----------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|
| PRÉCIS .                                                                                                                                            |                                                                                                                                                         |                                                                                                                                                  |
| TABLE OF CONTENTS...............................................................................................................................4   |                                                                                                                                                         |                                                                                                                                                  |
| INTRODUCTION .                                                                                                                                      |                                                                                                                                                         |                                                                                                                                                  |
| 1                                                                                                                                                   | Study Objectives .                                                                                                                                      |                                                                                                                                                  |
| 1.1                                                                                                                                                 | 1.1.1                                                                                                                                                   | Primary Objective: ............................................................................................................................9 |
| 1.1.2                                                                                                                                               | Secondary Objectives: .....................................................................................................................9            |                                                                                                                                                  |
| 1.1.3                                                                                                                                               | Exploratory Objectives: ................................................................................................................9               |                                                                                                                                                  |
| Background and Rationale .........................................................................................................10                |                                                                                                                                                         |                                                                                                                                                  |
| 1.2                                                                                                                                                 |                                                                                                                                                         |                                                                                                                                                  |
| 1.2.1                                                                                                                                               | Background on Disease                                                                                                                                   |                                                                                                                                                  |
| 1.2.2                                                                                                                                               | Mesothelin (MSLN) as a therapeutic target                                                                                                               |                                                                                                                                                  |
| 1.2.3                                                                                                                                               | Recombinant Immunotoxins (RITs) .....................................................................................13                                 |                                                                                                                                                  |
| LMB-100..........................................................................................................................................15 |                                                                                                                                                         |                                                                                                                                                  |
| 1.2.4                                                                                                                                               |                                                                                                                                                         |                                                                                                                                                  |
| 1.2.5                                                                                                                                               | Pharmacokinetics of LMB-100 and modeling of continuous infusion .....................24                                                                 |                                                                                                                                                  |
| 1.2.6                                                                                                                                               | Rationale for treating pancreatic cancer patients with LMB-100 and NAB-                                                                                 |                                                                                                                                                  |
| paclitaxel combination ................................................................................................................25           |                                                                                                                                                         |                                                                                                                                                  |
| 1.2.7                                                                                                                                               | Rationale for assessing continuous infusion of LMB-100.............................................25                                                   |                                                                                                                                                  |
| Rationale for the initial dose and schedule and subsequent dose escalation of                                                                       |                                                                                                                                                         |                                                                                                                                                  |
| 1.2.8                                                                                                                                               | cc                                                                                                                                                      |                                                                                                                                                  |
| 1.2.9                                                                                                                                               | Rationale for use of mesothelin testing (NSR device)                                                                                                    |                                                                                                                                                  |
| 2                                                                                                                                                   | ELIGIBILITY ASSESSMENT AND ENROLLMENT................................................................29                                                 |                                                                                                                                                  |
| 2.1                                                                                                                                                 | Eligibility Criteria .                                                                                                                                  |                                                                                                                                                  |
| 2.1.1                                                                                                                                               | Inclusion Criteria .........................................................................................................................29          |                                                                                                                                                  |
| Exclusion Criteria .............................................................................................................................31  |                                                                                                                                                         |                                                                                                                                                  |
| 2.1.2                                                                                                                                               |                                                                                                                                                         |                                                                                                                                                  |
| 2.2                                                                                                                                                 | Screening Evaluation .......................................................................................................................31          |                                                                                                                                                  |
| 2.3                                                                                                                                                 | Registration Procedures ..................................................................................................................32            |                                                                                                                                                  |
| 2.3.1                                                                                                                                               | Arm B1, Single Agent Lead in Cohort Subjects with Diseases other than                                                                                   |                                                                                                                                                  |
| Epithelioid Mesothelioma or Pancreatic Adenocarcinoma Only...............................32                                                         |                                                                                                                                                         |                                                                                                                                                  |
| 2.3.2                                                                                                                                               | All other subjects ..................................................................................................................................33 |                                                                                                                                                  |
| 2.3.3                                                                                                                                               | Treatment Assignment  Procedures ..........................................................................................33                           |                                                                                                                                                  |
| 3                                                                                                                                                   | STUDY IMPLEMENTATION .................................................................................................................34                |                                                                                                                                                  |
| 3.1                                                                                                                                                 | Study Design ..................................................................................................................................34       |                                                                                                                                                  |  
3.1.1 Study Schema for short infusion LMB-100 with nab-paclitaxel (Arm A1 (Phase  
I))...............................................................................................................................35  
| I)) 35   |                                                                                               |
|----------|-----------------------------------------------------------------------------------------------|
| 3.1.2    | Study Schema for continuous infusion LMB-100 (Arm B1 [Single Agent Leadin]) 36                                                                                               |
| 3.1.3    | Study Schema for continuous infusion LMB-100 with nab-paclitaxel (Arm B2) 36                  |
| 3.1.4    | Study Schema for Phase II 37                                                                  |
| 3.1.5    | Dose Limiting Toxicity 37                                                                     |
| 3.1.6    | Dose Escalation 38                                                                            |
| 3.2      | Drug Administration 42                                                                        |
| 3.2.1    | LMB-100 42                                                                                    |
| 3.2.2    | Nab-Paclitaxel 46                                                                             |
| 3.2.3    | Co-administration of Nab-paclitaxel and LMB-100 46                                            |
| 3.3      | Dose Modifications 46                                                                         |
| 3.3.1    | LMB-100 47                                                                                    |
| 3.3.2    | Nab-paclitaxel 50                                                                             |
| 3.4      | Study Calendars 51                                                                            |
| 3.4.1    | Calendar for patient receiving short infusion LMB-100 (Arms A1 and A2) 51                     |
| 3.4.2    | Calendars subjects in Arm B1 (single agent continuous infusion LMB-100) 54                    |
| 3.4.3    | Calendar for Subjects in Arm B2 (LMB-100 24-hour continuous infusion  combination therapy) 60 |
| 3.5      | Criteria for Removal from Protocol Therapy and Off Study Criteria 63                          |
| 3.5.1    | Criteria for removal from protocol therapy 63                                                 |
| 3.5.2    | Off-Study Criteria 63                                                                         |
| 4        | CONCOMITANT MEDICATIONS/MEASURES 63 4.1.1 Permitted Therapy 63 4.1.2 Prohibited Therapy 63    |
| 5        | BIOSPECIMEN COLLECTION 64                                                                     |
| 5.1      | Correlative Studies for Research/Pharmacokinetic Studies 64                                   |
| 5.1.1    | LMB-100 Pharmacokinetic Assessments 64                                                        |
| 5.1.2    | Nab-Paclitaxel Pharmacokinetic Assessments 65                                                 |
| 5.1.3    | Pharmacogenetic Studies 66                                                                    |
| 5.1.4    | Assessment of anti-drug antibodies (ADAs) 66                                                  |
| 5.1.5    | Retrospective Analysis of Mesothelin Expression in tumor tissue 67                            |
untitled h1
abbreviated title lmb-100 + abrx

