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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 IRB notification and an executed MTA.
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5.3.1 clinical pharmacology program

Upon arrival in the Clinical Pharmacology Program (CPP), OCD, CCR, NCI, all samples are barcoded, with data entered and stored in Patient Sample Data Management System (PSDMS), also known as *Labrador*, the system utilized by the CPP. This is a secure program, with access to the PSDMS system limited to defined CPP personnel, who are issued individual user accounts. PSDMS creates a unique barcode ID for every sample and sample box, which cannot be traced back to patients without PSDMS 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. There are patient demographics that can be obtained to correlate with the samples through PSDMS. 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. Samples will be stored until requested by the researcher assigned to the protocol. All requests are monitored and tracked in PSDMS. All researchers are required to sign a form stating that the samples are only to be used for research purposes associated with this trial (as per IRB approved protocol) and that any unused samples must be returned to the CPP. Following completion of this study, samples will remain in storage as detailed above. Access to these samples will only be granted following IRB approval of an additional protocol, granting the rights to use the material.
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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 de-identified of personal data, with access 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 -70qC 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 termination of this protocol, samples will remain in storage as detailed above. Access to these samples will only be granted following IRB approval of an additional protocol or an exemption from IRB approval, 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), and reported as such to the IRB.
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5.3.3 laboratory of jane trepel

Samples will be processed immediately by the Trepel laboratory. Biospecimens will be collected and processed using validated SOPs that will ensure both specimen quality and patient confidentiality. Using a computerized inventory system and a backup hardcopy process, all specimen collection and processing steps will be documented and the specific location of each specimen will be tracked. Each new specimen collected will be assigned a unique barcode identifier that can be linked to the original specimen collected and other relevant information within the inventory system. Specimen labels will indicate: protocol number, order in which the patient enrolled on the trial, type of sample, collection time, and total volume collected, as appropriate. The inventory process contains other security provisions sufficient to safeguard patient privacy and confidentiality. Access to the inventory system and associated documents will be restricted to appropriate individuals. Requests to use specimens stored in the repository must be approved. SOPs ensure that any changes in informed consent made by a patient and relayed to the PI will be reflected in the inventory system to ensure that specimens are destroyed as appropriate. All laboratory personnel will be trained to adhere to SOPs and will be monitored for high-quality performance.
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5.3.4 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 participant consent or an exemption from OHSRP. The PI will report any loss or destruction of samples to the NIH Intramural IRB as soon as he/she is made aware of such loss. The PI will report destroyed samples to the IRB if samples become unsalvageable because of environmental factors such as a broken freezer or lack of dry ice in a shipping container, or if a participant withdraws consent. Samples will also be reported as lost if they are lost in transit between facilities or misplaced by a researcher. Freezer problems, lost samples, or other problems associated with samples will also be reported to the IRB, the NCI Clinical Director, and the office of the CCR, NCI.
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5.4 samples for genetic analysis

Pharmacogenetic studies will be performed on this protocol as described in section 5.1.3 and samples will be stored and secured as described in section 5.3.1. Because the analysis is limited to genes that play a role in drug metabolism, none of which are currently associated with disease causing genes, incidental findings will not be returned on this study.
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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. Patients will be followed for adverse events for 30 days after removal from study treatment or until offstudy, whichever comes first. Adverse events occurring more than 30 days after the last dose of study therapy are only required to be recorded only if they are considered to be serious and related to the investigational agent/intervention. An abnormal laboratory value will be recorded in the database as an AE **only** if the laboratory abnormality is characterized by any of the following:
x Results in discontinuation from the study x Is associated with clinical signs or symptoms x Requires treatment or any other therapeutic intervention x Is associated with death or another serious adverse event, including hospitalization. x Is judged by the Investigator to be of significant clinical impact  
x 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, the IRB will be notified.
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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.
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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.
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when will the data be

_X_ Before publication. _X_ At the time of publication or shortly thereafter. 6.2.2 *Genomic Data Sharing Plan* The SNP arrays utilized on this study (DMET chip) cover approximately 2000 genes, which are not defined as large scale genomic data under the GDS policy.
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6.3 response criteria

For the purposes of this study, participants should be re-evaluated following cycle 2, then every 6 weeks (+/- 2 weeks) until disease progression. 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, using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).[43]
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 patients with pleural mesothelioma, modified RECIST criteria will be used to assess response. ORR, DCR and PFS measured according to these criteria will be reported as exploratory objectives. 6.3.1 *Definitions* Evaluable for toxicity: All participants will be evaluable for toxicity from the time of their first treatment with LMB-100. The dose determining population will consist of all participants evaluable for DLT. Participants are evaluable for DLT if they are evaluable for toxicity and discontinued earlier due to DLT or completed the DLT observation period the first cycle during phase I and have undergone safety evaluations. Evaluable for pharmacokinetic analysis: All participants that are evaluable for toxicity will be included in the PK analysis population. Participants 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 participants 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 participants will have their response classified according to the definitions stated below. (Note: Participants who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response: Participants 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 nontarget disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions. 6.3.2 *All Diseases except pleural mesothelioma* 6.3.2.1 Disease Parameters Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as:
x By chest x-ray: >20 mm;  
x By CT scan:
o Scan slice thickness 5 mm or under: as >10 mm o Scan slice thickness >5 mm: double the slice thickness x 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 participant, 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 t10 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.[44-46] 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.[47]
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 1.1 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 participant 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 participant's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| Target    | Non-Target             | New     | Overall                                           | Best Overall Response when   |
|-----------|------------------------|---------|---------------------------------------------------|------------------------------|
| Lesions   | Lesions                | Lesions | Response                                          | Confirmation is Required*    |
| CR        | CR                     | No      | CR                                                | >4 wks. Confirmation**       |
| CR        | Non                        |         |                                                   |                              |
| CR/Non-PD | No                     | PR      |                                                   |                              |
| CR        | Not                    | No      | PR                                                |                              |
| evaluated | >4 wks. Confirmation** |         |                                                   |                              |
| PR        | Non                        |         |                                                   |                              |
| CR/NonPD/not  evaluated           | No                     | PR      |                                                   |                              |
| SD        | Non                        |         |                                                   |                              |
| CR/NonPD/not  evaluated           | No                     | SD      | Documented at least once >4  wks. from baseline** |                              |
| PD        | Any                    | Yes or  | PD                                                |                              |
| No        |                        |         |                                                   |                              |
| Any       | PD***                  | Yes or  | no prior SD, PR or CR                             |                              |
| PD        |                        |         |                                                   |                              |
| No        |                        |         |                                                   |                              |
| Any       | Any                    | Yes     | PD                                                |                              |  
| Target   | Non-Target                                                                                                                                                                                                                                                                                                                       | New     | Overall   | Best Overall Response when   |
|----------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|-----------|------------------------------|
| Lesions  | Lesions                                                                                                                                                                                                                                                                                                                          | Lesions | Response  | Confirmation is Required*    |
| *        | 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:    | Participants 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*     |
| Not all evaluated                                                                                                                                                                                                                              | No            | not evaluated      |
| Unequivocal PD                                                                                                                                                                                                                                 | Yes or No     | PD                 |
| Any                                                                                                                                                                                                                                            | Yes           | PD                 |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is increasingly used as  an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be  measured is not advised |               |                    |
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6.3.3 pleural mesothelioma

