untitled h1
5.2 sample collection schedule

| 5.2.1                                                             | Arms A1 and A2 sample collection schedule   | Serum  mesothelin and  MPF                                        | PE            | mediated   |    |    |
|-------------------------------------------------------------------|---------------------------------------------|-------------------------------------------------------------------|---------------|------------|----|----|
| CLS  (Cytokines)                                                  | MDSC  Assessment                            |                                                                   |               |            |    |    |
| T-cell  epitopes                                                  | Tumor  Samplea                              |                                                                   |               |            |    |    |
| PK                                                                | ADA                                         |                                                                   |               |            |    |    |
| (5.1.1)                                                           | (5.1.2)                                     | (5.1.8)                                                           | (5.1.4,5.1.6) |            |    |    |
| Cycle                                                             | Day                                         | (5.1.7)                                                           |               |            |    |    |
| (5.1.3)                                                           | (5.1.5)                                     |                                                                   |               |            |    |    |
| 2                                                                 | mL                                          |                                                                   |               |            |    |    |
| K2EDTA  tube                                                      | 2 mL blood in  3.5 mL tiger top  tube       | 4 mL red SST                                                      | Eight 8 mL    |            |    |    |
| tube                                                              | whole blood  tubes                          | Three                                                             | 10            | mL         |    |    |
| sodium                                                            | heparin                                     | NA                                                                |               |            |    |    |
| (green top) tubes                                                 |                                             |                                                                   |               |            |    |    |
| 2                                                                 | mL                                          | K2EDTA                                                            |               |            |    |    |
| tube                                                              |                                             |                                                                   |               |            |    |    |
| Screening                                                         | Xa                                          |                                                                   |               |            |    |    |
| Screening                                                         | period ± 3  days                            | Pre-dose, EOI, 1, 2,  3, 4, and 6 hours  after start of  infusion |               |            |    |    |
| 1                                                                 | Pre-dose                                    | X                                                                 | Pre-dose      | Xb         | Xb | Xc |
| 3                                                                 | Pre-dose                                    |                                                                   |               |            |    |    |
| 1                                                                 | Pre-dose                                    |                                                                   |               |            |    |    |
| Pre-dose, EOI, 1, 2,  3, 4, and 6 hours  after start of  infusion |                                             |                                                                   |               |            |    |    |
| 5                                                                 | X                                           |                                                                   |               |            |    |    |
| 8                                                                 |                                             |                                                                   |               |            |    |    |  
| Serum  mesothelin and  MPF                                             | PE                                    | mediated         |               |    |
|------------------------------------------------------------------------|---------------------------------------|------------------|---------------|----|
| CLS  (Cytokines)                                                       | MDSC  Assessment                      |                  |               |    |
| T-cell  epitopes                                                       | Tumor  Samplea                        |                  |               |    |
| PK                                                                     | ADA                                   |                  |               |    |
| (5.1.1)                                                                | (5.1.2)                               | (5.1.8)          | (5.1.4,5.1.6) |    |
| Cycle                                                                  | Day                                   | (5.1.7)          |               |    |
| (5.1.3)                                                                | (5.1.5)                               |                  |               |    |
| 2                                                                      | mL                                    |                  |               |    |
| K2EDTA  tube                                                           | 2 mL blood in  3.5 mL tiger top  tube | 4 mL red SST     | Eight 8 mL    |    |
| tube                                                                   | whole blood  tubes                    | Three            | 10            | mL |
| sodium                                                                 | heparin                               | NA               |               |    |
| (green top) tubes                                                      |                                       |                  |               |    |
| 2                                                                      | mL                                    | K2EDTA           |               |    |
| tube Pre-dose, EOI, 1, 2,  3, 4, and 6 hours  after start of  infusion |                                       |                  |               |    |
| 1                                                                      | Pre-dose                              | X                | Pre-dose      |    |
| 2                                                                      | 3                                     | Pre-dose         |               |    |
| 5                                                                      | Pre-dose, EOI                         | Pre-dose         |               |    |
| 8                                                                      | X Pre-dose                            | X                |               |    |
| 1                                                                      | Pre-dose and EOI                      | Pre-dose         | X             | Xc |
| (end of cycle 2)                                                       |                                       |                  |               |    |
| 3                                                                      | Pre-dose                              |                  |               |    |
| 3 & 4                                                                  | 5                                     | Pre-dose and EOI | Pre-dose      |    |
| 8                                                                      | X                                     |                  |               |    |
| At time of  Progression                                                | X                                     |                  |               |    |
| End                                                                    | of                                    |                  |               |    |
| Treatment                                                              | X                                     | X                | X             |    |  
| Serum  mesothelin and  MPF                                                                                | PE                                    | mediated     |               |    |
|-----------------------------------------------------------------------------------------------------------|---------------------------------------|--------------|---------------|----|
| CLS  (Cytokines)                                                                                          | MDSC  Assessment                      |              |               |    |
| T-cell  epitopes                                                                                          | Tumor  Samplea                        |              |               |    |
| PK                                                                                                        | ADA                                   |              |               |    |
| (5.1.1)                                                                                                   | (5.1.2)                               | (5.1.8)      | (5.1.4,5.1.6) |    |
| Cycle                                                                                                     | Day                                   | (5.1.7)      |               |    |
| (5.1.3)                                                                                                   | (5.1.5)                               |              |               |    |
| 2                                                                                                         | mL                                    |              |               |    |
| K2EDTA  tube                                                                                              | 2 mL blood in  3.5 mL tiger top  tube | 4 mL red SST | Eight 8 mL    |    |
| tube                                                                                                      | whole blood  tubes                    | Three        | 10            | mL |
| sodium                                                                                                    | heparin                               | NA           |               |    |
| (green top) tubes                                                                                         |                                       |              |               |    |
| 2                                                                                                         | mL                                    | K2EDTA       |               |    |
| tube                                                                                                      |                                       |              |               |    |
| Follow-up  Visit                                                                                          | X                                     |              |               |    |
| ADA =anti-drug antibody; EOI =End of infusion; PK =pharmacokinetic; MDSC= myeloid derived suppressor cell |                                       |              |               |    |  
a. Archival or if not available, a fresh Biopsy or Tumor Effusion (mandatory). Even if archival sample is available, patient may be asked for optional biopsy sample.  
b. May be collected prior to day 1 at any time after the consent is signed (baseline). c. Optional biopsies - collected at baseline (biopsy if collected at screening can be used as baseline sample) and at any time after the completion of 2 cycles of therapy.  
| 5.2.2                                                             | Arms B1 and B2 Sample Collection Schedule                         | Serum  mesothelin and  MPF   | PE            | mediated   |    |    |
|-------------------------------------------------------------------|-------------------------------------------------------------------|------------------------------|---------------|------------|----|----|
| CLS  (Cytokines)                                                  | MDSC  Assessment                                                  |                              |               |            |    |    |
| T-cell  epitopes                                                  | Tumor  Samplea                                                    |                              |               |            |    |    |
| PK                                                                | ADA                                                               |                              |               |            |    |    |
| (5.1.1)                                                           | (5.1.2)                                                           | (5.1.8)                      | (5.1.4,5.1.6) |            |    |    |
| Cycle                                                             | Day                                                               | (5.1.7)                      |               |            |    |    |
| (5.1.3)                                                           | (5.1.5)                                                           |                              |               |            |    |    |
| 2                                                                 | mL                                                                |                              |               |            |    |    |
| K2EDTA  tube                                                      | 2 mL blood in  3.5 mL tiger top  tube                             | 4 mL red SST                 | Eight 8 mL    |            |    |    |
| tube                                                              | whole blood  tubes                                                | Three                        | 10            | mL         |    |    |
| sodium                                                            | heparin                                                           | NA                           |               |            |    |    |
| (green top) tubes                                                 |                                                                   |                              |               |            |    |    |
| 2                                                                 | mL                                                                | K2EDTA                       |               |            |    |    |
| tube                                                              |                                                                   |                              |               |            |    |    |
| Screening                                                         |                                                                   |                              |               |            |    |    |
| Screening                                                         | period ± 3                                                        | Xa                           |               |            |    |    |
| days                                                              | Pre-dose, EOI, 1, 2,  3, 4, and 6 hours  after start of  infusion |                              |               |            |    |    |
| 1                                                                 | Pre-dose                                                          | X                            | Pre-dose      | Xb         | Xb | Xc |
| 3                                                                 | Pre-dose                                                          |                              |               |            |    |    |
| 1                                                                 | Pre-dose                                                          |                              |               |            |    |    |
| Pre-dose, EOI, 1, 2,  3, 4, and 6 hours  after start of  infusion |                                                                   |                              |               |            |    |    |
| 5                                                                 | X                                                                 |                              |               |            |    |    |
| 8                                                                 | Pre-dose, EOI, 1, 2,  3, 4, and 6 hours  after start of  infusion | Pre-dose                     | X             | Pre-dose   |    |    |
| 2                                                                 | 1 3                                                               | Pre-dose                     |               |            |    |    |  
| Serum  mesothelin and  MPF   | PE                                    | mediated     |               |    |
|------------------------------|---------------------------------------|--------------|---------------|----|
| CLS  (Cytokines)             | MDSC  Assessment                      |              |               |    |
| T-cell  epitopes             | Tumor  Samplea                        |              |               |    |
| PK                           | ADA                                   |              |               |    |
| (5.1.1)                      | (5.1.2)                               | (5.1.8)      | (5.1.4,5.1.6) |    |
| Cycle                        | Day                                   | (5.1.7)      |               |    |
| (5.1.3)                      | (5.1.5)                               |              |               |    |
| 2                            | mL                                    |              |               |    |
| K2EDTA  tube                 | 2 mL blood in  3.5 mL tiger top  tube | 4 mL red SST | Eight 8 mL    |    |
| tube                         | whole blood  tubes                    | Three        | 10            | mL |
| sodium                       | heparin                               | NA           |               |    |
| (green top) tubes            |                                       |              |               |    |
| 2                            | mL                                    | K2EDTA       |               |    |
| tube                         |                                       |              |               |    |
| 5                            | Pre-dose, EOI                         | Pre-dose     |               |    |
| 8                            | X                                     | X            |               |    |
| 1                            | X                                     | Xc           |               |    |
| (end of cycle 2)             |                                       |              |               |    |
| 3 -6                         | 3 5 8                                 |              |               |    |
| At time of  Progression      | X                                     |              |               |    |
| End                          | of                                    |              |               |    |
| Treatment                    | X                                     | X            | X             |    |
| Follow-up  Visit             | X                                     |              |               |    |  
ADA =anti-drug antibody; EOI =End of infusion; PK =pharmacokinetic; MDSC= myeloid derived suppressor cell a. Archival or if not available, a fresh Biopsy or Tumor Effusion (mandatory). Even if archival sample is available, patient may be asked for optional biopsy sample.  
b. May be collected prior to day 1 at any time after the consent is signed (baseline).  
c. Optional biopsies - collected at baseline (biopsy if collected at screening can be used as baseline sample) and at any time after the completion of 2 cycles of therapy.
untitled h1
5.3 sample storage tracking and

Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples will not be sent outside NIH without appropriate approvals and/or agreements, if required.
untitled h1
5.3.1 clinical pharmacology program

All samples sent to the Clinical Pharmacology Program (CPP) will be barcoded, with data entered and stored in the Labmatrix utilized by the CPP. . This is a secure program, with access to t Labmatrix limited to defined CPP personnel, who are issued individual user accounts. Installation of Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password restricted login screen. Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced back to patients without Labmatrix access. The data recorded for each sample includes the patient ID, name, trial name/protocol number, time drawn, cycle, time point, dose, material type, as well as box and freezer location. Patient demographics associated with the clinical center patient number are provided in the system.. For each sample, there are notes associated with processing method (delay in sample processing, storage conditions on the ward, etc.) Barcoded samples are stored in barcoded boxes in a locked freezer at either -20°C or -80°C according to stability requirements. These freezers are located onsite in the CPP and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be accompanied by laboratory staff at all times. Access to stored clinical samples is restricted. Samples will be stored until requested by a researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All researchers are required to sign a form stating that the samples are only to be used for research purposes associated with this trial (as per the IRB approved protocol) and that any unused samples must be returned to the CPP. It is the responsibility of the NCI Principal Investigator to ensure that the samples requested are being used in a manner consistent with IRB approval. Following completion of this study, samples will remain in storage as detailed above. Access to these samples will only be granted following OHSRP/IRB approval of an additional protocol, granting the rights to use the material or if the use is not considered to be human subjects research.
untitled h1
5.3.2 leidos biomedical inc. lab

Blood and tissue collected during the course of this study will follow storage, handling and labeling procedures to ensure that security, confidentiality and sample integrity are maintained. All samples (blood or tissue) are tracked by distinct identification labels that include a unique patient identifier and date of specimen collection. Thus samples will be coded, with access to code key linking to personal data restricted to the study investigators. All cryopreserved samples are tracked for freezer location and storage criteria. All Samples are stored in a locked freezer at -70C according to stability requirements. These freezers are located offsite at NCI-Frederick, at the Leidos Biomedical, Inc. Lab in Frederick, MD. Samples will be stored until requested by a researcher named on the protocol. All use and requests for use will be recorded by the Leidos Biomedical, Inc. Lab. Any unused samples must be returned. Some samples as indicated below may be stored in monitored freezers/refrigerators in the investigator's laboratory at specified temperatures with alarm systems in place. At the completion of this protocol, samples will remain in storage as detailed above. If additional studies are to be performed on any samples retaining patient identifiers, obtained during the conduct of this trial, access to these samples will only be granted following IRB approval of an additional protocol, granting the rights to use the material. If specimens are to be discarded at any point, they will be disposed of in accordance with the environmental protection laws, regulations and guidelines of the Federal Government and the State of Maryland. If, at any time, a patient withdraws from the study and does not wish for their existing samples to be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed (or returned to the patient, if so requested).
untitled h1
5.3.3 laboratory of dr. raffit

This study will follow storage, handling and labeling procedures to ensure that security, confidentiality and sample integrity are maintained. All samples (blood or tissue) are tracked by distinct identification labels generated by Labmatrix that include a unique patient identifier and date of specimen collection. Thus samples will be coded, with access to the code key linking to personal data restricted to the study investigators. Depending on specimen type, samples are stored in liquid nitrogen, in monitored freezers/refrigerators at either -20 or -80C according to stability requirements or in a slide cabinet in the research Laboratory of Dr. Raffit Hassan (Building 10, Room 3B51)
untitled h1
5.3.4 nih flow cytometry laboratory

Specimens received in the flow cytometry laboratory are accessible only to the flow cytometry laboratory team, as the laboratory door is locked and key access is only provided to the flow cytometry laboratory members. Additionally, the flow cytometry laboratory is set behind a set of double doors that are accessible only by badge/key card access.
untitled h1
5.3.5 protocol completion/sample destruction

All specimens obtained in the protocol are used as defined in the protocol. Any specimens remaining at the completion of the protocol will be stored in the conditions described above. The study will remain open as long as sample or data analysis continues. Samples from consenting subjects will be stored until they are no longer of scientific value or until a subject withdraws consent for their continued use, at which time they will be destroyed. Once primary research objectives for the protocol are achieved, intramural researchers can request access to remaining samples, provided they have an IRB-approved protocol and patient consent or an exemption from OHSRP. The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be made per the requirements of section 7.2.1.
untitled h1
6 data collection and evaluation

Study data will be recorded and stored in the C3D and Labmatrix databases. The PI will be responsible for overseeing entry of data into an in-house password protected electronic system and ensuring data accuracy, consistency and timeliness. The principal investigator, associate investigators/research nurses and/or a contracted data manager will assist with the data management efforts. All data obtained during the conduct of the protocol will be kept in secure network drives or in approved alternative sites that comply with NIH security standards. Primary and final analyzed data will have identifiers so that research data can be attributed to an individual human subject participant. All adverse events, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until return to baseline or stabilization of event. Document AEs from the first study intervention, Study Day 1, through 30 days after the study intervention was last administered. Beyond 30 days after the last intervention, only adverse events which are serious and related to the study intervention need to be recorded. An abnormal laboratory value will be recorded in the database as an AE **only** if the laboratory abnormality is characterized by any of the following:
Results in discontinuation from the study  
Is associated with clinical signs or symptoms Requires treatment or any other therapeutic intervention
Is associated with death or another serious adverse event, including hospitalization.  
Is judged by the Investigator to be of significant clinical impact If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient's outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurred, this will be reported expeditiously per requirements in section 7.2.1. 6.2 DATA SHARING PLANS  
6.2.1 Human Data Sharing Plan
untitled h1
what data will be shared?