Version Date: 12/11/2018  
| Version Date: 12/11/2018                                                                                                                             |                                                                                                                                                         |                                                                                                                               |
|------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------|
| 5.1.6                                                                                                                                                | Cytokines for identification of mechanism for PE-mediated capillary leak                                                                                |                                                                                                                               |
| syndrome                                                                                                                                             |                                                                                                                                                         |                                                                                                                               |
| 5.1.7                                                                                                                                                | Circulating endothelial cells (CEP and CEC) for identification of mechanism for                                                                         |                                                                                                                               |
| PE-mediated capillary leak syndrome ..............................................................................68                                 |                                                                                                                                                         |                                                                                                                               |
| 5.1.8                                                                                                                                                | Immune subset analysis ......................................................................................................68                         |                                                                                                                               |
| Peripheral blood immune gene expression .........................................................................69                                  |                                                                                                                                                         |                                                                                                                               |
| 5.1.9                                                                                                                                                | CC                                                                                                                                                      |                                                                                                                               |
| 5.1.10                                                                                                                                               |                                                                                                                                                         |                                                                                                                               |
| 5.1.11                                                                                                                                               | Treatment Effect on Tumor Microenvironment ...............................................................70                                            |                                                                                                                               |
| Serum Megakaryocyte Potentiating Factor (MPF) level ...............................................70                                                |                                                                                                                                                         |                                                                                                                               |
| 5.1.12                                                                                                                                               |                                                                                                                                                         |                                                                                                                               |
| Sample Collection schedule .                                                                                                                         |                                                                                                                                                         |                                                                                                                               |
| 5.2                                                                                                                                                  |                                                                                                                                                         |                                                                                                                               |
| 5.2.1                                                                                                                                                | Sample Collection for Patients receiving short infusion LMB-100 (Arms A1 and                                                                            |                                                                                                                               |
| A2) ..............................................................................................................................................72 |                                                                                                                                                         |                                                                                                                               |
| 5.2.2                                                                                                                                                | Sample Collection for Patients receiving continuous infusion of LMB-100 (Arms                                                                           |                                                                                                                               |
| B1 and B2) .                                                                                                                                         |                                                                                                                                                         |                                                                                                                               |
| Sample Storage, Tracking and Disposition                                                                                                             |                                                                                                                                                         |                                                                                                                               |
| 5.3                                                                                                                                                  | 5.3.1                                                                                                                                                   | Clinical Pharmacology Program .............................................................................................80 |
| 5.3.2                                                                                                                                                | Leidos Biomedical, Inc. Lab                                                                                                                             |                                                                                                                               |
| 5.3.3                                                                                                                                                | Laboratory of Jane Trepel ........................................................................................................81                    |                                                                                                                               |
| 5.3.4                                                                                                                                                | Protocol Completion/Sample Destruction ..............................................................................81                                 |                                                                                                                               |
| 5.4                                                                                                                                                  | Samples for Genetic Analysis .............................................................................................................82            |                                                                                                                               |
| DATA COLLECTION AND EVALUATION                                                                                                                       |                                                                                                                                                         |                                                                                                                               |
| 6                                                                                                                                                    | DATA COLLECTION .....................................................................................................................................82 |                                                                                                                               |
| 6.1                                                                                                                                                  |                                                                                                                                                         |                                                                                                                               |
| 6.2                                                                                                                                                  | DATA Sharing Plans                                                                                                                                      |                                                                                                                               |
| 6.2.1                                                                                                                                                | Human Data Sharing Plan                                                                                                                                 |                                                                                                                               |
| Genomic Data Sharing Plan                                                                                                                            |                                                                                                                                                         |                                                                                                                               |
| 6.2.2                                                                                                                                                |                                                                                                                                                         |                                                                                                                               |
| 6.3                                                                                                                                                  | Response Criteria ...................................................................................................................................83 |                                                                                                                               |
| 6.3.1                                                                                                                                                | Definitions                                                                                                                                             |                                                                                                                               |
| 6.3.2                                                                                                                                                | All Diseases except pleural mesothelioma ............................................................................84                                 |                                                                                                                               |
| Pleural Mesothelioma ...............................................................................................................89               |                                                                                                                                                         |                                                                                                                               |
| 6.3.3                                                                                                                                                |                                                                                                                                                         |                                                                                                                               |
| 6.3.4                                                                                                                                                | Duration of Response                                                                                                                                    |                                                                                                                               |
| Progression-Free Survival ......................................................................................................91                   |                                                                                                                                                         |                                                                                                                               |
| 6.3.5                                                                                                                                                |                                                                                                                                                         |                                                                                                                               |
| 6.3.6                                                                                                                                                | Objective Response Rate .........................................................................................................91                     |                                                                                                                               |
| 6.3.7                                                                                                                                                | Disease Control Rate                                                                                                                                    |                                                                                                                               |  
| Version Date: 12/11/2018                                                                                                                     |                                                                                                                                                |                                                                                                                                               |
|----------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------|
| 6.4                                                                                                                                          | Toxicity Criteria                                                                                                                              |                                                                                                                                               |
| SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING                                                                                     |                                                                                                                                                |                                                                                                                                               |
| 7                                                                                                                                            | PLAN .                                                                                                                                         |                                                                                                                                               |
| Definitions                                                                                                                                  |                                                                                                                                                |                                                                                                                                               |
| 7.1                                                                                                                                          | 7.1.1                                                                                                                                          | A Adverse Event ...........................................................................................................................91 |
| 7.1.2                                                                                                                                        | Suspected adverse reaction ..............................................................................................92                    |                                                                                                                                               |
| Unexpected adverse reaction ..........................................................................................92                     |                                                                                                                                                |                                                                                                                                               |
| 7.1.3                                                                                                                                        | Serious                                                                                                                                        |                                                                                                                                               |
| 7.1.4                                                                                                                                        |                                                                                                                                                |                                                                                                                                               |
| 7.1.5                                                                                                                                        | Serious Adverse Event                                                                                                                          |                                                                                                                                               |
| 7.1.6                                                                                                                                        | Disability                                                                                                                                     |                                                                                                                                               |
| 7.1.7                                                                                                                                        | Life-threatening adverse drug experience ...........................................................................92                         |                                                                                                                                               |
| 7.1.8                                                                                                                                        | Protocol Deviation (NIH Definition) ................................................................................93                         |                                                                                                                                               |
| 7.1.9                                                                                                                                        | Non-compliance (NIH Definition)                                                                                                                |                                                                                                                                               |
| 7.1.10 Unanticipated Problem                                                                                                                 |                                                                                                                                                |                                                                                                                                               |
| NIH Intramural IRB and Clinical Director (CD) Reporting .............................................93                                      |                                                                                                                                                |                                                                                                                                               |
| 7.2                                                                                                                                          |                                                                                                                                                |                                                                                                                                               |
| 7.2.1                                                                                                                                        | NIH Intramural IRB and NCI CD Expedited Reporting of Unanticipated                                                                             |                                                                                                                                               |
| Problems and Deaths                                                                                                                          |                                                                                                                                                |                                                                                                                                               |
| 7.2.2                                                                                                                                        | NIH Intramural IRB Requirements for PI Reporting at Continuing Review ..........93                                                             |                                                                                                                                               |
| 7.2.3                                                                                                                                        | NIH Intramural IRB Reporting of IND Safety Reports                                                                                             |                                                                                                                                               |
| IND Sponsor Reporting Criteria ................................................................................................94            |                                                                                                                                                |                                                                                                                                               |
| 7.3                                                                                                                                          | Reporting Pregnancy                                                                                                                            |                                                                                                                                               |
| 7.3.1                                                                                                                                        |                                                                                                                                                |                                                                                                                                               |
| 7.4                                                                                                                                          | DATA AND SAFETY MONITORING Plan                                                                                                                |                                                                                                                                               |
| 7.4.1                                                                                                                                        | Principal Investigator/Research Team ..............................................................................95                          |                                                                                                                                               |
| Sponsor Monitoring Plan ...................................................................................................95                |                                                                                                                                                |                                                                                                                                               |
| 7.4.2                                                                                                                                        |                                                                                                                                                |                                                                                                                                               |
| 7.4.3                                                                                                                                        | Se                                                                                                                                             |                                                                                                                                               |
| 8                                                                                                                                            | STATISTICAL CONSIDERATIONS                                                                                                                     |                                                                                                                                               |
| Primary endpoints ........................................................................................................................96 |                                                                                                                                                |                                                                                                                                               |
| 8.1                                                                                                                                          |                                                                                                                                                |                                                                                                                                               |
| 8.1.1                                                                                                                                        | Part A ..................................................................................................................................96    |                                                                                                                                               |
| 8.1.2                                                                                                                                        | Part B: ....................................................................................................................................97 |                                                                                                                                               |
| 8.2                                                                                                                                          | Determination of Sample Size .......................................................................................................98         |                                                                                                                                               |
| 9                                                                                                                                            | HUMAN SUBJECTS PROTECTIONS ..........................................................................................98                        |                                                                                                                                               |
| 9.1                                                                                                                                          | Rationale For Subject Selection                                                                                                                |                                                                                                                                               |
| 9.2                                                                                                                                          | Participation of Children                                                                                                                      |                                                                                                                                               |  
| Version Date: 12/11/2018                                                                                                                            |                                                                                                                                                    |                       |
|-----------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|
| 9.3                                                                                                                                                 | Participation of Subjects Unable to Give Consent...............................................................9                                   |                       |
| Evaluation of Benefits and Risks/Discomforts .....................................................................9                                 |                                                                                                                                                    |                       |
| 9.4                                                                                                                                                 |                                                                                                                                                    |                       |
| 9.4.1                                                                                                                                               | Risks from Study Drugs                                                                                                                             |                       |
| 9.4.2                                                                                                                                               | Risks of study procedures ........................................................................................................100              |                       |
| Risks/Benefits Analysis ....................................................................................................................100     |                                                                                                                                                    |                       |
| 9.5                                                                                                                                                 | Consent and Assent Process and Documentation ................................................................100                                   |                       |
| 9.6                                                                                                                                                 |                                                                                                                                                    |                       |
| 9.6.1                                                                                                                                               | Consent procedure for non-English speaking patients                                                                                                |                       |
| 9.6.2                                                                                                                                               | Telephone consent procedure ...................................................................................................101                 |                       |
| PHARMACEUTICAL INFORMATION.........................................................................................101                              |                                                                                                                                                    |                       |
| 10                                                                                                                                                  | 10.1                                                                                                                                               | LMB-100 (IND # 12332) |
| 10.1.1                                                                                                                                              | SOURCE .                                                                                                                                           |                       |
| 10.1.2 Toxicity.................................................................................................................................102 |                                                                                                                                                    |                       |
| Formulation and preparation                                                                                                                         |                                                                                                                                                    |                       |
| 10.1.3                                                                                                                                              | Stability and Storage .....................................................................................................................104     |                       |
| 10.1.4                                                                                                                                              | Administration procedures ...........................................................................................................104           |                       |
| 10.1.5                                                                                                                                              |                                                                                                                                                    |                       |
| 10.1.6 Incompatibilities ....................................................................................................................104    |                                                                                                                                                    |                       |
| 10.2                                                                                                                                                | Nab -paclitaxel ...............................................................................................................................105 |                       |
| 10.2.1                                                                                                                                              | SOURCE .                                                                                                                                           |                       |
| 10.2.2                                                                                                                                              | TOXICITY                                                                                                                                           |                       |
| 10.2.3                                                                                                                                              | Formulation and preparation                                                                                                                        |                       |
| Stability and Storage ................................................................................................................107           |                                                                                                                                                    |                       |
| 10.2.4                                                                                                                                              |                                                                                                                                                    |                       |
| 10.2.5                                                                                                                                              | Administration procedures                                                                                                                          |                       |
| 10.2.6 Incompatibilities .....................................................................................................................108   |                                                                                                                                                    |                       |
| l l                                                                                                                                                 | REFERENCES .                                                                                                                                       |                       |
| 12                                                                                                                                                  | APPENDICES .                                                                                                                                       |                       |
| 12.1                                                                                                                                                | Appendix A - Performance Status Criteria ..............................................................................14                          |                       |
| Appendix B - Cockcroft-Gault Formula for Calculation of Creatinine Clearance .....115                                                               |                                                                                                                                                    |                       |
| 12.2                                                                                                                                                |                                                                                                                                                    |                       |
| 12.3                                                                                                                                                | Appendix C: Sample Chemotherapy Notes ..................................................................................16                         |                       |
| 12.3.1 For Part A.                                                                                                                                  |                                                                                                                                                    |                       |
| 12.3.2 For Arm B1                                                                                                                                   |                                                                                                                                                    |                       |
| For Arm B2 .                                                                                                                                        |                                                                                                                                                    |                       |
| 12.3.3                                                                                                                                              |                                                                                                                                                    |                       |
untitled h1
1 introduction 1.1 study objectives

1.1.1 *Primary Objective:* 1.1.1.1 Arm A1 (Phase I, short infusion):
x To determine the maximum tolerated dose (MTD) of short infusion LMB-100 when given in combination with nab-paclitaxel to participants with advanced pancreatic cancer 1.1.1.2 Arm B1 (Continuous infusion single agent lead-in:
x To determine the maximum tolerated dose of LMB-100 given in a continuous infusion format over 24 - 96 hours to patients with advanced solid tumors that express mesothelin 1.1.1.3 Arm B2 (Continuous infusion combination therapy):
x Establish a tolerated dose of LMB-100 given by continuous infusion in combination with nab-paclitaxel chemotherapy in participants with advanced pancreatic cancer 1.1.1.4 Arm A2 (Phase II short infusion):
x To determine the objective response rate (PR+CR) according to RECIST 1.1 criteria of short infusion LMB-100 in combination with nab-paclitaxel chemotherapy in participants with advanced pancreatic cancer 1.1.2 *Secondary Objectives:* 1.1.2.1 All Phases  
x To determine the safety and tolerability of LMB-100 or the combination with nabpaclitaxel in participants with advanced pancreatic cancer x To assess additional measures of efficacy including:
x change in the CA 19-9 serum marker with treatment (or other appropriate tumor marker for Arm B1 [Single Agent Lead-in])
x objective response rate (ORR) in Arms A1, B1 and B2 x disease control rate at 4 months (as defined in section 6.3.7) x progression free survival x overall survival x To define the pharmacokinetics of LMB-100 in the absence and presence of participant LMB-100 anti-drug antibodies (ADAs)
1.1.3 *Exploratory Objectives:*
Both phases x To identify a threshold titer of participant LMB-100 ADAs that predicts inadequate drug exposure x To examine the relationship between MSLN expression and response to treatment x To identify the mechanism for Pseudomonas endotoxin-mediated capillary leak syndrome x To examine the effect of immunotoxin treatment on the microenvironment in the Part B portion of the study x To determine the effect of LMB-100 on the pharmacokinetics of nab-paclitaxel x To correlate plasma concentrations of nab-paclitaxel to clinical response, toxicity, pharmacogenetic analyses and pharmacodynamic endpoints x To assess the genotype of the most relevant drug metabolizing enzymes and transporters
(DMET)
untitled h1
1.2 background and rationale 1.2.1