Malignant pleural mesothelioma (MPM) lesions are difficult to measure reliably.[48] 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
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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 x Complete Response (CR): Disappearance of all target lesions with no evidence of tumor elsewhere.  
x Partial Response (PR): At least a 30% decrease in the total tumor measurement  
89 x Confirmed response (PR and CR): require a repeat scan at least 4 weeks apart x 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).  
x 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.
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6.3.4 duration of response

Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements. 6.3.5 *Progression-Free Survival* Progression free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
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6.3.6 objective response rate

Objective response rate (ORR) is defined as the proportion of participants with partial response or complete response. 6.3.7 *Disease Control Rate* Disease control rate (DCR) is defined as the proportion of participants with stable disease, partial response or complete response
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6.4 toxicity criteria

The following adverse event management guidelines are intended to ensure the safety of each participant 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).
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7 safety reporting requirements/data and

Any untoward medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject's participation in research, whether or not considered related to the subject's participation in the research.
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7.1.2 suspected adverse reaction

Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 'reasonable possibility' means there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.
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7.1.3 unexpected adverse reaction

An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application. "Unexpected" also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.
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7.1.4 serious

An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious Adverse Event or if it compromises the safety, welfare or rights of subjects or others.
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7.1.5 serious adverse event

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator, it results in any of the following:
x Death,  
x A life-threatening adverse drug experience
x Inpatient hospitalization or prolongation of existing hospitalizationPersistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
x A congenital anomaly/birth defect. x 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 participant or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
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7.1.6 disability

A substantial disruption of a person's ability to conduct normal life functions.
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7.1.7 life-threatening adverse drug experience

Any adverse event or suspected adverse reaction that places the participant or subject, in the view of the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death. 7.1.8 *Protocol Deviation (NIH Definition)* Any change, divergence, or departure from the IRB-approved research protocol. 7.1.9 *Non-compliance (NIH Definition)* The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, IRB requirements, or regulatory requirements for the protection of human research subjects. 7.1.10 *Unanticipated Problem* Any incident, experience, or outcome that:
x Is unexpected in terms of nature, severity, or frequency in relation to
(a) the research risks that are described in the IRB-approved research protocol and informed consent document; Investigator's Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND
x Is related or possibly related to participation in the research; AND  
x Suggests that the research places subjects or others at a *greater risk of harm* (including physical, psychological, economic, or social harm) than was previously known or recognized.
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7.2 nih intramural irb and

7.2.1 *NIH Intramural IRB and NCI CD Expedited Reporting of Unanticipated Problems and* Deaths
The Protocol PI will report on the NIH Problem Form to the NIH Intramural IRB and NCI Clinical Director:
x All deaths, except deaths due to progressive disease x All Protocol Deviations  
x All Unanticipated Problems x All non-compliance
Reports must be received within 7 days of PI awareness via iRIS. 7.2.2 *NIH Intramural IRB Requirements for PI Reporting at Continuing Review* The protocol PI will report to the NIH Intramural IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation occurred, a brief description of the deviation and any corrective action.  
2. A summary of any instances of non-compliance 3. A tabular summary of the following adverse events:
x All Grade 2 **unexpected** events that are possibly, probably or definitely related to the research; x All Grade 3 and 4 events that are possibly, probably or definitely related to the research; x All Grade 5 events regardless of attribution; x All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.2.3 *NIH Intramural IRB Reporting of IND Safety Reports* Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to the NIH Intramural IRB.
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7.3 ind sponsor reporting criteria

Starting from the initiation of study therapy and continuing through the first 30 days after the subject receives the last administration of the investigational agent/intervention, the investigator must immediately report to the sponsor, using the mandatory MedWatch form 3500a or equivalent, any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event. For events that occur more than 30 days after the last administration of investigational agent/intervention, only report serious adverse events that have an attribution of at least possibly related to the agent/intervention. Required timing for reporting per the above guideline:  
x Deaths (except death due to progressive disease) must be reported via email within 24 hours. A complete report must be submitted within one business day.  
x Other serious adverse events as well as deaths due to progressive disease must be reported within one business day
Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov and to the CCR PI and study coordinator.
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7.3.1 reporting pregnancy 7.3.1.1 maternal