I will share human data generated in this research for future research as follows: _X_ Coded, linked data in an NIH-funded or approved public repository.  
_X_ Coded, linked data in BTRIS
_X_ Identified or coded, linked data with approved outside collaborators under appropriate agreements.
untitled h1
how and where will the

Data will be shared through: _X_ An NIH-funded or approved public repository. Insert name or names:__clinicaltrials.gov__.  
_X_ BTRIS (automatic for activities in the Clinical Center) _X_ Approved outside collaborators under appropriate individual agreements. _X_ Publication and/or public presentations.
untitled h1
when will the data be

_X_ Before publication. _X_ At the time of publication or shortly thereafter.  
6.2.2 Genomic Data Sharing Plan
No large scale genomic data will be generated on this study; therefore, the NIH GDS policy does not apply. 6.3 RESPONSE CRITERIA For the purposes of this study, patients should be re-evaluated for response every 6 weeks (2 cycles). In addition to a baseline scan, confirmatory scans should also be obtained no less than 4 weeks following initial documentation of objective response. Response and progression will be assessed by the investigator on the basis of physical examinations, computed tomography (CT) or Magnetic Resonance (MR) scans, and potentially other modalities according to standard of care. For peritoneal mesothelioma, the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)[34] will be used. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. For pleural mesothelioma, modified RECIST for MPM (malignant pleural mesothelioma)[35] should be used as described in section 6.3.3.
untitled h1
6.3.1 definitions

Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with LMB-100. The dose determining population will consist of all patients evaluable for DLT. Patients are evaluable for DLT if they are evaluable for toxicity and discontinued earlier due to DLT or completed the DLT observation period and have undergone safety evaluations. Evaluable for pharmacokinetic analysis: All patients that are evaluable for toxicity will be included in the PK analysis population. Patients will be excluded from the PK analysis population if they significantly violate the inclusion or exclusion criteria, deviate from the protocol, or if data are unavailable or incomplete which may influence the PK analysis. Excluded cases will be documented with the reason for exclusion. Evaluable for objective response: Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
untitled h1
6.3.2 peritoneal mesothelioma 6.3.2.1 disease

Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as:
By chest x-ray: >20 mm;  
By CT scan:
o Scan slice thickness 5 mm or under: as >10 mm o Scan slice thickness >5 mm: double the slice thickness
With calipers on clinical exam: >10 mm.  
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters) Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions.  
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target lesions** and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 6.3.2.2 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data, which may bias an investigator if it is not routinely or serially performed. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published.[36-38] In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer.[39] Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain).  
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD
based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDGPET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDGPET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.  
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.  
6.3.2.3 RECIST version 1.1 Response Criteria 6.3.2.3.1 Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. 6.3.2.3.2 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD): Appearance of one or more new lesions and/or *unequivocal progression* of existing non-target lesions. *Unequivocal progression* should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator). 6.3.2.3.3 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| For Patients with Measurable Disease (i.e., Target Disease) Target  Non-Target  New  Overall  Best Overall Response when  Lesions Lesions Lesions Response Confirmation is Required* CR CR No CR >4 wks. Confirmation** CR NonCR/Non-PD No PR CR Not  No PR evaluated >4 wks. Confirmation** No PR PR NonCR/NonPD/not  evaluated SD NonCR/NonPD/not  evaluated No SD Documented at least once >4  wks. from baseline** PD Any Yes or  PD No Any PD*** Yes or  PD No no prior SD, PR or CR Any Any Yes PD * See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. ** Only for non-randomized trials with response as primary endpoint. *** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as  disease progression. Note: Patients with a global deterioration of health status requiring discontinuation of treatment without  objective evidence of disease progression at that time should be reported as "symptomatic  deterioration." Every effort should be made to document the objective progression even after  discontinuation of treatment.   |
|---|  
| Non-Target Lesions   | New Lesions   | Overall Response   |
|----------------------|---------------|--------------------|
| CR                   | No            | CR                 |
| Non-CR/non-PD        | No            | Non-CR/non-PD*     |  
| Non-Target Lesions                                                                                           | New Lesions   | Overall Response   |
|--------------------------------------------------------------------------------------------------------------|---------------|--------------------|
| Not all evaluated                                                                                            | No            | not evaluated      |
| Unequivocal PD                                                                                               | Yes or No     | PD                 |
| Any                                                                                                          | Yes           | PD                 |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is increasingly used as |               |                    |  
* 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is increasingly used as  
an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised
untitled h1
6.3.3 pleural mesothelioma

Malignant pleural mesothelioma (MPM) lesions are difficult to measure reliably.[35] Therefore modified criteria were defined in 2004 adjusting target lesion measurements to the specific needs of this disease.  
6.3.3.1 Modified RECIST Criteria for MPM
untitled h1
target lesion

Measurable at baseline and defined as tumor thickness measurements perpendicular to the chest wall or mediastinum in two positions at three separate levels on transverse cuts of CT scan. The sum of those 6 measurements define a pleural unidimensional measure. For reproducibility of lesion identification in follow up scans, cuts were taken at least 1 cm apart and close to anatomical landmarks in the thorax. Reassessments should be done at same position at the same level and by the same reader. Nodal, subcutaneous, and other measurable lesion were measured as per RECIST criteria. All unidimensional measurements were added to obtain total tumor measurement. Evaluation of target lesions  
Complete Response (CR): Disappearance of all target lesions with no evidence of tumor elsewhere.  
Partial Response (PR): At least a 30% decrease in the total tumor measurement Confirmed response (PR and CR): require a repeat scan at least 4 weeks apart Progressive Disease (PD): At least a 20% increase in the total tumor measurement, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). (Note: the appearance of one or more new lesions is also considered progression).  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.  
6.3.3.2 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| Target   | Non-Target   | New       | Overall   | Best                                            | Response   | for   | this   |
|----------|--------------|-----------|-----------|-------------------------------------------------|------------|-------|--------|
| Lesions  | Lesions      | Lesions   | Response  | Category Also Requires:                         |            |       |        |
| CR       | CR           | No        | CR        | >4 wks. confirmation                            |            |       |        |
| CR       | Non-CR/NonPD              | No        | PR        | >4 wks. confirmation                            |            |       |        |
| PR       | Non-PD       | No        | PR        |                                                 |            |       |        |
| SD       | Non-PD       | No        | SD        | documented at least once >4  wks. from baseline |            |       |        |
| PD       | Any          | Yes or No | PD        |                                                 |            |       |        |
| Any      | PD*          | Yes or No | PD        | no prior SD, PR or CR                           |            |       |        |
| Any      | Any          | Yes       | PD        |                                                 |            |       |        |  
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression.  
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "*symptomatic deterioration"*. Every effort should be made to document the objective progression even after discontinuation of treatment.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the evaluation of complete response depends on this determination, it is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status.
untitled h1
6.3.4 duration of response

Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements. 6.3.5 Progression-Free Survival Progression free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. 6.3.6 Objective Response Rate Objective response rate (ORR) is defined as the proportion of patients with partial response or complete response. 6.3.7 Disease Control Rate Disease control rate (DCR) is defined as the proportion of patients with stable disease, partial response or complete response 6.3.8 Overall Survival Overall survival (OS) is defined as the duration of time from start of treatment to time of death 6.4 TOXICITY CRITERIA The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_40).
untitled h1
7 nih reporting requirements/data and

7.1 DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 7.2 OHSRP OFFICE OF COMPLIANCE AND TRAINING /IRB REPORTING
untitled h1
7.2.1 expedited reporting

Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies. 7.2.2 IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found here. 7.3 NCI CLINICAL DIRECTOR REPORTING Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death
untitled h1
7.4 nih required data and

The clinical research team will meet on a regular basis when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior patients. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Events meeting requirements for expedited reporting as described in section 7.2.1 will be submitted within the appropriate timelines.. The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
untitled h1
7.4.2 safety monitoring committee (smc)

This protocol will require oversight from the Safety Monitoring Committee (SMC). Initial review will occur as soon as possible after the annual IRB continuing review date. Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more frequently as may be required by the SMC. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within the review period. Written outcome letters will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. Note: The protocol is no longer SMC review as of 9/17/2018 as no patients have been on study therapy since the time of the next scheduled review.
untitled h1
8 sponsor safety reporting 8.1

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (ICH E6 (R2))
untitled h1
8.1.2 serious adverse event (sae)

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
Death,  
A life-threatening adverse event (see section 8.1.3) Inpatient hospitalization or prolongation of existing hospitalization o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the study), a planned hospitalization for pre-existing condition, or a procedure required by the protocol, without a serious deterioration in health, is not considered a serious adverse event.  
o A hospitalization/admission that is solely driven by non-medical reasons (e.g.,
hospitalization for patient convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria.  
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions A congenital anomaly/birth defect Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
untitled h1
8.1.3 life-threatening

An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32)
untitled h1
8.1.4 severity

The severity of each Adverse Event will be assessed utilizing the CTCAE version 4. 8.1.5 Relationship to Study Product All AEs will have their relationship to study product assessed using the terms: related or not related.  
Related - There is a reasonable possibility that the study product caused the adverse event.  
Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event.  
Not Related - There is not a reasonable possibility that the administration of the study product caused the event.  
8.2 ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution.
untitled h1
saes will be

Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  
Recorded on the appropriate SAE report form, the medical record and captured in the clinical database.  
Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events recorded from the time of first investigational product administration must be reported to the sponsor. 8.3 REPORTING OF SERIOUS ADVERSE EVENTS Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form. All SAE reporting must include the elements described in section 8.2. SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and instructions can be found at: https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842 Following the assessment of the SAE by OSRO, other supporting documentation of the event may be requested by the OSRO Safety and should be provided as soon as possible. 8.4 REPORTING PREGNANCY
untitled h1
8.4.1 maternal exposure

If a patient becomes pregnant during the course of the study, the study treatment should be discontinued immediately and the pregnancy reported to the Sponsor no later than 24 hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy becomes known. Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented.
untitled h1
8.4.2 paternal exposure

Male patients should refrain from fathering a child or donating sperm during the study and for 3 months after the last dose of LMB-100 or 6 months after the last dose of nab-paclitaxel, whichever occurs later. Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until the later or 3 months after the last dose of LMB-100 or 6 months after the last dose of nab-paclitaxel should, if possible, be followed up and documented. 8.5 REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND Following notification from the investigator, CCR, the IND sponsor, will report any suspected adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the study product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potential serious risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 312.32. All serious events will be reported to the FDA at least annually in a summary format.
untitled h1
9 clinical monitoring plan

As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring program. The CCR's program allows for confirmation of: study data, specifically data that could affect the interpretation of primary and secondary study endpoints; adherence to the protocol, regulations, ICH E6 and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on:
Informed consent process Eligibility confirmation Drug administration and accountability Adverse events monitoring Response assessment.  
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct.
untitled h1
10 statistical considerations

The primary objective of this phase I trial is to assess the safety and tolerability of LMB-100 with (Arms A1 and A2) and without (Arms B1 and B2) nab-paclitaxel in patients with malignant mesothelioma. Additional objectives are to determine the response rate at the RP2D, to retrospectively explore and describe the pharmacokinetic characteristics, including the number of effective cycles of LMB-100 therapy that can be given before the development of anti-LMB-100 neutralizing antibodies limits patient drug exposure.
untitled h1
10.1 arms a1 and a2

The dose de-escalation study Arm A1 builds upon and extends the findings from the closed phase I trial of LMB-100 (NCT02317419) in which 0/4 patients treated at170 mcg/kg experienced a DLT and 2/4 patients treated at 250 mcg/kg experienced a DLT. As a result of these prior findings, it was planned that 6 patients would be treated at 170 mcg/kg (Table 7). If 0 or 1/6 patients have a DLT, then 170 mcg/kg would be declared the RP2D. If 2 or more of the 6 patients have a DLT, then 3 to 6 patients would be treated at 140 mcg/kg following the usual 3+3 design. 0 or 1 DLT in 6 patients at 140 mcg/kg will result in this level being the RP2D. Otherwise, dose levels of 100 mcg/kg or lower would be explored. Dose de-escalation below 140 was deemed unlikely given the available monotherapy data with LMB-100 (Table 1). It was considered likely that accrual to this phase would not need to exceed 12 patients. Patients treated at the RP2D in Arm A1 were to be included in the efficacy analyses at the RP2D.  
For patients with malignant mesothelioma, low response rates are currently obtained with existing treatments. The goal of the dose expansion cohort would be to determine if using LMB-100 would rule out a 5% response rate and target a rate of 30%. The study will be conducted using a twostage Minimax phase II trial design in order to rule out an unacceptably low 5% PR+CR rate
(p0=0.05) in favor of an improved PR+CR response rate of 30% (p1=0.30). Both PR and CR will be considered a 'response' for purposes of this study. With alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.10 (probability of rejecting a good treatment=0.10), this cohort was to have initially enrolled 13 evaluable patients and if 0 of the 13 have a response, then no further patients would be accrued. If 1 or more of the first 13 patients had a response, then accrual would continue until a total of 16 patients were enrolled. As it may take several weeks to determine if a patient has experienced a response, a temporary pause in the accrual to the trial may be necessary to ensure that enrollment to the second stage is warranted. If there were 1 to 2 responses in 16 patients, this would be an uninterestingly low response rate. If there were 3 or more responses in 16 patients (18.8%), this would be sufficiently interesting to warrant further study in later trials. Under the null hypothesis (5% response rate), the probability of early termination is 51.3%. After the enrollment of 10 evaluable patients the pharmacokinetic and anti-drug antibody level (ADA) data underwent an interim analysis. Dr. William Figg, who has expertise in pharmacokinetics, in conjunction with the NCI CCR leadership committee analyzed the PK
data. Since the thresholds for ADA and its influence on pharmacokinetics are unclear, prespecified criteria for making changes to the protocol were not established. The objective of the assessment was to make recommendations as to whether a therapeutic threshold has been reached and what, if any adjustments should be made with regard to the eligibility criteria and/or study plan. No adjustments were recommended as a result of the interim analysis. With Amendment B, it was determined that the 170 mcg/kg dose would no longer be explored after DLT occurred in 3 of the first 3 subjects evaluated. The three existing patients were re-treated at the 140 mcg/kg dose and an additional 7 subjects were enrolled to be treated at 140 mcg/kg. Of 10 subjects, none experienced partial or complete response. Therefore, as of Amendment C, it is determined that patients will no longer be treated with LMB-100 monotherapy and all future subjects are to be enrolled on Arms B1 and B2.
untitled h1
10.2 arms b1 and b2

The dose de-escalation study (Arm B1) plans to evaluate up to two dose levels of LMB-100 in combination with nab-paclitaxel. Once the RP2D has been determined, a dose expansion cohort (Arm B2) will be treated at the RP2D using the design discussed below. Patients treated at the RP2D in Arm B1 will be included in the efficacy analyses at the RP2D. For patients with malignant mesothelioma, low response rates are currently obtained with existing treatments. The goal of the dose expansion cohort would be to determine if using LMB-100 would rule out a 5% response rate and target a rate of 30%. The study will be conducted using a twostage Minimax phase II trial design in order to rule out an unacceptably low 5% PR+CR rate
(p0=0.05) in favor of an improved PR+CR response rate of 30% (p1=0.30). Both PR and CR will be considered a 'response' for purposes of this study. With alpha=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.10 (probability of rejecting a good treatment=0.10), this cohort will initially enroll 13 evaluable patients and if 0 of the 13 have a response, then no further patients will be accrued. If 1 or more of the first 13 patients has a response, then accrual would continue until a total of 16 patients have been enrolled. As it may take several weeks to determine if a patient has experienced a response, a temporary pause in the accrual to the trial may be necessary to ensure that enrollment to the second stage is warranted. If there are 1 to 2 responses in 16 patients, this would be an uninterestingly low response rate. If there were 3 or more responses in 16 patients (18.8%), this would be sufficiently interesting to warrant further study in later trials. Under the null hypothesis (5% response rate), the probability of early termination is 51.3%.
untitled h1
10.3 justification of accrual ceiling