Pancreatic cancer is the fourth most common cause of cancer death in the United States, claiming more than 40,000 lives each year. Incidence nearly equals mortality with just 6% of patients living five years beyond their diagnosis. Most patients are diagnosed at an advanced stage, but even patients with early stage disease have a long term survival of less than 20%.[1] Combination chemotherapy with FOLFIRINOX provides the greatest survival advantage for patients who have advanced disease, but the median overall survival (OS) for this regimen does not reach one year and most pancreatic cancer patients are not fit enough to tolerate it.[2] Gemcitabine with NABpaclitaxel is an alternative regimen and extends median overall survival to 8.5 months from 6.7 months with gemcitabine alone. The response rate (RR) to this regimen in the first-line is 23%
with less than 1% of patients achieving a complete response (CR).[3] Prospective and retrospective cohort studies have estimated a 17% RR to this regimen when given in second-line to good performance status patients following FOLFIRINOX.[4, 5] Single agent gemcitabine remains the recommended treatment for patients with poor performance status. Erlotinib is the only targeted therapy with efficacy against this disease and extends median OS by approximately 10 days when added to gemcitabine at the expense of significant toxicity.[6] Median survival of patients able to receive second line therapy is approximately 3-6 months.[7] New paradigms for the effective treatment of pancreatic cancer are sorely needed.
untitled h1
1.2.2 mesothelin (msln) as a

MSLN is a cell surface glycoprotein that is a differentiation antigen for mesothelial cells; expression in normal tissues is confined to the pleura, pericardium and peritoneum. The normal function of MSLN is unknown. MSLN is expressed by a wide variety of solid tumors (Table 1) Expression of MSLN in PDAC has been reported in several published studies and ranges from 86 to 100%.[8-10] Please see Table 2 below for a summary of this expression. MSLN is also expressed in tumors from genetically engineered mouse models (GEMMs) of PDAC, including the KPC
model.[11] MSLN is specifically a marker of adenocarcinoma in the human disease and is not expressed in preceding pre-malignant stages of tumor development.[12] Increased MSLN
expression in early stage PDAC participants who undergo surgical resection confers decreased survival.[13] MSLN expression is also associated with more aggressive disease in cholangiocarcinoma, lung, ovarian and breast cancers.[14-17] In pancreatic cancer cell lines, overexpression of MSLN increases proliferation, motility and invasion and decreases survival of mice bearing tumors grown from these cells.[18] These properties make MSLN an attractive target for anti-neoplastic therapies, and more than five anti-MSLN agents are currently undergoing clinical testing.  
11  
| No. of Patients With MSLN   |                                 |
|-----------------------------|---------------------------------|
| Tumor Type                  | Expression–Positive Disease (%) |
| Mesothelioma                | 20 of 352 (82)                  |
| Epithelioid                 | 28 of 261 (95)                  |
| 0 of 23 (0)                 |                                 |
| Sarcomatoid                 |                                 |
| Pancreatic adenocarcinoma   | 33 of 357 (85)                  |
| Epithelial ovarian cancer   | 36 of 494 (70)                  |
| High-grade serous           | 28 of 332 (75)                  |
| Endometroid                 | 36 of 52 (69)                   |
| Mucinous                    | 2 of 19 (11)                    |
| Clear cell                  | 1 of 21 (52)                    |
| 1,157 of 2,036 (57)         |                                 |
| NSCLC                       |                                 |
| Adenocarcinoma              | 1,082 of 1,686 (64)             |
| Squamous                    | 40 of 188 (21)                  |
| SCLC                        | 0 of 55 (0)                     |
| Esophageal cancer           | 25 of 88 (28)                   |
| Gastric cancer              | 312 of 666 (47)                 |
| Biliary cancer              |                                 |
| Extrahepatic                | 93 of 98 (95)                   |
| Intrahepatic                | 1 of 10 (10)                    |
| Other or unspecified        | 36 of 85 (42)                   |
| Colorectal cancer           | 27 of 90 (30)                   |
| Cervical cancer             | 1 of 4 (25)                     |
| Endometrial cancer          | 34 of 58 (59)                   |
| Breast cancer               |                                 |
| Triple negative             | 3 of 50 (66)                    |
| Other                       | 1 of 61 (1.6)                   |
| Unspecified                 | 1 of 118 (9)                    |
untitled h1
table 1. prevalence of msln

| Negative                                                                                   | 1+ (1-25%   | 2+ (26-50%   | 3+ (>50%           | Total           | Reference       |
|--------------------------------------------------------------------------------------------|-------------|--------------|--------------------|-----------------|-----------------|
| clls)                                                                                      | clls)       | clls)        |                    |                 |                 |
| 10/60                                                                                      |             |              |                    |                 |                 |
| 0/60                                                                                       | 50/60       | 60/60        | Argani et al. (5)* |                 |                 |
| (100%)                                                                                     |             |              |                    |                 |                 |
| 0/14                                                                                       | 3/14        | 5/14         | 6/14               | 14/14           | Frierson et al. |
| (100%)                                                                                     | (2)*        |              |                    |                 |                 |
| 1/11                                                                                       | 0/11        | 2/11         | 8/11               | 10/11           | Ordonez (6)'    |
| (91%)                                                                                      |             |              |                    |                 |                 |
| 2/14                                                                                       | 0/14        | 3/14         | 9/14               | 12/14           | Ordonez (1)'    |
| (86%)                                                                                      |             |              |                    |                 |                 |
| 7/68                                                                                       | 2/68        | 3968         | 61/68              | Swierczynski et |                 |
| (90%)                                                                                      | al. (7)**   |              |                    |                 |                 |
| 0/18                                                                                       | 2/18        | 1/18         | 15/18              | 18/18           | Hassan et al.   |
| (100%)                                                                                     | (8)*        |              |                    |                 |                 |
| 10/185                                                                                     | 37/185      | 138/185      | 175/185            | Total           |                 |
| (5.4%)                                                                                     | (20%)       | (75%)        | ( 95%)             | prevalence      |                 |
| * 1% cutoff. *1+ was instead defined as focal (1-10% cells only) by Frierson et al. (2)    |             |              |                    |                 |                 |
| * Swierczynski et al. (7) demonstrated 10% of positive PDAC tumors could be missed in TMAs |             |              |                    |                 |                 |  
versus whole sections due to focal mesothelin staining.
untitled h1
1.2.3 recombinant immunotoxins (rits) 1.2.3.1

RITs are antibody-based therapeutics that carry a toxin payload. RITs that target MSLN contain a genetically engineered variant of Pseudomonas exotoxin A (PE) in which the native cell-binding domain of PE is replaced by a MSLN-binding antibody fragment. In this way, the RIT binds specifically to MSLN 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.[20]  
Figure 1: RIT Structure  
  
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 derived from mouse anti-mesothelin antibody 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 Astra Zeneca/ Medimmune, and LMB2, a CD25-targeted PE fusion protein developed by the National Cancer Institute (NCI). 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.
untitled h1
1.2.3.2 rationale for the development

The clinical use of SS1P, and of immunotoxins in general, has been hampered mainly by two key issues: firstly their high immunogenicity and secondly that they cause vascular leak syndrome (VLS) as a common severe side effect that is clinically difficult to manage. LMB-100 (see Figure 1 for structure) is a next generation PE-fusion protein that has been protein-engineered to maximally reduce its immunogenicity and its propensity to induce VLS by:
1. Using a fully humanized Fab fragment derived from the anti-mesothelin antibody SS1 for tumor targeting 2. Substituting the bulk of domain II (residues 251–273 and 284–394 of native PE) by an extended furin cleavable linker whose sequence is devoid of any T cell neoepitopes 3. Deimmunizing domain III of PE, which has the catalytic activity for ADP-ribosylation by introducing 7 point mutations that silence B- and T-cell epitopes Classical PE-based immunotoxins, such as SS1P, contain a 38 kD fragment of the exotoxin encompassing the so called translocation domain II and the catalytic domain III. Omission of the domain II from LMB-100 has not only removed a highly immunogenic 14 kD portion of PE that contains the main T-cell epitopes,[21] but has also resulted in reduced incidence of VLS.[22]
1.2.3.3 Nonclinical summary of previous generation MSLN-targeted RIT SS1P
The SS1P molecule is composed of the VL from SS1, an affinity-matured derivative of an antiMSLN monoclonal antibody, disulfide bonded to a fusion of VH of SS1 with PE38. Compared to wild type toxin, the PE38 fragment lacks the cell-binding domain I (residues 1–252) as well as the toxin portion encompassing positions 365380.  
Viability of tumor cell lines expressing mesothelin is potently reduced by treatment with SS1P, resulting in half-maximal inhibitory concentration values (IC50) in the single digit ng/mL range (equivalent to ~10 pM) or even lower for some tumor cell lines, while mesothelin-negative cancer cells are insensitive to SS1P even at 100 ng/mL.[23, 24]
Using primary tumor cells from ascites or pleural effusion from nine mesothelioma patients, Zhang et al.[25] found that in most cases mesothelin expression was lost upon in vitro culture. However, for the few samples that retained mesothelin positivity, the mesothelin level on the cell surface, which ranged from 600200,000 sites/cell, correlated with SS1P sensitivity.  
In mice, SS1P had severe off-target toxic effects on the liver, limiting the maximum tolerated dose
(MTD) in a 3 uper week QOD schedule to d0.5 mg/kg.[22] Using MTDs and the 3 uper week QOD regimen, SS1P was shown to have significant monotherapy efficacy in xenograft models of the NCI-H226 cell line (derived from pleural effusions of a mesothelioma patient).[26]
Monotherapy anti-tumor efficacy of SS1P has also been shown in xenografts of the stably transfected A431 K5 cell line,[27] that expresses very high levels of mesothelin on the cell surface
(25 million molecules per cell). In the same study, synergistic antitumor activity was found for the combination of SS1P with paclitaxel in vivo but not in vitro. The underlying mechanism has subsequently been claimed to be related to improved tumor penetration and intratumoral distribution of SS1P associated with a paclitaxel-mediated reduction of shedding of mesothelin from the tumor cells.[28, 29]
When given to BALB/c mice as IV bolus injections (100 μL/mouse) at doses of 0.125 or 0.4 mg/kg, SS1P has been reported to have a serum half-life of about 26 minutes, reaching a maximum serum concentration of 3.4 Pg/mL at 30 minutes post-injection. The mean residence time has been reported as 0.64 minutes and the area under the plasma concentration curve as 0.36 minutes mg/mL.[30]
Toxicology studies of SS1P were conducted in cynomolgus monkeys with different doses and schedules, including a 1 mg/kg 3 uper week QOD schedule. Decreased appetite and physical activity was observed in animals treated with the 1 mg/kg dose level of SS1P. Necropsy studies of SS1P-treated cynomolgus monkeys showed dose-dependent, microscopic inflammation of serosal membranes, suggesting that pleuritis and/or pericarditis could be dose limiting.[31]
untitled h1
1.2.3.4 clinical summary of previous