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. The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy agents (s) should be documented in box B5 of the MedWatch form "Describe Event or Problem". Pregnancy itself is not regarded as an SAE. However, as patients who become pregnant on study risk intrauterine exposure of the fetus to agents which may be teratogenic, the CCR is requesting that pregnancy should be reported in an expedited manner as Grade 3 "*Pregnancy, puerperium* and perinatal conditions - *Other (pregnancy*)" under the Pregnancy, puerperium and perinatal conditions SOC.  
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and handled as SAEs. Elective abortions without complications should not be handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented. If any pregnancy occurs in the course of the study, then the investigator should inform the Sponsor within 1 day, i.e., immediately, but **no later than 24 hours** of when he or she becomes aware of it. The designated Sponsor representative will work with the investigator to ensure that all relevant information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days for all other pregnancies. The same timelines apply when outcome information is available.
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7.3.1.2 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 nab-paclitaxel. 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 3 months after the last dose should, if possible, be followed up and documented.
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7.4 data and safety monitoring

The clinical research team will meet on a regular basis when participants are being actively treated on the trial to discuss each participant. Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior participants. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Adverse events will be reported as required above. Any safety concerns, new information that might affect either the ethical and or scientific conduct of the trial, or protocol deviations will be immediately reported to the IRB using iRIS. The principal investigator will review adverse event and response data on each participant 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.
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7.4.2 sponsor 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 study endpoints; adherence to the protocol, regulations, and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on:
x Informed consent process x Eligibility confirmation  
x Drug administration and accountability x Adverse events monitoring x Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating center. This trial will be monitored by personnel employed by an NCI 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. Safety Monitoring Committee (SMC)
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7.4.3 safety monitoring committee

This protocol will require oversight from the Safety Monitoring Committee (SMC). Initial review will occur as soon as possible after the annual NIH Intramural IRB continuing review date.  
Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more frequently as may be required by the SMC. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within the review period. Written outcome letters will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
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8 statistical considerations 8.1 primary

1) determine the MTD of LMB-100 in combination with chemotherapy (NAB-paclitaxel) in participants with advanced pancreatic cancer both as a short infusion and as a continuous infusion 2) determine the response rate of the combination as a short infusion
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8.1.1 part a

Arm A1 - Phase I. Part A begins with a two dose level escalation using a 3 + 3 design with LMB100 potentially evaluated at 100, and 140 mcg/kg in combination with chemotherapy. A lower dose of 65 mcg/kg may also be evaluated. If both intended dose levels are explored and each requires up to 6 participants, then up to 12 participants may be required for the phase I portion of the trial. Note: Subjects enrolled prior to Amendment C (n=3) in which the maximum number of cycles was reduced, are included in the MTD evaluation as they have received at least 1 cycle of LMB-100. After the enrollment of patients to the first 2 dose levels the pharmacokinetic and anti-drug antibody level (ADA) data will be analyzed before enrolling new patients. Dr. William Figg, who has expertise in pharmacokinetics, will, in conjunction with the NCI CCR leadership committee analyze the data. Since the thresholds for ADA and its influence on pharmacokinetics are unclear, pre-specified criteria for making changes to the protocol cannot be established at this time. The objective of the assessment will be 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. Arm A2 -Phase II portion of Part A. In Arm A2 we will evaluate the combination identified as being the MTD from Arm A1. As of 5/1/18, this is anticipated to be at dose level -1. If dose level -1 is not found to be same during Arm A1, we will not proceed to Arm A2. If Arm A2 does proceed, since the participants to be treated on the phase II portion will have the same eligibility criteria as those on phase I, the 6 participants treated at 65 mcg/kg (the anticipated RP2D from Arm A1) will be the 6 initial participants treated on the first stage of the phase II cohort. Based upon results from two small trials of NAB-paclitaxel treatment beyond the first-line setting, the response rate of participants with advanced pancreatic cancer to NAB-paclitaxel is at most 5%.[49, 50] It would be desirable if this were improved by 15-20% or more. As such, the goal would be to determine if using the combination would rule out a 5% response rate to target a rate of 25%. The trial will be conducted using a Simon Minimax two-stage phase II trial design[51] in order to rule out an unacceptably low PR+CR rate of 5% (p0 = 0.05) in favor of an improved response rate of 25% (p1 = 0.25). With α = 0.10 (probability of accepting a poor treatment = 0.10) and β = 0.10 (probability of rejecting a good treatment = 0.10). This first stage will enroll 13 evaluable participants, and if 0 of the 13 have a clinical response, then no further participants will be accrued. If 1or more of the first 13 participants has a response, then accrual would continue until a total of 20 evaluable participants have been enrolled. As it may take up to several months to determine if a participant has experienced a response, a temporary pause in the accrual may be necessary to ensure that enrollment to the second stage is warranted. If there are 1 to 2 participants with a response out of 20 participants, this would be an uninterestingly low response rate. If there were 3 or more of 20 (15%) who experienced a response, this would be sufficiently interesting to warrant further study in later trials. Under the null hypothesis (5% response rate), the probability of early termination is 51%.
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8.1.2 part b