The Arm B1 dose de-escalation cohorts may require up to 12 patients, and the expansion portion (Arm B2) may require up to 16 evaluable patients. However, with 6 patients from the Arm B1 dose de-escalation cohorts potentially being included in the analysis at the RP2D, up to 22 individual patients may be required. In order to allow for a small number of inevaluable patients in Arms B1 and B2 and adding the 10 patients already enrolled on the completed Arms A1 and A2, the accrual ceiling will be set at 34 patients. If 1-2 patients per month enroll on this trial, accrual would be expected to be completed in approximately 2.5 years.
untitled h1
11 collaborative agreements 11.1 clinical

A Clinical Trial Agreement (CTA \#01059-17) in place between the National Cancer Institute and Celgene for the provision of the nab-paclitaxel.
untitled h1
12 human subjects protections 12.1

LMB-100 is a mesothelin-targeted cFP and has shown preclinical dose-dependent activity in monotherapy and/or combination in xenografts representing MSLN-positive indications (NSCLC, mesothelioma, triple negative breast cancer, gastric cancer, pancreas, ovarian, potentially other tumor indications). The rationale to include MSLN- positive tumors of epithelial cell origin is based on preclinical models demonstrating promising anti-tumor efficacy. In addition, molecular pathology data demonstrated a high prevalence of mesothelin protein in these tumors. The rationale to evaluate LMB-100 +/- nab-paclitaxel in advanced/metastatic mesothelioma is to preliminarily assess the safety and the anti-tumor activity of LMB-100 in this indication.
untitled h1
12.2 participation of children

There are no dosing or adverse event data are currently available on the use of LMB-100 with or without nab-paclitaxel in patients <18 years of age; therefore, children are excluded from this study.
untitled h1
12.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section 12.5), all subjects will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment of whether an individual has the capacity to provide consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
untitled h1
12.4 evaluation of benefits and

Patient safety will be managed by careful proactive patient selection prior to study to exclude patients at risk from study treatment due to their pre-existing conditions. During the study, safety of patients will be proactively managed by protocol-mandated physical examinations, vital signs assessments, chest X-rays, ECGs, clinical laboratory assessments, and collection of adverse events and their assessment. The risks of the study include those associated with study agent as discussed in section 13.
untitled h1
12.4.2 radiation risks

Subjects in this study may undergo up to 2 CT guided research biopsies which will result in exposure to approximately 1.5 rem. This amount is below the guideline of 5 rem per year allowed for adult research subjects by the NIH Radiation Safety Committee.
untitled h1
12.5 risks/benefits analysis

Patients with advanced and/or metastatic mesothelioma, are in continuous need of improved therapy options. This is especially true for patients where no standard therapy exists such as the patient population that will be eligible for this trial. Preclinical data has demonstrated promising anti-tumor efficacy of LMB-100 in xenograft models in monotherapy and combination therapy.  
Therefore, LMB-100 +/- nab-paclitaxel may improve clinical outcome of patients with mesothelioma. A number of clinically appropriate strategies to minimize risk to patients have been built into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, and management guidelines. Overall, the potential benefits of mesothelin targeted cFP for cancer patients retaining the ability to consent and those who lose capacity to consent during the course of the trial outweigh the risks associated with the proposed entry-into-human trial with LMB-100 +/- nab-paclitaxel.
untitled h1
12.6 consent process and documentation

All patients will be thoroughly screened by the physician and the research nurse prior to completing the consent. During the initial consultation, the patient and family or friends, if present, will be presented with a forthright and detailed overview of the treatment option available to them at the NIH. The experimental nature of the treatment, its objectives, its theoretical advantages and disadvantages will be presented. The Informed Consent document is given to the patient and they are asked to review it, make notes and ask questions prior to agreeing to participate in this protocol. The patient is reassured that participation on this trial is entirely voluntary and that he/she can withdraw or decide against treatment at any time without adverse consequences. The physician assures the patient that if alternative therapy or no therapy at all is preferred, we will do all that we can to facilitate consultation with the appropriate referral organizations. The Informed Consent document may be obtained from the patient by the principal investigator, associate investigators, or the medical staff fellow under the supervision of the principal investigator. Consent for the optional biopsies on this study will be obtained at the time of the procedure, using the procedure consent. If the patient refuses the optional biopsy at that time, the refusal will be documented in the medical record and in the research record. 12.6.1 Telephone re-consent procedure Re-consent on this study may be obtained via telephone. Telephone consent will be obtained per OHSRP/IRBO and CCR policies and procedures.
untitled h1
13 regulatory and operational considerations

The clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation and completion. An individualized quality management plan will be developed to describe a site's quality management. Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution. Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and reported in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.
untitled h1
13.2 conflict of interest policy

The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the NCI has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.
untitled h1
13.3 confidentiality and privacy

Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorized third party without prior written approval of the sponsor. All research activities will be conducted in as private a setting as possible. The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records. The study participant's contact information will be securely stored at each clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be stored at the NCI CCR. This will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites and by NCI CCR research staff will be secured and password protected. At the end of the study, all study databases will be archived at the NCI CCR To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the National Institutes of Health (NIH). This certificate protects identifiable research information from forced disclosure. It allows the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to participants.
untitled h1
14 pharmaceutical information 14.1 lmb-100

LMB-100 was transferred to the NIH CC Pharmacy by Roche, the drug manufacturer. For this trial, the drug will be supplied by the NIH CC Pharmacy.
untitled h1
14.1.2 toxicity

Information in this section is based on preclinical studies with LMB-100, and clinical studies of the cytolytic fusion protein SS1-P. Patients should receive a full dose of LMB-100 unless a DLT and/or a treatment limiting toxicity is observed. In case of DLT and/or treatment limiting toxicities, treatment with LMB-100 will be stopped until resolution of toxicity to NCI CTCAE Grade  2 hematological toxicities or Grade  1 non-hematological toxicities. A delay of LMB-100 administration for up to three weeks of the planned schedule will be acceptable to allow for resolution of toxicity to NCI CTCAE Grade  2 hematological toxicities or Grade  1 nonhematological toxicities. If toxicity does not resolve to NCI CTCAE Grade  2 hematological toxicities or Grade  1 non-hematological toxicities and the patient is unable to resume treatment with LMB-100 after this time, no additional doses will be administered and the patient will be withdrawn from study treatment. 14.1.2.1 Infusion-Related Reactions and Hypersensitivity Including Anaphylaxis LMB-100 administration may cause infusion-associated symptoms such as fever, chills, hypotension, shortness of breath, skin rash, headache, nausea, and/or vomiting. Such reactions typically occur during or shortly after an infusion, predominantly the first infusion. Patients may also develop IgE-mediated hypersensitivity reactions to LMB-100. IRRs may be indistinguishable from an anaphylactic reaction. Patients should receive full supportive care to treat IRRs or anaphylaxis according to institutional practice. If infusion-associated signs or symptoms occur, patients should be monitored until complete resolution.  
In vitro data suggest that the risk for the release of pro-inflammatory cytokines upon first administration of LMB-100 to humans is low (human whole blood assay, see section 1.2.3.3.3). Past experience with monoclonal antibodies that demonstrated a risk in the whole blood assay has shown that this risk could be effectively managed in the clinic with appropriate risk-minimization measures. The release of pro-inflammatory cytokines is believed to be partially responsible for the occurrence of IRRs. 14.1.2.2 Risk of Immunogenicity and Potential Safety Impact LMB-100 may cause the formation of ADAs. These may trigger hypersensitivity reactions or immune complex-mediated responses. The development of ADAs to LMB-100, an improved cytolytic fusion protein with a humanized targeting moiety directed against mesothelin and a dehumanized, truncated Pseudomonas exotoxin A is expected to be less likely than SS1P. Clinical trials with SS1P have led to the development of neutralizing ADAs in 75% and 88% of patients after 1 cycle of therapy, in the IV bolus and continuous infusion trials respectively.[12]
Patients will be monitored at regular intervals for the development of ADAs and cytokines. In particular, any clinical signs and symptoms suggestive of a hypersensitivity reaction and/or an immune complex-mediated reaction possibly due to ADA formation will be carefully investigated. 14.1.2.3 Risk of Inflammatory Reactions to Serosal Membranes LMB-100 administration may cause inflammatory reactions to serosal membranes including pleuritis, characterized by pleuritic chest pain, dyspnea, and hypoxia and pericarditis, characterized by precordial chest pain, congestive heart failure, hypotension, and uremia. Clinical trials with SS1P monotherapy have led to reversible pleuritis and pericarditis. Patients who develop symptoms of serosal inflammation should be closely monitored and receive standard treatments which may include corticosteroids.
untitled h1
14.1.2.4 risk of vascular leak