SS1P has been tested in a clinical setting by the NCI in the United States.[31] The related adverse events (AEs) included pleuritic pain, VLS, hypoalbuminemia, weight gain, fatigue, fever, and edema. In an initial Phase I trial, a cohort of 17 patients received SS1P QOD u6 doses. The MTD
was 18 Pg/kg and the dose-limiting toxicities (DLTs) included Grade 3 urticaria (1 patient) and Grade 3 VLS (2 patients). To allow further SS1P dose escalation, another 17 patients were treated on a QOD u3 doses schedule with the MTD reaching 45 μg/kg. The DLT observed was Grade 3 pleuritis (2 of 2 patients treated at 60 Pg/kg and 1 of 9 patients treated at 45 μg/kg). A second trial evaluated the safety and PK profile of SS1P given as continuous infusion for 10 days.[31] The MTD
in this study was 25 μg/kg/day u10 doses, where 1 of 6 patients had a DLT due to reversible VLS.  
The most common adverse events were edema (71%), hypoalbuminemia (62%), fatigue, (62%), weight gain/VLS (54%), nausea (46%), fever (46%), hypotension (38%), and allergy/rash (33%).  
The clinical efficacy of SS1P in humans has been limited to date, with 4 minor responses out of 33 evaluable patients in the initial IV bolus monotherapy trial[31] and 1 partial response out of 24 patients in the continuous infusion trial.[31] This is most likely due to the immunogenicity of the compound, which led to the development of neutralizing ADAs in the vast majority of the patients after 1 cycle of therapy in both the IV bolus and the continuous infusion trials. This hypothesis is supported by an exploratory trial currently ongoing by the NCI in which patients are pretreated with an immunosuppressive chemotherapy regimen (pentostatin and cyclophosphamide) for 14 days prior to administration of SS1P. In this trial, 3 out of 10 patients achieved a partial response and another 3 patients achieved durable disease stabilization.[31, 32] One of the three patients achieving a partial response did so after receiving just two cycles of SS1P before developing neutralizing anti-SS1P antibodies and coming off treatment. In addition, a recent Phase1b study was published where SS1P was given with pemetrexed and cisplatin in advanced malignant pleural mesothelioma (MPM). SS1P was shown to be safe and well tolerated and exhibited significant antitumor activity in patients with unresectable, advanced pleural mesothelioma.[33]
Based on the safety profile described previously for SS1P when given as single agent or in combination, the potential risks of treatment with LMB-100 were expected to include VLS, hypoalbuminemia, edema, pleuritis, infusion-related reactions, and immunogenicity. Precautions for diagnosis, monitoring, prevention, and treatment of adverse events will be provided in the Phase I studies.
untitled h1
1.2.4 lmb-100 1.2.4.1 nonclinical studies

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 mesothelinpositive 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 1001000 fold less potent on mesothelin-positive target cell lines, confirming low cytotoxic potential of PE24 lacking a targeting moiety.  
Animal studies demonstrated that a single cycle of LMB-100 treatment given at an optimal dose of approximately 2 mg/kg, 3 uper 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 A431H9 cell line or the pancreatic cancer cell line KLM1. These results support evidence that LMB-100 may provide clinical benefit to participants with cancer.  
1.2.4.1.2 Combination of taxane with LMB-100 A favorable in vivo interaction between paclitaxel and SS1P was first described by the Pastan lab nearly ten years ago[27] Pre-administration of paclitaxel was demonstrated to increase the amount of immunotoxin internalized by tumor cells and to reduce levels of shed MSLN in the intra-tumoral environment so that more immunotoxin could bind tumor cells.[28] Consistent with this mechanism, no synergy was observed in vitro. A
similar effect has been observed with LMB100.[34, 35] The effect is even more pronounced with NAB-paclitaxel in a pancreatic cancer model, where all combination treated mice develop complete regressions of their tumors (Figure 2). Strikingly, the tumors never regrew in most of the animals. Similar results have been seen with in A431 cells stably overexpressing MSLN and also in tumors grown from primary mesothelioma cells. Research in our laboratory has demonstrated that this synergistic interaction can also be observed *in vitro* suggesting that a direct mechanism accounts for at least part of the effect (data not shown, manuscript in preparation). The exact mechanism remains under investigation. These data support testing of this combination in the clinic as it may have clinical benefit for pancreatic cancer patients.  
Figure 2
untitled h1
1.2.4.1.3 pharmacokinetics in animals

The pharmacokinetics (PK) of LMB-100 were tested in cynomolgus monkeys following single IV administration at doses ranging from 0.03 mg/kg to 0.3 mg/kg. Two different enzyme-linked immunosorbent based formats were used for analyzing plasma levels of LMB-100; free and total drug assay (where the total drug assay was the sum of free LMB-100 and LMB-100 complexed with binding molecules). LMB-100 showed a relatively rapid plasma clearance and a volume of distribution at steady-state similar to the plasma volume. Within the dose range tested, non-linear PK was observed for free drug with an extended half-life at higher doses (mean terminal half-life approximately 0.6 hours at 0.3 mg/kg compared to 0.3 hours at 0.03 mg/kg) suggesting saturation of MSLN-mediated clearance pathways. Clearance of total drug was consistently lower than that for free drug implying the presence of soluble binding partners such as soluble mesothelin and ADAs. Induction of anti-drug antibodies (ADA) responses was frequently detectable in all dose groups tested. Overall, given the limited predictive value of immunogenicity reactions in animals to human, a risk for immunogenicity in humans cannot be excluded. Toxicokinetics after repeated IV dosing in cynomolgus monkeys demonstrated an increase in total exposure in a dose proportional manner between 0.1 mg/kg and 3.0 mg/kg. No accumulation was observed over 5 consecutive days of treatment or over two dosing cycles with 3 uper week dosing. Almost all monkeys developed ADAs upon treatment, while induction of high ADA levels impaired the exposure of free drug. In some cases, the induction of ADAs may have induced a slight increase in exposure The relationship between systemic drug exposure and anti-tumoral 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 (r36%) 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.
untitled h1
1.2.4.1.4 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 u3 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 LMB100 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 t1 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 t0.3 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 u3 dosing),
markedly reduced Injection site findings were observed after administration of a batch with reduced levels of product related modifications of LMB-100. In this study, the HNSTD was 1 mg/kg, resulting in an AUC for total drug of 27.4 and 23.6 μg·h/mL after the first and third dose (preliminary data). The potential of LMB-100 to induce off-target vascular leak in lungs was assessed in female Wistar rats. Mild perivascular edema was reported microscopically, but did not correlate with macroscopic or serum chemistry findings consistent with 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 cytokinemediated 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.
untitled h1
1.2.4.2 previous roche clinical 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 MSLNexpressing metastatic or locally advanced solid tumors for whom no standard therapy was available. Secondary objectives included determination of the RP2D and schedule, exploration of preliminary anti-tumor activity by assessing objective response rate (ORR) and disease control rate (DCR), and assessment of pharmacodynamic effects. A total of 15 participants were enrolled onto the study before termination. Median age of participants was 60.8 years and 53.3% were female. All participants had received prior anti-cancer therapy for their tumors. Enrolled participants had advanced mesothelioma (7), ovarian cancer (3), pancreatic cancer (3), and gastroesophageal cancer (2). Tumors from 13 of the 15 participants treated had moderately to strongly positive MSLN expression as measured by central IHC analysis.  
LMB-100 was administered intravenously on Days 1, 3 and 5 of a 21-day treatment cycle. No premedications were given. Treatment was initiated at the MTD of SS1P, 45 mcg/ kg. Five different dose levels were tested (see Table 3). 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 toxic 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 3. 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      |                 |              |  
  
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) and rash with fever (1), 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 (see Table 4 and Table 5 which are adapted from Roche Final Study Report, "Summary of Adverse Events Related to Study Medication, Safety-Evaluable Patients Protocol: BP29387"). Two of four patients treated at 250 mcg/kg experienced serious 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. In summary, safety and tolerability of LMB-100 were as expected.  
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.
untitled h1
table 5 adverse events attributed

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  
| Dose (mcg/kg)                                                                                                       | 45     | 65   | 100   | 170   | 250   | ALL   |    |
|---------------------------------------------------------------------------------------------------------------------|--------|------|-------|-------|-------|-------|----|
| # of patients treated                                                                                               | 1      | 1    | 3     | 4     | 4     | 13    |    |
| 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     |    |
| 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 |        |      |       |       |       |       |    |  
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."
untitled h1
1.2.4.2.2 anti-drug antibodies (adas) and

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 antidrug antibody (ADA) titers. 5 of 15 participants had detectable ADAs at study enrollment while the remaining participants did not, however, the remaining participants developed detectable ADAs by the end of Cycle 2. Immunogenicity of LMB-100 did affect serum drug levels. These data are summarized in Figure 3. 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 7 ). In summary these data show that the presence of ADAs is not predictive of ability to achieve measurable LMB-100 concentration in the serum, which is the most important parameter for drug efficacy.  
  
| Cycle 1   | Cycle 2   |         |        |         |      |         |
|-----------|-----------|---------|--------|---------|------|---------|
| Patient   | Dose      | ADA     | Cmax   | ADA     | Cmax | dC1/dC2 |
| (mcg/kg)  | (Day1)    | (ng/ml) | (Day1) | (ng/ml) | (%)  |         |
| 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 Table 7: LMB-100 drug levels and ADAs in patients WITHOUT pre-existing ADAs  
| Cycle 1   | Cycle 2   | Cycle 3   |         |        |         |        |        |         |        |
|-----------|-----------|-----------|---------|--------|---------|--------|--------|---------|--------|
| Patien    | Dose      | ADA       | Cmax    | ADA    | Cmax    | dC1/dC | ADA    | Cmax    | dC1/dC |
| t         | (mcg/kg)  | (Day1)    | (ng/ml) | (Day1) | (ng/ml) | (%)    | (Day1) | (ng/ml) | (%)    |
| 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.  
1.2.4.2.3 Comparison of toxicity and immunogenicity of LMB-100 to SS1P In the Roche Phase 1 trial, 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 4). These data demonstrate that LMB-100 is both less toxic and less immunogenic than SS1P.  
Figure 4: LMB-100 vs SS1P[31] **Cycle 2 Blood Levels**
untitled h1
1.2.4.3 nci phase i study

Clinical testing of LMB-100 in a second single agent study has recently been completed. In this trial, LMB-100 given by short infusion dosing was assessed in 10 patients with malignant mesothelioma (NCT02798536). Doses of 170 mcg/kg and 140 mcg/kg given as a 30-120 minute infusion every other day x3 doses were tested. Reversible renal toxicity that prolonged hospitalization was observed at the 170 mcg/kg dose. Therefore, **single agent short infusion MTD** of 140 mcg/kg was established. Toxicities and peak drug levels have thus far been similar to what was seen in the completed Roche study. Low serum LMB-100 levels and a high rate of infusionrelated reactions were observed after cycle 2, presumably due to the development of anti-LMB100 antibodies.  
1.2.4.4 Results in current study (16C0128 as of 16 July 2018)
untitled h1
part a - short infusion

As of 7/16/2018, 14 subjects have been enrolled to receive escalating doses of LMB-100 in combination with a fixed dose (125 mg/m2) of nab-paclitaxel. LMB-100 was administered on days 1, 3 and 5 of a 21-day cycle, while nab-paclitaxel was administered on days 1 and 8. Six subjects received LMB-100 at dose level 1 (100 mcg/kg), of whom five were evaluable. Of the five, two experienced DLTs of grade 3 myalgia. Therefore, per dose escalation rules, the next LMB-100 dose level evaluated was 65 mcg/kg (dose level -1). Eight subjects have been enrolled, two of whom are deemed inevaluable. One of the six evaluable subjects experienced DLT of grade 3 edema related to LMB-100 vascular leak.. This arm of the study (Arm A1) is now completed and closed to further accrual. Dose Level -1 is the recommended Phase 2 dose. Arm A2 has opened to accrual of patients at this dose and schedule.
untitled h1
part b - continuous infusion