Arm B1 -Phase I, Continuous Infusion Single Agent Lead-In. While patients who are eligible for enrollment into Part A are being treated on Part A, patients who have pancreatic cancer who do not meet eligibility criteria for nab-paclitaxel and patients with other MSLN-expressing solid tumors will be enrolled onto Part B Single Agent Lead-in. This portion of the trial has dose finding using a 3 + 3 design with LMB-100 alone as a continuous infusion, potentially evaluated at doses of 65, 100, 140 and 200 mcg/kg/day over 24, 24 *2, 48, 72 and 96 hours using a flexible escalation scheme. This will establish the single agent MTD for continuous infusion. Enrollment in this arm has been capped at a maximum of 30 participants being treated. If each dose level requires all 6 participants, then five dose levels may be examined. After the first 3 patients were enrolled, the pharmacokinetic data were analyzed before enrolling new patients. Dr. William Figg, who has expertise in pharmacokinetics, in conjunction with the NCI CCR leadership committee analyzed the data. The objective of the assessment was to make recommendations as to whether drug levels near that projected by the simulation can be achieved (feasibility, safety) and what, if any adjustments should be made with regard to the dose escalation and/ or study plan. The first assessment completed just prior to the implementation of Amendment F. leading to the new dose escalation plan and the addition of a bolus dose submitted in Amendment F. Similar assessments will continue at the completion of each dose level. Arm B2 - **Continuous Infusion, Combination therapy:** After the Part B Single Agent Lead-in is completed, assessment of continuous infusion of LMB-100 in combination with chemotherapy will be tested in the same population of pancreatic cancer patients enrolling in Part A. A single dose level of LMB-100 will be assessed in combination with chemotherapy in Phase I Part B. This will require a maximum of 6 additional evaluable patients. If safety and tolerability of this combination is established in these 6 patients, then an additional 4 patients will be enrolled (total of 10 patients) to complete a small pilot investigation of the response rate of the combination of continuous infusion LMB-100 and Nab-paclitaxel. This is being kept deliberately small to permit more rapid assessment of any evidence of efficacy. These 10 patients' clinical responses will be reported along with an appropriate confidence interval, and will be used to characterize the potential clinical efficacy of the combination. Therefore, 10 total participants with pancreatic cancer will be required to complete Phase I and pilot investigation of response rate. At the conclusion of the trial, the response information from the phase II portion of Part A and the pilot in Part B will be used to identify parameters which may merit further exploration in a more definitive subsequent trial.
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8.2 determination of sample size

Part A: the phase I portion of the trial may require up to 12 participants, and the phase II portion, if explored, may require up to 20 evaluable participants. However, with 6 participants from phase I potentially being included in phase II, up to 12+20-6=26 individual participants may be required. Part B: The lead-in with single agent continuous LMB-100 may require up to 30 patients. Evaluation of the combination with nab-paclitaxel will require 10 patients if the combination is deemed safe and feasible. Therefore, up to 40 patients may be required. Candidates for the phase 1 lead in portion of the study will be screened on the current protocol. With an anticipated screen failure rate of 50%, up to 30/0.5 = 60 subjects may need to enroll to this portion of the study. With an additional 26 subjects required in part A (phase I and II) and 10 subjects in the combination therapy portion of Part B, the overall accrual ceiling will be set at 100 (26+60+10 +4 = 100 in order to allow for a small number of inevaluable participants). If 1-2 eligible pancreatic cancer patients enroll per month and 2-3 patients with other MSLN-expressing tumor types enroll on this trial, accrual would be expected to be completed in approximately 3 to 5 years if the second stage of Phase II Part A is reached.
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9 human subjects protections 9.1

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 in advanced/metastatic PDA and in mesothelin expressing solid tumors is to preliminarily assess the safety of LMB-100 alone or in combination with the standard of care (SoC) chemotherapy nab-paclitaxel and We will also assess the preliminary anti-tumor activity of LMB-100 in PDA.
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9.2 participation of children

As this is a first in human study, there are no dosing or adverse event data are currently available on the use of LMB-100 in combination with nab-paclitaxel in participants <18 years of age; therefore, children are excluded from this study.
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9.3 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 9.5), 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 MAS Policy 87-4 and 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.
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9.4 evaluation of benefits and

Participant safety will be managed by careful proactive participant selection prior to study to exclude participants at risk from study treatment due to their pre-existing conditions. During the study, safety of participants 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 agents as discussed in section 10. Additional risks may also be encountered from the use of the agents in combination as discussed below.
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9.4.1.1 potential toxicities of combining

The most common clinically significant adverse reactions associated with the use of *nab-*paclitaxel have been neutropenia, peripheral neuropathy, arthralgia/myalgia, and gastrointestinal disorders.  
In the *nab-*paclitaxel treated population, the most frequently (t40% of participants) reported treatment emergent adverse events (TEAEs) were fatigue, nausea, peripheral neuropathy, alopecia, peripheral edema, diarrhea, anemia, neutropenia, and pyrexia. The most frequently reported Grade 3 or higher TEAEs in the *nab-*paclitaxel arm were neutropenia, fatigue, peripheral neuropathy, thrombocytopenia, and anemia.
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9.4.2 risks of study procedures

Study procedures such as research blood collection and ECGs are of minimal risk to the subject. Higher risk procedures performed include:
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9.4.2.1 ct guided research biopsy

The risks of the optional research biopsy collected in cycle 2 include pain, bleeding and infection at the biopsy site. In addition, as the biopsy may be collected under CT guidance, subjects in this study may be exposed to approximately 0.77 rem. This amount is below the guideline of 5 rem per year allowed for adult research subjects by the NIH Radiation Safety Committee. 9.4.2.2 Central Line Insertion All subjects in Arms B1 and B2 are required to receive study therapy through a central line or an existing mediport. In addition, per PI discretion, some subjects in Arms A1 and A2 may also require central line insertion. The risks of this procedure include catheter contamination, pneumothorax, arrhythmia and air embolus. All care will be taken to minimize complications of central insertion during the procedure.
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9.5 risks/benefits analysis