LMB-100 administration may cause VLS characterized by hypotension, hypoalbuminemia, edema, weight gain, and hemoconcentration. Clinical trials with SS1P monotherapy have led to the development of reversible VLS. Patients will be monitored with frequent assessments of chest xrays, weight, edema, blood pressure, and serum albumin levels prior to and during treatment.  
Patients who develop symptoms of VLS should be closely monitored and receive standard symptomatic treatments.
untitled h1
14.1.2.5 risk of renal toxicity

LMB-100 administration may cause renal toxicity characterized by increased creatinine, BUN, and proteinuria. In preclinical cynomolgus monkey studies, LMB-100 has shown increases in creatinine and histological changes including regenerative and degenerative changes to the tubular epithelium. Hemolytic uremic syndrome has been reported for other cytolytic fusion antibodies in development. Patients should be monitored with renal laboratory assessments including creatinine, BUN, and urinalysis. 14.1.2.6 Injection Site Reactions LMB-100 administration may cause adverse reactions at the infusion site characterized by pain, swelling, induration, and nodules. In preclinical NHP studies for both SS1P and LMB-100 reddening and swelling of the infusion site were noted. Patients who develop symptoms of infusion site reactions can be administered pain relieving medication (analgesic) as required, and rotation of infusion sites is recommended.
untitled h1
14.1.2.7 pregnancy

No studies assessing the reproductive and developmental toxicity of LMB-100 have been conducted to date. It is not known whether LMB-100 can cross the placenta or cause harm to the fetus when administered to pregnant women or whether it affects reproductive capacity. LMB-100 should not be administered to pregnant women. Use of effective contraceptive methods is recommended in all patients receiving LMB-100, including up to 4 months and 2 months following the last LMB-100 dose for women and men, respectively. 14.1.3 Formulation and preparation LMB-100 drug product (20 mg/20 mL) is provided for syringe infusion as a sterile, colorless to brownish, preservative-free liquid in single-use, 20 mL vials. The nominal fill volume is 20 mL and the approximate concentration of LMB-100 recombinant fusion protein in the vials is 1 mg/mL. 14.1.4 Stability and Storage Chemical and physical in-use stability for undiluted LMB-100 drug product in syringes has been demonstrated for 24 hours at 2-8 °C and 24 hours at ambient temperature.  
Storage conditions should generally be at 2-8C, but syringes may be held at room temperature for up to a maximum of 4 hours. 14.1.5 Administration procedures Please refer to section 3.2.1 14.1.6 Incompatibilities Pharmacodynamic drug interaction studies have not been conducted. LMB-100 is contraindicated in subjects with a history of severe allergic anaphylactic reactions to humanized, chimeric or mouse peptides/antibodies or to any components of the product.
untitled h1
14.1.6.1 mechanism of action

LMB-100 is a novel recombinant anti-mesothelin targeted cytolytic fusion protein (cFP) developed for the treatment of patients with solid tumors that express the mesothelin protein. Mesothelin is a suitable candidate for targeted therapy due to its very limited expression in normal/non-malignant tissue and its high expression in several tumor entities including mesothelioma, ovarian cancer, pancreatic cancer, gastric cancer, breast cancer, and lung cancer. To target mesothelin, a humanized Fab fragment of the anti-mesothelin antibody SS1 is linked to a truncated and de-immunized recombinant 24 kD fragment of Pseudomonas exotoxin (PE24). After binding to mesothelin, the complex is internalized by endocytosis and kills cells by inhibition of eukaryotic elongation factor 2 (eEF2), leading to arrest of protein synthesis and secondarily triggering cell death by apoptosis or necrosis. 14.1.6.2 Molecular Weight: approximately 73 kDa  
 14.1.6.3 Chemical Structure 14.2 NAB-PACLITAXEL Please refer to package insert for additional information.
untitled h1
14.2.1 source

As of Amendment E, the study drug nab-paclitaxel will be provided under a Clinical Trial Agreement with the manufacturer, Celgene.. Commercially purchased nab-paclitaxel may be used until the Celgene supply is in place.
untitled h1
14.2.2 toxicity

The most common clinically significant adverse reactions reported with nab-paclitaxel in patients with pancreatic cancer include: neutropenia, anemia, thrombocytopenia, pancytopenia peripheral neuropathy, cardiac failure, tachycardia, dyspnea, pneumonitis, nausea, vomiting, diarrhea abdominal pain, intestinal obstruction, colitisarthralgia/myalgia, renal failure, increased alanine aminotransferase, increased aspartate aminotransferase, increased bilirubin, and increased creatinine. Hypersensitivity reactions including fatal anaphylactic reactions have rarely been reported with nab-paclitaxel. If a hypersensitivity reaction occurs, nab-paclitaxel should be discontinued immediately, symptomatic treatment should be initiated, and the participant should not be rechallenged with paclitaxel.  
Bone marrow suppression (primarily neutropenia) occurs frequently with *nab-*paclitaxel. Frequent monitoring of blood cell counts should be performed. Participants should not be retreated with subsequent cycles of nab-paclitaxel until neutrophils recover to  1500 cells/mm2 and platelets to 100,000 cells.  
Sensory neuropathy occurs frequently with nab-paclitaxel, though generally not severe. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose reduction.  
Sepsis was reported in 5% of participants with or without neutropenia who received nabpaclitaxel.[40] Complications due to underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors. Pneumonitis occurred in 4% of participants using nab-paclitaxel. Closely monitor all participants for signs and symptoms of pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with nab-paclitaxel and promptly initiate appropriate treatment with supportive measures. Hepatic impairment may increase the toxicity of *nab-*paclitaxel, particularly myelosuppression. Administration of nab-paclitaxel in participants with hepatic impairment should be performed with caution. Congestive heart failure and left ventricular dysfunction have rarely been observed in participants receiving *nab-*paclitaxel. Most of these participants were previously exposed to cardiotoxic medicinal products such as anthracyclines or had underlying cardiac history. Participants receiving nab-paclitaxel should be vigilantly monitored for the occurrence of cardiac events. Nausea, vomiting, and diarrhea following administration of nab-paclitaxel may be treated with commonly used anti-emetics and constipating agents. In the very elderly ( ≥75 years) who received nab-paclitaxel, there was a higher incidence of serious adverse reactions and adverse reactions that led to discontinuation including hematologic toxicities, peripheral neuropathy, decreased appetite, and dehydration. Participants 75 years or older should be carefully assessed for their ability to tolerate nab-paclitaxel with special consideration to performance status, co-morbidities, and increased risk of infections.  
14.2.3 Formulation and preparation
untitled h1
formulation

ABRAXANE is supplied as a lyophilized powder containing 100 mg of paclitaxel formulated as albumin-bound particles in single-use vial for reconstitution.
untitled h1
preparation

1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP.  
2. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL.  
  
3. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as this will result in foaming.  
4. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized cake/powder.  
5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder occurs. Avoid generation of foam.  
6. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides.  
Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel. Calculate the exact total dosing volume of 5 mg/mL suspension required for the participant: Dosing volume (mL) = Total dose (mg)/5 (mg/mL) The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion. Inject the appropriate amount of reconstituted ABRAXANE® into an empty, sterile IV bag (plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type IV bag). The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer ABRAXANE infusions. The use of an in-line filter is not recommended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. 14.2.4 Stability and Storage Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between 20°C to 25°C (68°F to 77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Product should be retained in the original packaging to protect from bright light.
untitled h1
stability of reconstituted suspension in

Reconstituted ABRAXANE should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 24 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any unused portion.
untitled h1
stability of reconstituted suspension in

The suspension for infusion when prepared as recommended in an infusion bag should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) and protected from bright light for a maximum of 24 hours..  
14.2.5 Administration procedures Please see section 3.2.2. 14.2.6 Incompatibilities Please refer to the package insert.
untitled h1
15 references

11. Weldon JE, Pastan I: **A guide to taming a toxin--recombinant immunotoxins**
constructed from Pseudomonas exotoxin A for the treatment of cancer. *The FEBS* journal 2011, 278(23):4683-4700.  
12. Hassan R, Bullock S, Premkumar A, Kreitman RJ, Kindler H, Willingham MC, Pastan I:
Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus
1. Sugarbaker DJ, Garcia JP, Richards WG, Harpole DH, Jr., Healy-Baldini E, DeCamp MM,
Jr., Mentzer SJ, Liptay MJ, Strauss GM, Swanson SJ: Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma. Results in 120 consecutive patients. *Annals of surgery* 1996, 224(3):288-294; discussion 294-286.  
2. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C *et al*: **Phase III study of pemetrexed in combination** with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2003, 21(14):2636-2644.  
3. Moolgavkar SH, Meza R, Turim J: **Pleural and peritoneal mesotheliomas in SEER: age**
effects and temporal trends, 1973-2005. *Cancer causes & control : CCC* 2009, 20(6):935-944.
4. Yan TD, Deraco M, Baratti D, Kusamura S, Elias D, Glehen O, Gilly FN, Levine EA, Shen P, Mohamed F *et al*: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2009, 27(36):6237-6242.  
5. Park BJ, Alexander HR, Libutti SK, Wu P, Royalty D, Kranda KC, Bartlett DL: Treatment of primary peritoneal mesothelioma by continuous hyperthermic peritoneal perfusion (CHPP). *Annals of surgical oncology* 1999, 6(6):582-590.  
6. Feldman AL, Libutti SK, Pingpank JF, Bartlett DL, Beresnev TH, Mavroukakis SM,
Steinberg SM, Liewehr DJ, Kleiner DE, Alexander HR: Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy. *Journal of clinical oncology :* official journal of the American Society of Clinical Oncology 2003, 21(24):4560-4567.  
7. Loggie BW, Fleming RA, McQuellon RP, Russell GB, Geisinger KR, Levine EA:
Prospective trial for the treatment of malignant peritoneal mesothelioma. The American surgeon 2001, 67(10):999-1003.  
8. Ordonez NG: **Application of mesothelin immunostaining in tumor diagnosis**. The American journal of surgical pathology 2003, 27(11):1418-1428.
9. Kelly RJ, Sharon E, Pastan I, Hassan R: **Mesothelin-targeted agents in clinical trials and**
in preclinical development. *Molecular cancer therapeutics* 2012, 11(3):517-525.  
10. Pastan I, Hassan R: **Discovery of mesothelin and exploiting it as a target for**
immunotherapy. *Cancer research* 2014, 74(11):2907-2912. I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. *Clinical cancer research : an official journal of the American* Association for Cancer Research 2007, 13(17):5144-5149.  
13. Kreitman RJ, Hassan R, Fitzgerald DJ, Pastan I: **Phase I trial of continuous infusion antimesothelin recombinant immunotoxin SS1P**. *Clinical cancer research : an official* journal of the American Association for Cancer Research 2009, 15(16):5274-5279.  
14. Hassan R, Bullock S, Premkumar A, Kreitman RJ, Kindler H, Willingham MC, Pastan I:
Phase I study of SS1P a recombinant anti-mesothelin immunotoxin given as a bolus IV infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. *Clinical Cancer Research* 2007, 13(17):5144-5149.  
15. Oratz R, Speyer JL, Wernz JC, Hochster H, Meyers M, Mischak R, Spitler LE:
Antimelanoma Monoclonal-Antibody Ricin-a Chain Immunoconjugate (Xmmme001-Rta) Plus Cyclophosphamide in the Treatment of Metastatic MalignantMelanoma - Results of a Phase-Ii Trial. *J Biol Resp Modif* 1990, 9(4):345-354.  
16. Selvaggi K, Saria EA, Schwartz R, Vlock DR, Ackerman S, Wedel N, Kirkwood JM, Jones H, Ernstoff MS: Phase I/Ii Study of Murine Monoclonal Antibody-Ricin-a Chain (Xomazyme-Mel) Immunoconjugate Plus Cyclosporine-a in Patients with Metastatic Melanoma. *J Immunother* 1993, 13(3):201-207.  
17. Hassan R, Williams-Gould J, Watson T, Pai-Scherf L, Pastan I: Pretreatment with rituximab does not inhibit the human immune response against the immunogenic protein LMB-1. Clinical cancer research : an official journal of the American Association for Cancer Research 2004, 10(1 Pt 1):16-18.  
18. Mossoba ME, Onda M, Taylor J, Massey PR, Treadwell S, Sharon E, Hassan R, Pastan I,
Fowler DH: **Pentostatin plus cyclophosphamide safely and effectively prevents** immunotoxin immunogenicity in murine hosts. *Clinical cancer research : an official* journal of the American Association for Cancer Research 2011, 17(11):3697-3705.  
19. Hassan R, Miller AC, Sharon E, Thomas A, Reynolds JC, Ling A, Kreitman RJ, Miettinen MM, Steinberg SM, Fowler DH *et al*: **Major cancer regressions in mesothelioma after** treatment with an anti-mesothelin immunotoxin and immune suppression. *Science* translational medicine 2013, 5(208):208ra147.  
20. Mazor R, Vassall AN, Eberle JA, Beers R, Weldon JE, Venzon DJ, Tsang KY, Benhar I,
Pastan I: Identification and elimination of an immunodominant T-cell epitope in recombinant immunotoxins based on Pseudomonas exotoxin A. Proceedings of the National Academy of Sciences of the United States of America 2012, 109(51):E3597-3603.
21. Weldon JE, Xiang L, Zhang J, Beers R, Walker DA, Onda M, Hassan R, Pastan I: A
recombinant immunotoxin against the tumor-associated antigen mesothelin reengineered for high activity, low off-target toxicity, and reduced antigenicity. Molecular cancer therapeutics 2013, 12(1):48-57.  
22. Liu W, Onda M, Lee B, Kreitman RJ, Hassan R, Xiang L, Pastan I: Recombinant immunotoxin engineered for low immunogenicity and antigenicity by identifying and silencing human B-cell epitopes. *Proceedings of the National Academy of Sciences of the* United States of America 2012, 109(29):11782-11787.  
23. Hollevoet K, Mason-Osann E, Liu XF, Imhof-Jung S, Niederfellner G, Pastan I: **In vitro**
and in vivo activity of the low-immunogenic antimesothelin immunotoxin RG7787 in pancreatic cancer. *Molecular cancer therapeutics* 2014, 13(8):2040-2049.  
24. Alewine C, Xiang L, Yamori T, Niederfellner G, Bosslet K, Pastan I: Efficacy of RG7787, a next-generation mesothelin-targeted immunotoxin, against triple-negative breast and gastric cancers. *Molecular cancer therapeutics* 2014, 13(11):2653-2661.  
25. van Meerbeeck J, Debruyne C, van Zandwijk N, Postmus PE, Pennucci MC, van Breukelen F, Galdermans D, Groen H, Pinson P, van Glabbeke M *et al*: Paclitaxel for malignant pleural mesothelioma: a phase II study of the EORTC Lung Cancer Cooperative Group. *British journal of cancer* 1996, 74(6):961-963.  
26. Vogelzang NJ, Herndon JE, 2nd, Miller A, Strauss G, Clamon G, Stewart FM, Aisner J,
Lyss A, Cooper MR, Suzuki Y *et al*: **High-dose paclitaxel plus G-CSF for malignant** mesothelioma: CALGB phase II study 9234. *Annals of oncology : official journal of the* European Society for Medical Oncology / ESMO 1999, 10(5):597-600.  
27. Yardley DA: **nab-Paclitaxel mechanisms of action and delivery**. *J Control Release* 2013, 170(3):365-372.  
28. Kalra N, Zhang J, Thomas A, Xi L, Cheung M, Talarchek J, Burkett S, Tsokos MG, Chen Y, Raffeld M *et al*: **Mesothelioma patient derived tumor xenografts with defined BAP1** mutations that mimic the molecular characteristics of human malignant mesothelioma. *BMC Cancer* 2015, 15:376.  
29. Robinson BW, Creaney J, Lake R, Nowak A, Musk AW, de Klerk N, Winzell P, Hellstrom KE, Hellstrom I: **Mesothelin-family proteins and diagnosis of mesothelioma**. *Lancet* 2003, 362(9396):1612-1616.
30. Hassan R, Remaley AT, Sampson ML, Zhang J, Cox DD, Pingpank J, Alexander R,
Willingham M, Pastan I, Onda M: Detection and quantitation of serum mesothelin, a tumor marker for patients with mesothelioma and ovarian cancer. *Clinical cancer* research : an official journal of the American Association for Cancer Research 2006, 12(2):447-453.  
31. Hassan R, Sharon E, Thomas A, Zhang J, Ling A, Miettinen M, Kreitman RJ, Steinberg SM, Hollevoet K, Pastan I: Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125. *Cancer* 2014, 120(21):3311-3319.  
32. Siegall CB, Liggitt D, Chace D, Mixan B, Sugai J, Davidson T, Steinitz M:
Characterization of vascular leak syndrome induced by the toxin component of Pseudomonas exotoxin-based immunotoxins and its potential inhibition with nonsteroidal anti-inflammatory drugs. Clinical cancer research : an official journal of the American Association for Cancer Research 1997, 3(3):339-345.  
33. Kuan CT, Pai LH, Pastan I: **Immunotoxins containing Pseudomonas exotoxin that**
target LeY damage human endothelial cells in an antibody-specific mode: relevance
to vascular leak syndrome. *Clinical cancer research : an official journal of the American* Association for Cancer Research 1995, 1(12):1589-1594.  
34. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J,
Arbuck S, Gwyther S, Mooney M *et al*: **New response evaluation criteria in solid** tumours: revised RECIST guideline (version 1.1). *European journal of cancer* 2009, 45(2):228-247.  
35. Byrne MJ, Nowak AK: Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2004, 15(2):257-260.  
36. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA,
Higano C, Bubley GJ, Dreicer R *et al*: **Design and end points of clinical trials for patients** with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008, 26(7):1148-1159.  
37. Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, Eisenhauer E, Sagae S, Greven K, Vergote I *et al*: **Re: New guidelines to evaluate the response to** treatment in solid tumors (ovarian cancer). *Journal of the National Cancer Institute* 2004, 96(6):487-488.  
38. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD,
Freidlin B, Halabi S, Hudes G *et al*: **Eligibility and response guidelines for phase II** clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. *Journal of clinical oncology : official* journal of the American Society of Clinical Oncology 1999, 17(11):3461-3467.  
39. Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK,
Friedlander M, Jakobsen A, Vermorken JB: **Re: new guidelines to evaluate the response** to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. Journal of the National Cancer Institute 2000, 92(18):1534-1535.  
40. European Medicines Agency, Committee for Medicinal Products for Human Use
(CHMP). Summary of opinion - ABRAXANE (available online at: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/11/W C500155476.pdf ).
untitled h1
16 appendices