Subjects are being evaluated on Arm B1, dose exploration for continuous infusion LMB-100 monotherapy. Dose level 1 was discarded after treatment of 3 patients due to erratic PK results. 1 of 6 patients at dose level 2 experienced DLT (grade 3 proteinuria). However, a planned dose deescalation was initiated to try to determine a better tolerated schedule since 3 of 6 patients at dose level 2 experienced non-DLT VLS resulting in >5 kg weight gain. As of 7/16/18, 6 participants have been treated at dose level 3 and completed the DLT period. None of the participants experienced significant VLS. 3 of the 6 participants received on the Day 1 and not the Day 4 dose of LMB-100 due to complications from their disease unrelated to study drug (question of partial small bowel obstruction, fever and hypotension from cholangitis, dehydration from nausea and vomiting due to overeating), and were therefore inevaluable. 1 of the 3 evaluable participants did not receive the Day 4 dose of LMB-100 due to transient grade 2 creatinine elevation that was attributed at least partially to study drug. This was considered an investigator-determined DLT since the patient was unable to receive the full course of treatment due to a study-drug related toxicity.
untitled h1
1.2.5 pharmacokinetics of lmb-100 and

The initial Roche trial demonstrated that LMB-100 has an unexpectedly short drug half-life of 61 minutes as compared to 466 minutes for the predecessor drug SS1P.[36]
It is not known what factors contribute to the longer half-life in circulation of SS1P.  
Using these clinical pharmacokinetic data, estimations of individual pharmacokinetic parameters that would be achieved with a continuous infusion format can be calculated (see Table 8). Using a one compartment population PK model, it is estimated through simulations that steady state maximum plasma concentration will be reached by 7 hours and that drug concentration will remain at this plateau level until the infusion is stopped (Figure 5). Peak plasma drug concentration (C max) using the continuous infusion is expected to be 92% lower than those seen following short infusion of the same amount of drug. Following completion of the continuous infusion, drug levels are expected to fall to near zero within 5 hours from the end of infusion. Results from patients enrolled onto the first Level of the Arm B1 Single Agent Lead-in have confirmed Cmax at or lower than that  
  
predicted by the model and also that drug levels fall to near zero in less than 4 hours from the end of infusion.  
| Bolus Infusion (actual)                                                      | Continuous Infusion (simulated)    |             |         |       |           |
|------------------------------------------------------------------------------|------------------------------------|-------------|---------|-------|-----------|
| AUC0-24                                                                      | *AUC0-24                           |             |         |       |           |
| Dose                                                                         | Cmax                               | (hr*ng/mL   | Dose    | Cmax  | (hr*ng/mL |
| (ug/kg/day)                                                                  | (ng/mL)                            | (ug/kg/day) | (ng/mL) |       |           |
| )                                                                            |                                    |             |         |       |           |
| 45                                                                           | 598                                | 674         | 45      | 42.2  | 957       |
| 65                                                                           | 100                                | 245         | 65      | 61.0  | 1382      |
| 100                                                                          | 1431                               | 2341        | 100     | 93.8  | 2126      |
| 140                                                                          | 1214                               | 2309        | 140     | 131.3 | 2978      |
| 170                                                                          | 206                                | 3921        | 170     | 159.5 | 3615      |
| 200                                                                          | 2435                               | 4342        | 200     | 187.6 | 4253      |
| 250                                                                          | 4311                               | 6706        | 250     | 234.5 | 5317      |
| *Simulated AUC0-24 was a single day's exposure during a simulated 5-day CIVI |                                    |             |         |       |           |
untitled h1
1.2.6

Rationale for treating pancreatic cancer patients with LMB-100 and NAB-paclitaxel combination LMB-100 targets the cell surface antigen MSLN and is ineffective against tumor or normal cells that lack MSLN.  Expression of MSLN in pancreatic adenocarcinoma has been examined in several published studies and ranges from 86 to 100%, [8-10] making this tumor type a good target for LMB-100.  There is clearly an unmet need to identify improved therapies for this patient population as patients with metastatic pancreatic cancer have a median OS of less than one year with the best currently available therapies.  
Pre-clinical studies have demonstrated that combination of LMB-100 with nab-paclitaxel results in synergistic anti-tumor efficacy.  NAB-
paclitaxel is part of an FDA approved regimen for patients with advanced pancreatic cancer and addition of LMB-100 to nab-paclitaxel may improve outcomes for these patients.  Given the overall poor prognosis of these patients, the potential to directly benefit from treatment with the combination regimen outweighs the risks of participating in the study.
untitled h1
1.2.7 rationale for assessing continuous

Clinical trials have shown that LMB-100 has a short half-life in humans of only 1 hour. Drugs with short half-lives can be administered by continuous infusion in order to improve drug exposure. Short half-life standard of care chemotherapies such as 5-FU and cytarabine are preferentially administered in this format. In the case of 5-FU the continuous infusion is preceded by a single bolus dose. Short half-life protein based therapeutics also appear to benefit from continuous infusion.  For example, the dual specificity CD19/ CD3 bispecific T cell engaging
(BiTE) antibody construct, blinatumomab, has a half-life of just over 2 hours. In initial clinical trials using a 2-4 hour infusion given 2-3 times per week, the drug performed poorly and these trials were terminated early due to poor risk to benefit ratio.[37] Subsequently, the drug was reintroduced in a continuous infusion format. Decreased toxicity and significant efficacy, including complete remissions in patients with chemotherapy-refractory disease, were observed.[38] Blinatumomab has since been approved by the FDA for administration in the continuous infusion format. We hypothesize that sustained infusion of LMB-100 will be safer and more effective than short infusion. We expect LMB100 toxicity to decrease when given in the continuous infusion format because peak drug levels (Cmax) will be lower and this should reduce non-specific toxicity from the drug. We expect greater efficacy because pre-clinical data suggest that duration of exposure to LMB-100 rather than peak dose may be more important for killing tumor cells. Specifically, we have found that sustained exposure of cultured cells to lower doses of LMB-100 can be more cytotoxic than treatments with higher doses given for shorter durations (Figure 6). In addition, previously published studies in mouse models with another short half-life immunotoxin demonstrated that continuous infusion of immunotoxin administered by means of surgically inserted intraperitoneal osmotic pump is less toxic; continuous infusion of these immunotoxins at MTD resulted in at least 2.5 times higher AUC than could be achieved safely with a short infusion at MTD. Because of this, better anti-tumor efficacy was achieved with the continuous infusion dosing.[39]
Figure 6 Instability of LMB-100 at 37°C precludes the ability to directly test its efficacy when administered continuously for several days in mouse pre-clinical tumor models. This is because the drug must be administered in a pump kept within the peritoneal cavity at mouse body temperature throughout the experiment and the drug loses activity within 24 hours when stored at these temperatures. However, preliminary data from pre-clinical studies performed by the LMB Immunotoxin group have shown increased efficacy and decreased toxicity when using 1) intraperitoneal continuous delivery of a related short half-life MSLN-targeted immunotoxin that is stable at 37°C and 2) bolus dosing of a long-half-life anti-MSLN immunotoxin that contains an albumin-binding domain that prolongs half-life. Both studies demonstrated increased anti-tumor efficacy compared to bolus dosing of LMB-100 (Figure 7).
untitled h1
figure 7

Continuous infusion dosing of the LMB-100 predecessor drug, SS1P, has been examined in a Phase I clinical trial. Although the long half-life of SS1P is expected to lessen the clinical impact of switching from short to continuous infusion format, these data also support our hypothesis. As predicted by the preclinical modeling, using a continuous infusion format allowed patients to achieve a higher total drug exposure. At MTD, continuous infusion resulted in an AUC of 1800 mcg min/ mL[40] as compared to 590 mcg min/mL with the short infusion.[36] Unfortunately, comparative efficacy of the two formats could not be adequately assessed since the immunogenicity of SS1P prevented effective dosing over multiple cycles. Since multiple cycles of LMB-100 can be administered to most patients prior to the development of anti-drug antibodies, this provides an ideal opportunity to determine whether a continuous infusion format can improve therapeutic window in the clinic as predicted by pre-clinical models. Continuous LMB-100 will be delivered at a slow rate, i.e. which may be less than one mL per hour in some cases. The FDA has issued a warning regarding such low infusion rates particularly pertaining to high risk or life-sustaining therapies. However, LMB-100, is not considered to be a high risk (based on the fact that patients are currently tolerating infusions given over 30-60 minutes) or life-sustaining therapy. 1.2.8 *Rationale for the initial dose and schedule and subsequent dose escalation of continuous* infusion LMB-100 Continuous infusion of 96 hours was deemed to be the optimal duration for infusion after taking into consideration feasibility of administration and the potential risk to participants from deconditioning while in hospital receiving continuous infusion of study drug, balanced against the possibility for increased efficacy with longer exposure times. As outlined in section 1.2.5 existing clinical PK data were used to generate a model that could simulate PK parameters during continuous infusion of LMB-100. This model predicts that continuous infusion of the same dose of LMB-100 over each 24 hours by continuous infusion as compared to daily bolus dosing would result in similar total LMB-100 exposure levels but much lower Cmax. Lower Cmax should result in decreased off-target toxicity (such as VLS), and our preclinical data suggest this should not adversely affect efficacy. The effect of lower Cmax on on-target off-tumor toxicities (such as serosal membrane irritation) is not predictable, although increased on-target off-tumor toxicity was not apparent during clinical trial using a continuous infusion format of a predecessor mesothelin-targeted immunotoxin.[40]
Taking potential risk for increased on-target off-tumor toxicity into consideration, a reduction in starting dose compared to short-infusion MTD will be used. A dose of 65 mcg/ kg was chosen as the initial dose for the escalation because it had been a) previously tested in the short infusion format in the Roche study of single agent LMB-100, and b) would also result in participants receiving ~60% less drug per cycle compared to short infusion LMB-100 given at the MTD of 140 mcg/kg every 48 hours for 3 doses (19.5 mg/ cycle versus 31.5 mg/cycle). Based upon our simulations, we predict that participant drug exposure during a 96-hour continuous infusion of 65 mcg/ kg/ day of LMB-100 will be 80% of that compared to patients who receive short-infusion LMB-100 given at MTD (5528 versus 6927 hr*ng/ml/ cycle). Subsequent dose levels administering 100, 140 and 200 mcg/kg/day over 96 hour continuous infusion were included although simulated drug exposures will exceed that of the short infusion MTD because the unacceptable toxicities seen with short-infusion LMB-100 at dosages higher than the established MTD for this format (VLS and reversible acute kidney injury which prolonged hospitalization) are off-target toxicities, and likely to be minimized by the lower Cmax that is predicted with continuous infusion. Although 96 hours is considered the optimal duration for continuous infusion, initial dose levels will test continuous infusions of 65 mcg/kg/day of drug for shorter durations since simulated drug exposure over each 48 hours of continuous infusion at 65 mcg/kg/day is 20% higher than for the short infusion MTD (2764 versus 2309 hr*ng/mL/48hr). This is because just one dose of LMB100 is given over 48 hours in the short infusion format.  
A loading dose of 40 mcg/kg LMB-100 given over 30-180 minutes will be administered prior to initiation of the continuous infusion beginning after Level 1. The loading dose is expected to improve efficacy by reducing tumor site barrier effect. Such affect has been observed in preclinical studies and may impair access of LMB-100 to the tumor during continuous infusion.
untitled h1
1.2.9 rationale for use of