Patients with advanced and/or metastatic cancer are in continuous need of improved therapy options. This is especially true for patients where no standard therapy exists such as the 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 even more so when LMB-100 has been combined with chemotherapy. Therefore, LMB-100 may improve clinical outcome of patients with pancreatic ductal adenocarcinoma in combination with *nab-*paclitaxel, an approved agent in advanced/metastatic PDA as well as the outcome of patients with mesothelin positive solid tumors receiving LMB-100 monotherapy. A number of clinically appropriate strategies to minimize risk to participants have been built into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, and management guidelines. Overall, the potential benefits of LMB-100 for cancer participants, those able to consent and those who lose the capacity to do so during the course of the trial, outweigh the risks associated with the proposed entry-into-human trial with LMB-100.
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9.6 consent and assent process

All participants will be thoroughly screened by the physician and the research nurse prior to completing the consent. During the initial consultation, the participant 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 participant and they are asked to review it, make notes and ask questions prior to agreeing to participate in this protocol. The participant 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 participant 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. Consent for optional biopsy will be obtained at the time of the procedure. If the patient refuses the optional biopsy at that time, the refusal will be documented in the medical record and in the research record. The Informed Consent document may be obtained from the participant by the principal investigator, associate investigators, or the medical staff fellow under the supervision of the principal investigator. 9.6.1 *Consent procedure for non-English speaking patients* If there is an unexpected enrollment of a research participant for whom there is no translated extant IRB approved consent document, the principal investigator and/or those authorized to obtain informed consent will use the Short Form Oral Consent Process as described in MAS Policy M772, OHSRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2). The summary that will be used is the English version of the extant IRB approved consent document. Signed copies of both the English version of the consent and the translated short form will be given to the subject or their legally authorized representative and the signed original will be filed in the medical record. Unless the PI is fluent in the prospective subject's language, an interpreter will be present to facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a family member) will assist in presenting information and obtaining consent. Whenever possible, interpreters will be provided copies of the relevant consent documents well before the consent conversation with the subject (24 to 48 hours if possible). We request prospective IRB approval of the use of the short form process and will notify the IRB at the time of continuing review of the frequency of the use of the Short Form.
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9.6.2 telephone consent procedure

Consent for screening and re-consent on this study may be obtained via telephone according to the following procedure: the informed consent document will be sent to the subject. An explanation of the study will be provided over the telephone after the subject has had the opportunity to read the consent form. The subject will sign and date the informed consent. A witness to the subject's signature will sign and date the consent. The original informed consent document will be sent back to the consenting investigator who will sign and date the consent form with the date the consent was obtained via telephone. A fully executed copy will be returned via mail for the subject's records. The informed consent process will be documented on a progress note by the consenting investigator.
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10 pharmaceutical information

Nab-paclitaxel is approved for use as a first line agent in metastatic pancreatic cancer. It is not approved for use as a second line agent, the use in the current protocol. The investigation is not intended to support a new indication for use or any other significant changes to labeling or advertising in any of the commercial agents used on the study. The investigation does not involve a route of administration or dosage level in use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug products.
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10.1 lmb-100 (ind # 123332)

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.
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10.1.2 toxicity

Information in this section is based on preclinical studies with LMB-100, and clinical studies of the cytolytic fusion protein SS1-P. Participants 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 d2 hematological toxicities or Grade d1 non-hematological toxicities. A delay of LMB-100 administration for up to two weeks of the planned schedule will be acceptable to allow for resolution of toxicity to NCI CTCAE Grade d2 hematological toxicities or Grade d1 nonhematological toxicities. If toxicity does not resolve to NCI CTCAE Grade d2 hematological toxicities or Grade d1 non-hematological toxicities and the participant is unable to resume treatment with LMB-100 after this time, no additional doses will be administered and the participant will be withdrawn from study treatment. 10.1.2.1 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. Participants may also develop IgE-mediated hypersensitivity reactions to LMB-100. IRRs may be indistinguishable from an anaphylactic reaction. Participants should receive full supportive care to treat IRRs or anaphylaxis according to institutional practice. If infusion-associated signs or symptoms occur, participants should be monitored until complete resolution. In vitro data and previous clinical experience with LMB-100 suggest that the risk for the release of pro-inflammatory cytokines upon first administration of LMB-100 to humans is low (human whole blood assay, see section 1.2.4.1.4). 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. 10.1.2.2 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 participants after 1 cycle of therapy, in the IV bolus and continuous infusion trials respectively.[31]
Participants 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. 10.1.2.3 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. Participants who develop symptoms of serosal inflammation should be closely monitored and receive standard treatments which may include corticosteroids. 10.1.2.4 Risk of Vascular Leak Syndrome LMB-100 administration may cause VLS characterized by hypotension, hypoalbuminemia, edema, weight gain, and hemoconcentration. Clinical trials with SS1P monotherapy have led to the development of reversible VLS. Participants will be monitored with frequent assessments of chest x-rays, weight, edema, blood pressure, and serum albumin levels prior to and during treatment. Participants who develop symptoms of VLS should be closely monitored and receive standard symptomatic treatments.
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10.1.2.5 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. Participants should be monitored with renal laboratory assessments including creatinine, BUN, and urinalysis.
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10.1.2.6 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. Participants who develop symptoms of infusion site reactions can be administered pain relieving medication (analgesic) as required, and rotation of infusion sites is recommended.
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10.1.2.7 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.
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10.1.3 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.
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10.1.4 stability and storage

Chemical and physical in-use stability for undiluted LMB100 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 2-8qC, but syringes may be held at room temperature for up to a maximum of 4 hours. Roche has extensively studied the stability of LMB-100. Vials of LMB-100 can be stored at 4°C for at least 24 months without loss of activity or degradation of the drug product. At 25°C, no loss of activity is observed over a 4week period, and 94% of potency is retained even after 3 months of exposure to this temperature (Figure 9). However, when vials of LMB-100 are exposed to temperatures of 37°C, the drug begins to lose activity within 12 hours. 10.1.5 *Administration procedures* Please refer to section 3.2.1  
  