| ECOG Performance Status Scale                                                                          | Karnofsky Performance Scale                                                                                            |            |                                                                    |           |                                 |                                   |
|--------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|------------|--------------------------------------------------------------------|-----------|---------------------------------|-----------------------------------|
| Grade                                                                                                  | Descriptions                                                                                                           | Percent    | Description                                                        |           |                                 |                                   |
| 100                                                                                                    | Normal,                                                                                                                | no         | complaints,                                                        | no        |                                 |                                   |
| Normal activity. Fully active, able                                                                    | evidence of disease.                                                                                                   |            |                                                                    |           |                                 |                                   |
| 0                                                                                                      | to                                                                                                                     | carry      | on                                                                 | all       | pre-disease                     | Able to carry on normal activity; |
| performance without restriction.                                                                       | 90                                                                                                                     | minor      | signs                                                              | or        | symptoms                        | of                                |
| disease.                                                                                               |                                                                                                                        |            |                                                                    |           |                                 |                                   |
| 80                                                                                                     | Normal activity with effort; some  signs or symptoms of disease.                                                       |            |                                                                    |           |                                 |                                   |
| 1                                                                                                      | Symptoms,                                                                                                              | but        | ambulatory.                                                        |           |                                 |                                   |
| Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or | Cares for self, unable to carry on                                                                                     |            |                                                                    |           |                                 |                                   |
| sedentary                                                                                              | nature                                                                                                                 | (e.g.,     | light                                                              | 70        | normal activity or to do active |                                   |
| housework, office work).                                                                               | work.                                                                                                                  |            |                                                                    |           |                                 |                                   |
| In                                                                                                     | bed                                                                                                                    | <50%       | of                                                                 | the       | time.                           | Requires occasional assistance,   |
| 60                                                                                                     | but is able to care for most of                                                                                        |            |                                                                    |           |                                 |                                   |
| Ambulatory and capable of all                                                                          | his/her needs.                                                                                                         |            |                                                                    |           |                                 |                                   |
| 2                                                                                                      | self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                  | 50         | Requires considerable assistance  and frequent medical care.       |           |                                 |                                   |
| 40                                                                                                     | Disabled, requires special care  and assistance.                                                                       |            |                                                                    |           |                                 |                                   |
| 3                                                                                                      | In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours. | 30         | Severely disabled, hospitalization  indicated. Death not imminent. |           |                                 |                                   |
| 20                                                                                                     | Very                                                                                                                   | sick,      | hospitalization                                                    |           |                                 |                                   |
| indicated. Death not imminent.                                                                         |                                                                                                                        |            |                                                                    |           |                                 |                                   |
| 4                                                                                                      | 100%                                                                                                                   | bedridden. | Completely                                                         |           |                                 |                                   |
| disabled.                                                                                              | Cannot carry on any                                                                                                    |            |                                                                    |           |                                 |                                   |
| self-care. Totally confined to bed  or chair.                                                          | 10                                                                                                                     | Moribund,  | fatal                                                              | processes |                                 |                                   |
| progressing rapidly.                                                                                   |                                                                                                                        |            |                                                                    |           |                                 |                                   |
| 5                                                                                                      | Dead.                                                                                                                  | 0          | Dead.                                                              |           |                                 |                                   |
untitled h1
version date 02/16/2021

16.2 APPENDIX B - COCKCROFT-GAULT FORMULA FOR CALCULATION OF CREATININE  
CLEARANCE
A commonly used surrogate marker for actual creatinine clearance is the Cockroft-Gault formula, which employs creatinine measurements and a patient's weight to predict the clearance. The formula, as originally published, is
(140 - age) × weight r =
untitled h1
72 x creatinine

This formula expects weight (actually mass) to be measured in kilograms and creatinine to be measured in mg/dL, as is standard in the USA. The resulting value is multiplied by a constant of 0.85 if the patient is female. This formula is useful because the calculations are relatively simple and can often be performed without the aid of a calculator.  
A modification of this formula, useful for the common units of measure, is:
(140 - age) × weight × constant r =
creatinine This formula uses metric units (weight in kilograms, creatinine in um ol/L). The constant is 1.23 for men and 1.04 for women.