In order to be eligible for the Arm B1 lead in portion of the study, participants are required to have positive mesothelin expression in archival tumor tissue, defined as at least 25% of tumor cells expressing mesothelin. Mesothelin expression testing is not FDA approved for this purpose; however, it is being used as an in-vitro diagnostic device. According to 21 CFR 812.3(m), a significant risk device presents a potential for serious risk to the health, safety and welfare of a subject and meets the significant risk criteria listed in the table below along with the sponsor's conclusions with regard to the applicability of these criteria to the current study. The device has been assessed by the sponsor as non-significant risk per the below.  
| Significant Risk Criteria                                                                                                                   | Applicable to   | Justification                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |            |    |    |                          |
|---------------------------------------------------------------------------------------------------------------------------------------------|-----------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|----|----|--------------------------|
| current study                                                                                                                               |                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |            |    |    |                          |
| Is an implant                                                                                                                               | No              | The mesothelin test is not introduced into  the subject                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |            |    |    |                          |
| Is                                                                                                                                          | used            | in                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | supporting | or | No | The device is diagnostic |
| sustaining human life Is of substantial importance in  diagnosing mitigating or  treating disease or preventing  impairment of human health | No              | While the device is diagnostic, we do not  believe in presents a potential for serious  risk to the health and welfare of the subject.  The assessment of mesothelin positivity is  only used in tumors that may not have a  high rate of mesothelin expression, and is  assessed to help to increase the possibility  that all persons enrolling on the study might  derive benefit from therapy. Persons that  are deemed ineligible to enroll on the basis  of this test are eligible for studies within  TGMB that are not reliant on this test. |            |    |    |                          |
| Otherwise poses a risk                                                                                                                      | No              | Testing will be performed on archival  samples or on fresh tissue that is collected  at screening for confirmation of diagnosis.  No additional collection of tissue will occur  for purposes of mesothelin testing.                                                                                                                                                                                                                                                                                                                                 |            |    |    |                          |
untitled h1
2 eligibility assessment and enrollment

2.1.1 *Inclusion Criteria* 2.1.1.1 For participants who will be receiving nab-paclitaxel (all arms except Arm B1 Single Agent Lead-in)
2.1.1.1.1 Histologically confirmed recurrent, advanced or metastatic pancreatic ductal adenocarcinoma as determined by NCI Laboratory of Pathology.  
2.1.1.1.2 No treatment with paclitaxel or nab-paclitaxel within 4 months prior to initiation of study therapy 2.1.1.1.3 ECOG performance status (PS) 01 (Appendix A).
2.1.1.1.4 Adequate hematological function: neutrophil count of t1.0 u109 cells/L, platelet count of t95,000/PL, hemoglobin ≥ 9 g/dL
2.1.1.1.5 Measurable disease as per the RECIST Criteria v 1.1 (see section 6.3)
2.1.1.2 For participants who will NOT receive nab-paclitaxel (Arm B1 Single Agent Lead-in only)
2.1.1.2.1 Histologically confirmed solid tumor malignancy for which no curative therapy exists with at least 25% of tumor cells expressing mesothelin as determined by NCI Laboratory of Pathology. Determination can be made using archival tumor tissue or fresh biopsy. Subjects with epithelioid mesothelioma and pancreatic adenocarcinoma are automatically eligible and are not required to have this test 2.1.1.2.2 ECOG performance status (PS) 02 (Appendix A).  
2.1.1.2.3 Adequate hematological function: neutrophil count of t1.0 u109 cells/L, platelet count of t85,000/Pl, hemoglobin ≥ 8.5 g/dL
2.1.1.2.4 Measurable and/or evaluable disease as per the RECIST Criteria v 1.1 (see section 6.3) 2.1.1.3 For all arms of the protocol 2.1.1.3.1 Participants must have received at least one prior chemotherapy regimen for their disease.  
2.1.1.3.2 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 persons <18 years of age, children are excluded from this study.  
2.1.1.3.3 Participants must be more than 14 days removed from most recent minor surgical procedure (such as biliary stenting), 28 days from most recent major surgical procedure, 14 days removed from most recent radiation therapy, chemotherapy or experimental drug treatment with published half-life known to be 72 hours or less and 28 days removed from last experimental drug treatment with unpublished or half-life greater than 72 hours.  
2.1.1.3.4 All acute toxic effects of any prior radiotherapy, chemotherapy, experimental drug treatment or surgical procedure must have resolved to Grade d1, except alopecia (any grade) and peripheral neuropathy.  
2.1.1.3.5 Serum albumin ≥ 2.5 mg/dL without intravenous supplementation 2.1.1.3.6 Adequate liver function: Bilirubin, AST and ALT < 2.5 x ULN. AST and ALT up to 5x ULN is permitted for patients with liver metastases.  
2.1.1.3.7 Adequate renal function: creatinine clearance (by Cockcroft Gault formula Appendix B
or measured) t50 mL/min.  
2.1.1.3.8 Must have left ventricular ejection fraction ≥ 50% 2.1.1.3.9 Must have an ambulatory oxygen saturation of > 88% on room air 2.1.1.3.10 The effects of LMB-100 alone or in combination with nab-paclitaxel on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry until 3 months the last dose of study therapy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.  
2.1.1.3.11 Ability of participant to understand and the willingness to sign a written informed consent document.
untitled h1
2.1.2 exclusion criteria

2.1.2.1 Exclusion criteria for all study arms 2.1.2.1.1 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.  
2.1.2.1.2 Evidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including significant pulmonary disease other than that related to the primary cancer, uncontrolled diabetes mellitus, and/or significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, unstable angina, or clinically significant pericardial effusion)
2.1.2.1.3 Any known diagnoses, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition (other than mesothelin [+] cancer diagnosis) that would contraindicate the use of an investigational drug, interfere with tumor measurement or lead to an expected life expectancy of less than 6 months as judged by the investigator 2.1.2.1.4 Active or uncontrolled infections. 2.1.2.1.5 Live attenuated vaccinations within 14 days prior to treatment 2.1.2.1.6 Dementia or altered mental status that would prohibit informed consent 2.1.2.1.7 Pregnant women are excluded from this study because the effects of LMB-100 on the developing fetus are unknown and may have the potential to cause teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LMB-100, 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.  
2.1.2.1.8 Known hypersensitivity to any of the components of LMB-100 2.1.2.1.9 Baseline QTcF interval of > 470 ms, participants with baseline resting bradycardia < 45 beats per minute, or baseline resting tachycardia !100 beats per minute.  
2.1.2.2 Exclusion criteria specific to patients who will be receiving nab-paclitaxel (all arms except Arm B1 Single Agent Lead-in)
2.1.2.2.1 Participants with contra-indication and/or history of severe hypersensitivity reactions to nab-paclitaxel 2.1.2.2.2 Participants with baseline peripheral neuropathy greater than grade 2. 2.1.2.2.3 HIV or active HBV or HCV infection due to risk of progression while receiving immunosuppressive chemotherapy
untitled h1
2.2 screening evaluation

Assessments will be performed any time prior to study enrollment.  
x Archival tumor sample for NCI LP confirmation of diagnosis. A block of primary tissue
(or 10 unstained sections on charged slides) from the time of diagnosis will be required from each participant. Tissue blocks from a known recurrence will be accepted if original tumor samples are unavailable. Referring institutions will send the tumor block or 10 unstained sections on charged slides to CCR/NCI for correlative studies and confirmation of diagnosis. A fresh biopsy may be collected if tumor tissue is not available.  
x For patients on the Arm B1 Single Agent Lead-in who do not have a diagnosis of epithelioid mesothelioma or pancreatic adenocarcinoma ONLY: archival tissue or fresh biopsy samples sufficient to assess tumor MSLN expression by immunohistochemistry analysis.
Assessments performed within 28 days prior to study enrollment  
x History and physical exam x Vital signs including ambulatory oxygen saturation by pulse oximetry x ECOG performance status x Pregnancy test in women of childbearing potential x ECG x Echocardiogram x CT scan of chest, abdomen and/or pelvis and areas of known or suspected disease involvement; MRI may also be performed when appropriate x 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, CK, vitamin D, 1,25-dihydroxy, Coagulation (PT, PTT), lactate dehydrogenase x CA 19-9 serum tumor marker for pancreatic cancer patients (or other appropriate tumor marker for patients enrolled in Arm B1 Single Agent Lead-in who do not have pancreatic cancer)
x Testing for HIV, HCV, HBV: anti-HIV antibody, Anti-HCV Antibody, HBs Ag Screening
(except for Arm B1 Single Agent Lead-in)
x Urinalysis
untitled h1
2.3 registration procedures

2.3.1 *Arm B1, Single Agent Lead in Cohort Subjects with Diseases other than Epithelioid* Mesothelioma or Pancreatic Adenocarcinoma Only Registration will be a two-part process as patients in this cohort that are not diagnosed with pancreatic adenocarcinoma or epithelioid mesothelioma are screened on this protocol. Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours of signing consent. To initially register a subject after the participant has signed the consent, complete the top portion the registration Eligibility Checklist from the website (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) indicating that the patient is being registered for screening and send via encrypted email to: NCI Central Registration Office ncicentralregistration-l@mail.nih.gov. Once eligibility is confirmed after completion of screening studies, complete the remainder of the form which is the eligibility checklist, indicating that the patient is being registered for treatment and email the completed registration checklist to the CRO at 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. Subjects that do not meet screening criteria should be removed from the study following the procedure in section 3.5.2.1.
untitled h1
2.3.2 all other subjects

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 participant 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. 2.3.3 *Treatment Assignment Procedures*  
| Number                                                                                                  | Name                                                                                                                   | Description                                                                                                                                                                             |
|---------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| A1                                                                                                      | Phase I Short Infusion                                                                                                 | The first 6 - 12 subjects with pancreatic cancer meeting nabpaclitaxel eligibility criteria* to determine an MTD for part A.                                                                                                                                                                                         |
| Cohort                                                                                                  |                                                                                                                        |                                                                                                                                                                                         |
| A2                                                                                                      | Phase II Short Infusion                                                                                                | The next 14 - 20 subjects with pancreatic cancer meeting nabpaclitaxel eligibility criteria* (until at least 13 subjects have                                                                                                                                                                                         |
| Cohort                                                                                                  | been evaluated at the Part A MTD [stage 1]– a determination  will then be made on whether to continue to 20 [stage 2]) |                                                                                                                                                                                         |
| B1                                                                                                      | Continuous Infusion,  Single Agent Lead-In  Cohort                                                                     | Up to 30 evaluable subjects with pancreatic cancer not meeting  nab-paclitaxel eligibility criteria* or subjects with other  mesothelin expressing tumors for part B MTD determination. |
| B2                                                                                                      | Continuous Infusion,  Combination Therapy Cohort                                                                       | Up to 6 subjects with pancreatic cancer meeting nab-paclitaxel  eligibility criteria, followed by an additional 4 subjects if  safety is established.                                   |
| * criteria specific for nab-paclitaxel are found in sections 2.1.1.1 and 2.1.2.2; criteria specific for |                                                                                                                        |                                                                                                                                                                                         |  
| Arms  Number         | Name                                                                                                                | Description                                                                                                                                                                                       |
|----------------------|---------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| A1                   | Phase I, Short infusion                                                                                             | Subjects infused with escalating doses of LMB-100 on days 1,  3 and 5 of each 21-day cycle. Infusion length 30 - 180  minutes. Subjects will also receive nab-paclitaxel on day 1 of  each cycle. |
| A2                   | Phase II, Short infusion                                                                                            | Subjects infused at the LMB-100 dose determined in A1.  Subjects will also receive nab-paclitaxel on day 1 of each  cycle.                                                                        |
| B1                   | Continuous Infusion,                                                                                                | Subjects infused with LMB-100 monotherapy at escalating                                                                                                                                           |
| Single Agent Lead-In | doses or escalating durations once per cycle– duration may  range from 24 - 96 hours                                |                                                                                                                                                                                                   |
| B2                   | Continuous Infusion,                                                                                                | Subjects infused with LMB-100 at the dose level/dose                                                                                                                                              |
| Combination Therapy  | duration determined after B1 is complete. Subjects will also  receive nab-paclitaxel on day 1 of each 14-day cycle. |                                                                                                                                                                                                   |
untitled h1
arm assignment