10.1.6 *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. 10.1.6.1 Mechanism of action LMB-100 is a novel recombinant anti-mesothelin targeted cytolytic fusion protein (cFP) developed for the treatment of participants 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. 10.1.6.2 Molecular Weight: approximately 73 kDa  
 10.1.6.3 Chemical Structure
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10.2 nab-paclitaxel

Please refer to package insert for additional information. 10.2.1 *Source* Nab-paclitaxel will be purchased from commercial sources by the NIH CC Pharmacy.
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10.2.2 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.[52] 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.  
10.2.3 *Formulation and preparation*
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formulation

ABRAXANE is supplied as a lyophilized powder containing 100 mg of paclitaxel formulated as albumin-bound particles in single-use vial for reconstitution.
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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. 10.2.4 *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.
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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.
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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...  
10.2.5 *Administration procedures* Please see section 3.2.2. 10.2.6 *Incompatibilities* Please refer to the package insert.
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11 references

1. Siegel R, Naishadham D, Jemal A: **Cancer statistics, 2012**. CA: a cancer journal for clinicians 2012, 62(1):10-29.  
2. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C *et al*: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. *The New England journal of medicine* 2011, 364(19):1817-1825.  
3. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN *et al*: **Increased survival in pancreatic cancer with nabpaclitaxel plus gemcitabine**. *The New England journal of medicine* 2013, 369(18):16911703.  
4. Zhang Y, Hochster H, Stein S, Lacy J: Gemcitabine plus nab-paclitaxel for advanced pancreatic cancer after first-line FOLFIRINOX: single institution retrospective review of efficacy and toxicity. *Experimental hematology & oncology* 2015, 4:29.  
5. Portal A, Pernot S, Tougeron D, Arbaud C, Bidault AT, de la Fouchardiere C, Hammel P,
Lecomte T, Dreanic J, Coriat R *et al*: **Nab-paclitaxel plus gemcitabine for metastatic** pancreatic adenocarcinoma after Folfirinox failure: an AGEO prospective multicentre cohort. *British journal of cancer* 2015, 113(7):989-995.  
6. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P,
Walde D, Wolff RA *et al*: **Erlotinib plus gemcitabine compared with gemcitabine alone** in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. *Journal of clinical oncology : official journal* of the American Society of Clinical Oncology 2007, 25(15):1960-1966.  
7. Rahma OE, Duffy A, Liewehr DJ, Steinberg SM, Greten TF: Second-line treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials. Annals of oncology : official journal of the European Society for Medical Oncology /
ESMO 2013, 24(8):1972-1979.  
8. Einama T, Kamachi H, Nishihara H, Homma S, Kanno H, Takahashi K, Sasaki A, Tahara M, Okada K, Muraoka S *et al*: **Co-expression of mesothelin and CA125 correlates with** unfavorable patient outcome in pancreatic ductal adenocarcinoma. *Pancreas* 2011, 40(8):1276-1282.  
9. Hassan R, Laszik ZG, Lerner M, Raffeld M, Postier R, Brackett D: **Mesothelin is**
overexpressed in pancreaticobiliary adenocarcinomas but not in normal pancreas and chronic pancreatitis. *American journal of clinical pathology* 2005, 124(6):838-845.  
10. Scales SJ, Gupta N, Pacheco G, Firestein R, French DM, Koeppen H, Rangell L, BarryHamilton V, Luis E, Chuh J *et al*: An antimesothelin-monomethyl auristatin e conjugate with potent antitumor activity in ovarian, pancreatic, and mesothelioma models. Molecular cancer therapeutics 2014, 13(11):2630-2640.  
11. Stromnes IM, Schmitt TM, Hulbert A, Brockenbrough JS, Nguyen HN, Cuevas C, Dotson AM, Tan X, Hotes JL, Greenberg PD *et al*: T Cells Engineered against a Native Antigen Can Surmount Immunologic and Physical Barriers to Treat Pancreatic Ductal Adenocarcinoma. *Cancer cell* 2015, 28(5):638-652.
12. Maitra A, Adsay NV, Argani P, Iacobuzio-Donahue C, De Marzo A, Cameron JL, Yeo CJ,
Hruban RH: **Multicomponent analysis of the pancreatic adenocarcinoma progression** model using a pancreatic intraepithelial neoplasia tissue microarray. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2003, 16(9):902-912.  
13. Winter JM, Tang LH, Klimstra DS, Brennan MF, Brody JR, Rocha FG, Jia X, Qin LX,
D'Angelica MI, DeMatteo RP *et al*: A novel survival-based tissue microarray of pancreatic cancer validates MUC1 and mesothelin as biomarkers. *PloS one* 2012, 7(7):e40157.
14. Cheng WF, Huang CY, Chang MC, Hu YH, Chiang YC, Chen YL, Hsieh CY, Chen CA:
High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma. *British journal of cancer* 2009, 100(7):1144-1153.  
15. Wang L, Niu Z, Zhang L, Liu X, Wang X, Li F, Wang Y: **Clinicopathological significance**
of mesothelin expression in invasive breast cancer. The Journal of international medical research 2012, 40(3):909-916.  
16. Thomas A, Chen Y, Steinberg SM, Luo J, Pack S, Raffeld M, Abdullaev Z, Alewine C,
Rajan A, Giaccone G *et al*: **High mesothelin expression in advanced lung** adenocarcinoma is associated with KRAS mutations and a poor prognosis. *Oncotarget* 2015, 6(13):11694-11703.  