Subjects will be directly assigned to each arm as follows:
x Subjects in Cohort A1 will be directly assigned to Arm A1.  
x Subjects in Cohort A2 will be directly assigned to Arm A2 once an MTD has been determined in Arm A1. Accrual to stage 2 of Arm A2 may commence after stage 1 is completed, but priority will be given to Arms B1 and B2. Note: Cohort/Arm A2 will not be opened if dose level -1 is not deemed safe in part Cohort/Arm A1.  
x Subjects in Cohort B1 will be enrolled concurrently with subjects in Arm A1 & Arm A2
(if this arm is opened) and will be directly assigned to Arm B1. Priority will be given to Arm A1 followed by B1 then A2.  
x Subjects in Cohort B2 will be enrolled after Cohort/Arm B1. These subjects are directly assigned to Arm B2. Enrollment to Arm B2 will be given priority over Arm A2 if these arms enroll concurrently.
untitled h1
3 study implementation 3.1 study

This is a first-in-human, open-label, Phase I/II study of LMB-100. It will be conducted in four parts. Three of the four parts accrue the same population of patients with advanced pancreatic cancer (indicated by black outline around the arrows in the schema below):  
  
x Arm A1 (Phase I study): Dose escalation of short infusion LMB-100 with fixed dose nabpaclitaxel in patients with advanced pancreatic cancer x Arm B1 Single Agent Lead-in: Dose escalation of continuous infusion LMB-100 as a single agent in patients with any solid tumor malignancy expressing MSLN. This part will run concurrently with Arm A1 since it accrues a different patient population.  
x Arm B2: Single dose level of continuous infusion LMB-100 with fixed dose nab-paclitaxel in patients with advanced pancreatic cancer. This part can begin accrual after completion of Arm B1 Single Agent Lead-in.  
x Arm A2 (Phase II study): Investigates the clinical activity at MTD and/or RP2D for short infusion combination therapy with *nab-*paclitaxel in a 2-stage design. The arm may not be explored if dose level -1 is deemed to be unsafe in Arm A1. If Arm A2 is opened, stage 2 will only be accrued if pre-specified response criteria for Stage 1 are met. Priority will be given to accrual of Arm B2 (which requires the same patient population) over either stage of Arm 2.  
* Eligibility requirements allow for accrual of patients with any solid tumor malignancy that expresses MSLN. Participants in this arm will NOT receive nab-paclitaxel 3.1.1 *Study Schema for short infusion LMB-100 with nab-paclitaxel (Arm A1 (Phase I))*  
  
Participants will be treated with short infusion LMB-100 in combination with nab -paclitaxel for 2 cycles or until unacceptable toxicities, disease progression (per PI discretion), withdrawal from treatment for other reasons, or death, whichever occurs first.  During the phase I portion of the study, participants who withdraw prior to completing the DLT assessment period (for any reason other than toxicity) will be replaced. Arm A1 (Phase I) will utilize a dose escalation with LMB-100 administered in combination with a fixed dose of nab -paclitaxel (IV, 125 mg/m²). All cycles will be 21-days.  Nab -paclitaxel will be administered on days 1 and 8.  Participants will receive LMB-100 IV over 30 -180 minutes on Days 1, 3 and 5 (QOD x3).  
Study Schema for continuous infusion LMB-100 (Arm B1 [Single Agent Lead-in])  
  
1  
  
Participants will be treated with LMB-100 by continuous infusion over 24 - 96 hours with or without a loading dose depending on dose level for 2 cycles or until unacceptable toxicities, disease progression (per PI discretion), withdrawal from treatment for other reasons, or death, whichever occurs first.  During the phase I portion of the study, participants who withdraw prior to completing the DLT assessment period, for any reason other than toxicity, will be replaced.  
This arm will utilize a dose escalation of LMB-100.  All cycles will be 21-days.  Participants will receive continuous infusion of LMB-100 IV for the 1, 2, 3 or 4 days of each cycle depending on dose level.  
3.1.3 Study Schema for continuous infusion LMB-100 with nab-paclitaxel (Arm B2)  
  
  
  
| 2     | 214   |
|-------|-------|
| ADA   |       |
| Nab-P |       |  
Up to 6 evaluable participants will be treated with LMB-100 by continuous infusion over 24 hours with a loading dose in combination with nab-paclitaxel for 3 cycles of 14 days duration or until unacceptable toxicities, disease progression (per PI discretion), withdrawal from treatment for other reasons, or death, whichever occurs first. The DLT period will include the first 28 days following initial infusion of LMB-100 on C1D1. Participants who withdraw prior to completing the DLT assessment period, for any reason other than toxicity, will be replaced. Participants may be enrolled concurrently. If no more than 2 of the 6 evaluable subjects experience unacceptable toxicity (as defined by DLT criteria in section 3.1.5), up to 4 additional participants may be accrued concurrently to better assess the safety and activity of this regimen. This arm will utilize a single dose of LMB-100 in combination with a fixed dose of nab-paclitaxel
(IV, 125 mg/m2). All cycles will be 14 days. Nab-paclitaxel will be administered on Day 1 .  
Participants will receive a 24-hour infusion of LMB-100 IV on Day 1 of each cycle for a total of 3 cycles.
untitled h1
3.1.4 study schema for phase

Participants enrolled on the Phase II portion of the trial will be treated using the same schedule of short infusion LMB-100 and nab-paclitaxel as given for Arm A1 (See Section 3.1.1), at the 65 mcg/kg dose of LMB-100, the RP2D in Part A. They will be treated for 2 cycles or until unacceptable toxicities, disease progression (per PI discretion), withdrawal from treatment for other reasons, or death, whichever occurs first. During the phase II portion of the study, participants who are not evaluable for response assessment will be replaced. The phase II study (Arm A2) will be conducted in a Simon Minimax two stage phase II design. The first stage will enroll 13 evaluable participants, including the six participants treated at 65 mcg/kg. If 1 or more has a response, then accrual would continue until a total of 20 evaluable participants have been enrolled.
untitled h1
3.1.5 dose limiting toxicity

The DLT period for Arm A1, A2 and B1 will consist of the 21 days following first administration of LMB-100 (1 cycle), while that for Arm B2 will include 28 days following first administration of LMB-100 (2 cycles). 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 during the DLT period:
untitled h1
hematological toxicities

x Grade 4 neutropenia (i.e. absolute neutrophil count (ANC) <0.5 x 109 cells/L) for a minimum duration of 7 days)
x 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 x Grade 4 thrombocytopenia (≤25.0 x109 cells/L)
x Grade 3 thrombocytopenia associated with bleeding episodes
untitled h1
grade >= 3 non-hematological toxicity

x Grade 3 nausea and vomiting without appropriate treatment x Grade 3 diarrhea lasting for ≤ 2 days with no fever or dehydration x Grade 3 infusion-related reactions are not considered to be DLTs since, based on  
experience with monoclonal antibodies, IRRs are idiosyncratic and not dose-related events.  
x Asymptomatic grade 3 elevation of ALT, AST, GGT, bilirubin or alkaline phosphatase attributable to study drug that persists for less than 7 days. (Please note that all grade 4 elevations in these parameters should be considered a DLT)
x Asymptomatic laboratory values (other than ALT, AST, GGT, bilirubin, alkaline phosphatase or creatinine) of Grade 3 that are judged not clinically significant by the investigator.  
x **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:
x Infusion-related reactions
untitled h1
other toxicities

x Any other drug related toxicity considered significant enough to be qualified as a DLT in the opinion of the principal investigator.
If a participant experiences a DLT of any grade, the investigator will have the option to either stop the LMB-100 treatment or to resume the treatment at the next lowest dose level of LMB-100 based on best clinical judgment. This can be done to allow participants, who could potentially benefit from LMB-100, to remain on the study drug treatment, if considered the most beneficial therapeutic option for the participant while managing and monitoring the participant's safety risks.
untitled h1
3.1.6 dose escalation

Dose escalation will proceed in cohorts of 3–6 participants. The MTD is the dose level at which no more than 1 of up to 6 participants experience DLT during cycle 1, and the dose below that at which at least 2 (of ≤6) participants have DLT from the study drug. If a participant 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 level to ensure that at least 3 participants 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 1, dose level -1 will be evaluated.  
| Dose Escalation Schedule Arm A1 (Phase I)  Dose Level Dose of LMB-100 in μg/kg  Level -1 65  Level 1 100 Level 2 140   |
|------------------------------------------------------------------------------------------------------------------------|  
| Dose/ Duration Escalation Scheme  LMB-100  (mcg/kg/day)                                                                                                                                                                                                                                     | Schedule   |               |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|---------------|
| Level 1                                                                                                                                                                                                                                                                                     | 65         | 48h           |
| Level 2                                                                                                                                                                                                                                                                                     | 100        | 48h           |
| Level 3                                                                                                                                                                                                                                                                                     | 100        | 24h, D1 & 4   |
| Level 3R                                                                                                                                                                                                                                                                                    | 100        | 24 h, D1 only |
| Level 4                                                                                                                                                                                                                                                                                     | 140        | 24 h, D1 &4   |
| R(educed) - As the occurrence of more than 1 DLT will not  automatically trigger a return to a previously attempted dose  level, dose levels with an R designation will be identified for  exploration as the study proceeds should more than 1 DLT  occur in a previously named dose level |            |               |
untitled h1
table 10