17. Nomura R, Fujii H, Abe M, Sugo H, Ishizaki Y, Kawasaki S, Hino O: Mesothelin expression is a prognostic factor in cholangiocellular carcinoma. *International surgery* 2013, 98(2):164-169.  
18. Li M, Bharadwaj U, Zhang R, Zhang S, Mu H, Fisher WE, Brunicardi FC, Chen C, Yao Q: Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer. *Molecular cancer therapeutics* 2008, 7(2):286-296.  
19. Hassan R, Thomas A, Alewine C, Le DT, Jaffee EM, Pastan I: Mesothelin Immunotherapy for Cancer: Ready for Prime Time? Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2016, 34(34):4171-4179.  
20. 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.  
21. 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.  
22. 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.  
23. Hassan R, Lerner MR, Benbrook D, Lightfoot SA, Brackett DJ, Wang QC, Pastan I:
Antitumor activity of SS(dsFv)PE38 and SS1(dsFv)PE38, recombinant antimesothelin immunotoxins against human gynecologic cancers grown in organotypic culture in vitro. Clinical cancer research : an official journal of the American Association for Cancer Research 2002, 8(11):3520-3526.  
24. Li Q, Verschraegen CF, Mendoza J, Hassan R: **Cytotoxic activity of the recombinant**
anti-mesothelin immunotoxin, SS1(dsFv)PE38, towards tumor cell lines established from ascites of patients with peritoneal mesotheliomas. *Anticancer research* 2004, 24(3a):1327-1335.  
25. Zhang J, Qiu S, Zhang Y, Merino M, Fetsch P, Avital I, Filie A, Pastan I, Hassan R: Loss of mesothelin expression by mesothelioma cells grown in vitro determines sensitivity to anti-mesothelin immunotoxin SS1P. *Anticancer research* 2012, 32(12):5151-5158.  
26. Fan D, Yano S, Shinohara H, Solorzano C, Van Arsdall M, Bucana CD, Pathak S, Kruzel E, Herbst RS, Onn A *et al*: **Targeted therapy against human lung cancer in nude mice** by high-affinity recombinant antimesothelin single-chain Fv immunotoxin. *Molecular* cancer therapeutics 2002, 1(8):595-600.
27. Zhang Y, Xiang L, Hassan R, Paik CH, Carrasquillo JA, Jang BS, Le N, Ho M, Pastan I:
Synergistic antitumor activity of taxol and immunotoxin SS1P in tumor-bearing mice. Clinical cancer research : an official journal of the American Association for Cancer Research 2006, 12(15):4695-4701.  
28. Zhang Y, Hansen JK, Xiang L, Kawa S, Onda M, Ho M, Hassan R, Pastan I: A flow cytometry method to quantitate internalized immunotoxins shows that taxol synergistically increases cellular immunotoxins uptake. *Cancer research* 2010, 70(3):1082-1089.  
29. Zhang Y, Xiang L, Hassan R, Pastan I: Immunotoxin and Taxol synergy results from a decrease in shed mesothelin levels in the extracellular space of tumors. *Proceedings of* the National Academy of Sciences of the United States of America 2007, 104(43):1709917104.  
30. Filpula D, Yang K, Basu A, Hassan R, Xiang L, Zhang Z, Wang M, Wang QC, Ho M,
Beers R *et al*: **Releasable PEGylation of mesothelin targeted immunotoxin SS1P** achieves single dosage complete regression of a human carcinoma in mice. Bioconjugate chemistry 2007, 18(3):773-784.  
31. 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 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.  
32. Pastan I: Personal communication.
33. 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.  
34. 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.  
35. 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.  
36. Ho M, Bera TK, Willingham MC, Onda M, Hassan R, FitzGerald D, Pastan I: Mesothelin expression in human lung cancer. *Clinical cancer research : an official journal of the* American Association for Cancer Research 2007, 13(5):1571-1575.  
37. Nagorsen D, Kufer P, Baeuerle PA, Bargou R: **Blinatumomab: a historical perspective**.  
Pharmacol Ther 2012, 136(3):334-342.
38. Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S, Noppeney R, Viardot A,
Hess G, Schuler M *et al*: **Tumor regression in cancer patients by very low doses of a T** cell-engaging antibody. *Science* 2008, 321(5891):974-977.  
42. 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.  
39. Benhar I, Reiter Y, Pai LH, Pastan I: Administration of disulfide-stabilized Fvimmunotoxins B1(dsFv)-PE38 and B3(dsFv)-PE38 by continuous infusion increases their efficacy in curing large tumor xenografts in nude mice. *International journal of* cancer Journal international du cancer 1995, 62(3):351-355.  
40. 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.  
41. 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.  
43. 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.  
44. 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.  
45. 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.  
46. 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.  
47. 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.  
48. 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.  
49. Peddi PF, Cho M, Wang J, Gao F, Wang-Gillam A: **Nab-paclitaxel monotherapy in**
refractory pancreatic adenocarcinoma. *Journal of gastrointestinal oncology* 2013, 4(4):370-373.
50. Hosein PJ, de Lima Lopes G, Jr., Pastorini VH, Gomez C, Macintyre J, Zayas G, Reis I,
Montero AJ, Merchan JR, Rocha Lima CM: **A phase II trial of nab-Paclitaxel as secondline therapy in patients with advanced pancreatic cancer**. *American journal of clinical* oncology 2013, 36(2):151-156.  
51. Simon R: **Optimal two-stage designs for phase II clinical trials**. *Control Clin Trials* 1989, 10(1):1-10.  
52. **European Medicines Agency, Committee for Medicinal Products for Human Use**
(CHMP). Summary of opinion - **ABRAXANE (available online at:** http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/11/W C500155476.pdf ).
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12 appendices