| Dose Steps   | LMB-100   |
|--------------|-----------|
| (mcg/kg/day) |           |
| I            | 65        |
| II           | 100       |
| III          | 140       |
| IV           | 200       |  
Table 11  
| Duration   | Infusion Duration   |
|------------|---------------------|
| Steps      | (hrs)               |
| A          | 24                  |
| B          | 24, D1 & D4         |
| C          | 48                  |
| D          | 72                  |
| E          | 96                  |  
For Arm B1 (Single Agent Lead-in), the initial dose for Level 1 was defined at 65 mcg/kg/day over 48 hours and was completed after accrual of 3 participants (2 of whom were evaluable for DLT). No safety or efficacy signal was observed at this dose level. Based on these results, Dose Step I (65 mcg/kg/d) may no longer be used, such that the minimum Dose Step after Dose Level 1 is Dose Step II (100 mcg/kg/d). Beginning with Level 2, participants will receive short infusion of 40 mcg/kg LMB-100 over the first 30-180 minutes followed by the continuous infusion defined in Table 9. DLT was observed in 1/6 patients at Level 2, and testing proceeded to Level 3, a planned dose de-escalation. After accruing 6 patients to dose level 3, 3 of which were evaluable for toxicity due to hold of day 4 dose for toxicity unrelated to study drug, it was determined by the investigator to close this arm of the and begin accrual to Arm B2. If a Level is determined to be unsafe as defined in section 3.1.6.1.3, then: a) the preceding Level may be declared the MTD, or b) additional Levels may be tested so long as either the dose or the duration of infusion is stepped down) to a lower level that has not been previously tested as predefined in Table 10 and Table 11. Such doses carry the R designation for reduced in Table 9. For this arm of the study, there is no pre-defined number of dose levels. Dose tuning may continue until both the maximum drug dose and duration of infusion are defined or a maximum of 30 participants are treated on this arm. As dose tuning progresses, slots must be reserved in a manner that insures at least 6 participants can be treated at the RP2D. For Arm B2, a single dose of LMB-100 has been chosen based upon safety and tolerability seen with single agent LMB-100 given in continuous infusion format in Arm B1 and taking into consideration safety and tolerability seen in Arm A1 with the combination. Given the low incidence of VLS causing weight gain greater than 5 kg with 24-hour continuous infusion given on Day 1 and that 48-hour continuous infusion given on Day 1 is the MTD for long infusion, the following LMB-100 dose will be tested in combination with standard nab-paclitaxel (125 mg/m2):
x 40 mcg/kg IV loading dose of LMB-100 given over 30 minutes (to follow nab-paclitaxel administration by 30 minutes ±20 minutes) on Day 1 x 100 mcg/kg LMB-100 IV given over 24 hours to immediately following loading dose These drugs will be given on a 14-day cycle to improve tolerability, rather than giving nabpaclitaxel on Days 1 and 8 as in Part A.  
| 3.1.6.1.3                                                                 | Dose finding will follow the rules outlined in the Table below.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
|---------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Number of Participants  with DLT                                          | Escalation /De-Escalation Decision Rule                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| at a Given Dose Level  0 out of 3                                         | Enter up to 3 participants at the next (integer) dose  level OR may treat 1-3 additional participants to better  define safety signal.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| > 2                                                                       | Per the discretion of the investigator, dose escalation  may be stopped. This dose level will be declared the  maximally administered dose (highest dose  administered). Up to three (3) additional participants  will be entered at the next lowest previously explored  dose level that resulted in fewer than 2 DLTs if only 3  participants were treated previously at that dose.  OR  Enter up to 3 participants at the next dose level (R  designation) meeting criteria of not previously  explored and at either lower dose or lower infusion  duration                                                                                                            |
| 1 out of 3                                                                | Enter up to 3 more participants at this dose level. x If 0 of these 3 participants experience DLT,  proceed to the next integer dose level.  x If 1 or more of this group suffer DLT, then:  o dose escalation may be stopped per PI  discretion, and this dose is declared the  maximally administered dose. UP to three (3)  additional participants will be entered at the  next lowest dose level that resulted in fewer  than 2 DLTs if only 3 participants were  treated previously at that dose.  OR  o Enter up to 3 participants at the next dose level  (R designation) meeting criteria of not  previously explored and at either lower dose  or lower duration |
| <1 out of 6 at highest dose  level below the maximally  administered dose | This is the MTD.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
untitled h1
3.2 drug administration

Standard templates for a Chemotherapy Note for a patient on this study are available in Appendix C.
untitled h1
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 or group allocation of each participant. Short infusion LMB-100 will be given as an IV solution on Days 1, 3 and 5 (QOD x3) of a 21-day cycle. Infusion duration should be 30-180 minutes. Continuous infusion LMB-100 will be given as an IV solution by syringe driver pump 1, 2, 3 or 4 days of a 21-day cycle depending on dose level. For continuous infusion Levels 2 and above, a loading dose of 40 mcg/kg LMB-100 given as an IV solution over 30-180 minutes will precede the start of continuous infusion on Day 1 and if applicable, Day 4.  
LMB-100 must be administered in a hospital or clinic equipped for IV chemotherapy. Full emergency resuscitation facilities should be immediately available and participants 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. LMB-100 is to be handled following all hazardous precautions. 3. Do not use the solution if there is particulate matter or if it is discolored. 4. Do not shake or freeze the vial contents. 5. Ensure the drug vial content is protected from light during preparation and administration
(ambient light conditions are acceptable but avoid exposure to direct sunlight).  
6. LMB-100 drug product does not contain any preservatives. Vials are for single use only and partially used vials must not be reused.  
7. Any unused product should be kept for drug reconciliation. 8. No dilution of LMB-100 drug product into 0.9% saline bags should be performed.
9. Do not administer as IV push or bolus.  
10. 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.  
3.2.1.2 Specific Instructions
LMB-100 is diluted with 0.9% NaCl **in-line** immediately prior to administration (see Figure 8 below). The undiluted LMB-100 drug product (DP), filled in a disposable syringe, is administered by intravenous syringe infusion using a syringe driver pump. So as not to compromise drug product physico-chemical stability, the dilution with 0.9% NaCl should be done **in line**, immediately prior to administration of the neat DP. 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 8). The side flow should be set-up at 1:10 in order to deliver 0.1 mg/mL DP. During continuous infusion, the minimum rate for 0.9% NaCl infusion should be 20 mL/ hour (to prevent line occlusion), even if this results in a less concentrated infusion of study drug. 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 must be administered using a central venous catheter or an existing mediport for  
 infusions lasting longer than 150 minutes. Central line access is neither required nor anticipated for patients in the short-infusion cohorts; however, a central line or use of an existing mediport may be permitted per PI discretion. For continuous infusion, syringes should be switched out every 12 hours (± 1 hour), which will require 2 syringes per 24 hour infusion, 4 syringes per 48 hour infusion, 6 syringes per 72 hour infusion and 8 syringes per 96 hour infusion.  
The stopcock will be changed every 24 hours to prevent microbial ingress. In line filters for the LMB-100 drug product as well as the saline will 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.  
2. An in-line filter will 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 or 0.22 μm pore size) should be positioned between the syringe extension line and the injection/infusion valve (see Figure 8). The filtration must occur **before** in-line dilution with 0.9% saline. An in-line filter will be used during saline infusion as shown in Figure 8.  
3. Withdraw up to 3 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 9).  
4. The prepared syringe should be stored and transported with a closing cone/stopper.  
5. 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 storage times of prepared syringes should not exceed 12 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.  
6. A freshly prepared syringe of drug product is required for every 12 hours of LMB-100 infusion and for the loading dose. To limit the potential for microbial growth, when preparing syringes for continuous infusion, drug vials may not be stored and reused to prepare syringes at later time points. The syringe for the loading dose and that for the initial 12 hours of continuous infusion may be prepared from the same vial. All other syringes must be prepared from a fresh vial. Saline bags must be changed at least every 24 hours.  
7. Continuous infusion may be stopped for a total of up to 90 minutes within each 24 hour period for logistical purposed. All stoppages should be documented in CRIS (both actual or estimated stop time and actual restart time)
8. Establish the saline flow first by flushing the lines including the 4-way stopcock and extension lines with saline.  
9. 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.  
10. The end of infusion is defined as the time point at which the syringe driver finishes administering the total volume of IMP to be infused.  
11. In case of any adverse events related to the infusion, please refer to the specific recommendation described in section 3.3.1.  
12. The line for drawing blood for PK samples should be placed in the opposite extremity from the one with the infusion line.
untitled h1
3.2.1.3 monitoring 3.2.1.3.1 short infusion

During short 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) for 2 hours after the end of the first infusion. For subsequent infusions, if no IRR has been reported, monitoring will continue for 30 minutes after the end of the infusion. Vital signs during the infusion are not required to be captured in the eCRF unless abnormalities are observed.
untitled h1
3.2.1.3.2 continuous infusion

During continuous 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) for the first two hours of the infusion, and thereafter, every 60 minutes (±10 minutes) for the next 4 hours of the infusion, and then every 6 hours until the infusion is completed. Vital signs should also be recorded 2 hours (±10 minutes) after the end of infusion. 3.2.1.4 Standard Pre-medication for Participants Receiving LMB-100 Due to the prevalence of infusion related reactions (IRRs) seen in the previous study of LMB-100, all patients will be pre-medicated 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
Dexamethasone 8 mg IV should be physically available in the infusion unit in case of severe IRR during LMB-100 administration.  
3.2.1.4.1 Additional Precautions at subsequent Infusions of LMB-100 in patients with prior IRR
during short infusion of LMB-100
Participants receiving short infusion having experienced an IRR of Grade 2 to 4 on a previous infusion despite standard pre-mediation should also receive:  
o Dexamethasone 20 mg, PO, 6-12 hours prior to LMB-100 administration, OR o Dexamethasone 8 mg, IV, 30 - 60 minutes (+30 minutes) prior to LMB-100 administration, OR
o equivalent dose of another corticosteroid as clinically indicated
(See section 3.3.1 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  
3.2.1.4.2 Additional Precautions for administration of LMB-100 in patients with IRR during continuous infusion of LMB-10
Participants receiving continuous LMB-100 infusion having experienced an IRR of Grade 2 to 4 earlier in the current infusion or during a previous infusion despite standard pre-mediation should receive for the remainder of the infusion and all subsequent infusions accompanied by:  
o Diphenhydramine 25-50 mg PO or IV, q6 hours o Ranitidine 150 mg PO, q12 hours o Acetaminophen 650 mg PO, q12 hours o Dexamethasone as described earlier in this section, q12 hours
(See section 3.3.1 for complete instructions on response to IRRs) Participants who experienced an IRR of Grade 3 or 4 where dexamethasone or another steroid was pre-administered within the last 12 hours should not receive further LMB-100 and will be discontinued from study therapy.  
| Dose (mg)         | Route   |          |
|-------------------|---------|----------|
| Acetaminophen     | 650     | PO       |
| Diphenhydramine   | 25-50   | PO or IV |
| Ranitidine        | 150     | PO       |
| Dexamethasone PRN | 8       | IV       |
| OR                |         |          |
| Dexamethasone PRN | 20      | PO       |
untitled h1
table 12 - premedications for

Nab-paclitaxel will be administered according to the package inserts at a dose of 125 mg/m2, intravenously over 30 minutes ± 10 minutes on Days 1 and 8 of each 21-day cycle. 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.
untitled h1
3.2.3 co-administration of nab-paclitaxel and

On days when both LMB-100 and nab-paclitaxel are both scheduled to be administered (Day 1 of each cycle), nab-paclitaxel will be administered first. LMB-100 infusion will be initiated 30 minutes ± 20 minutes after completion of the *nab-*paclitaxel.
untitled h1
3.3 dose modifications

Potential overlapping toxicities of LMB-100 and *nab-*paclitaxel must be considered. In this context, peripheral edema (10%) and arthralgia (11-13%) have been seen with both drugs. Nabpaclitaxel has been shown to cause life-threatening pneumonitis in a small percentage of patients.  
Symptomatology of pneumonitis related to *nab-*paclitaxel could overlap with pleuritis, which is an identified toxicity risk with LMB-100. Study participants will be carefully monitored for adverse events associated with these organ systems.