| 12.1                                                                                                                                                            | APPENDIX A - PERFORMANCE STATUS CRITERIA ECOG Performance Status Scale Karnofsky Performance Scale   |                                                                    |                 |           |             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|-----------------|-----------|-------------|
| Grade                                                                                                                                                           | Descriptions                                                                                         | Percent                                                            | Description     |           |             |
| 100                                                                                                                                                             | Normal,                                                                                              | no                                                                 | complaints,     | no        |             |
| evidence of disease.                                                                                                                                            |                                                                                                      |                                                                    |                 |           |             |
| Normal activity. Fully active, able                                                                                                                             |                                                                                                      |                                                                    |                 |           |             |
| 0                                                                                                                                                               | to                                                                                                   | carry                                                              | on              | all       | pre-disease |
| performance without restriction.                                                                                                                                | Able to carry on normal activity;                                                                    |                                                                    |                 |           |             |
| 90                                                                                                                                                              | minor                                                                                                | signs                                                              | or              | symptoms  | of          |
| disease.                                                                                                                                                        |                                                                                                      |                                                                    |                 |           |             |
| Symptoms,                                                                                                                                                       | but                                                                                                  | ambulatory.                                                        |                 |           |             |
| Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). | 80                                                                                                   | Normal activity with effort; some  signs or symptoms of disease.   |                 |           |             |
| 1                                                                                                                                                               | Cares for self, unable to carry on                                                                   |                                                                    |                 |           |             |
| 70                                                                                                                                                              | normal activity or to do active  work.                                                               |                                                                    |                 |           |             |
| In                                                                                                                                                              | bed                                                                                                  | <50%                                                               | of              | the       | time.       |
| Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                            | Requires occasional assistance,                                                                      |                                                                    |                 |           |             |
| 60                                                                                                                                                              | but is able to care for most of  his/her needs.                                                      |                                                                    |                 |           |             |
| 2                                                                                                                                                               | 50                                                                                                   | Requires considerable assistance  and frequent medical care.       |                 |           |             |
| 40                                                                                                                                                              | Disabled, requires special care  and assistance.                                                     |                                                                    |                 |           |             |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                          |                                                                                                      |                                                                    |                 |           |             |
| 3                                                                                                                                                               | 30                                                                                                   | Severely disabled, hospitalization  indicated. Death not imminent. |                 |           |             |
| 20                                                                                                                                                              | Very                                                                                                 | sick,                                                              | hospitalization |           |             |
| indicated. Death not imminent.                                                                                                                                  |                                                                                                      |                                                                    |                 |           |             |
| 100%                                                                                                                                                            | bedridden.                                                                                           | Completely                                                         |                 |           |             |
| disabled.                                                                                                                                                       | Cannot carry on any                                                                                  |                                                                    |                 |           |             |
| self-care. Totally confined to bed  or chair.                                                                                                                   |                                                                                                      |                                                                    |                 |           |             |
| 4                                                                                                                                                               | 10                                                                                                   | Moribund,                                                          | fatal           | processes |             |
| progressing rapidly.                                                                                                                                            |                                                                                                      |                                                                    |                 |           |             |
| 5                                                                                                                                                               | Dead.                                                                                                | 0                                                                  | Dead.           |           |             |
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12.2 a ppendix b -

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:
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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 perform ed 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 umol/L). The constant is 1.23 for men and 1.04 for women.
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12.3 appendix c sample chemotherapy

12.3.1 *For Part A* (1) Nab-paclitaxel, 125 mg/m2, IV over 30 minutes ± 10 minutes on Days 1 and 8 (2) LMB-100, <dose as per escalation scheme> mcg/kg, IV on Days 1, 3 and 5 On Day 1, administer 30 minutes ± 20 minutes following completion of Nab-paclitaxel infusion Pre-medications:
o Diphenhydramine 25-50 mg PO or IV o Ranitidine 150 mg PO o Acetaminophen 650 mg PO
Additional medications: -Dexamethasone 8 mg IV, PRN severe infusion related reaction (should be available on unit) -Ondansetron 8 mg PO q8h, PRN nausea Please encourage oral hydration of 1.5 to 2L daily while receiving LMB-100. 12.3.2 *For Arm B1* (1) Loading dose of LMB-100 LMB-100, 40 mcg/kg, IV on Day 1 and if applicable, Day 4 Continuous infusion LMB-100 to immediately following loading dose on Day 1 and if applicable, Day 4 LMB-100, <dose as per escalation scheme> mcg/kg/day IV, for \# hrs Syringes of drug must be changed q12hrs. In-line filtration required. Dose per 12 hours = <dose as per escalation scheme> / 2 = \# mcg/kg Infusion rate = <Dose per 12 hours> / 12 = \# ml/hr Run with Normal Saline at 20cc/hour IV for in-line dilution. Pre-medications on Day 1:
o Diphenhydramine 25-50 mg PO or IV
o Ranitidine 150 mg PO o Acetaminophen 650 mg PO
Additional medications: -Dexamethasone 8 mg IV, PRN severe infusion related reaction (should be available on unit) -Ondansetron 8 mg PO q8h, PRN nausea Please encourage oral hydration daily of 1.5 to 2L daily while receiving LMB-100.  
12.3.3 For Arm B2 (1) Nab-paclitaxel, 125 mg/m2, IV over 30 minutes ± 10 minutes on Days 1 (2) Loading dose of LMB-100 LMB-100, 40 mcg/kg, IV on Day 1 Continuous infusion LMB-100 to immediately following loading dose on Day 1 LMB-100, 100 mcg/kg/day IV, for 24 hrs Syringes of drug must be changed q12hrs. In-line filtration required. Dose per 12 hours = 50 mcg/kg * <patient weight> = \# mg Infusion rate = <Dose per 12 hours (mg)> / 1 mg/mL / 12 hrs = \# ml/hr Run with Normal Saline at 20cc/hour IV for in-line dilution. On Day 1, administer 30 minutes ± 20 minutes following completion of Nab-paclitaxel infusion Pre-medications:
o Diphenhydramine 25-50 mg PO or IV o Ranitidine 150 mg PO
o Acetaminophen 650 mg PO
Additional medications: -Dexamethasone 8 mg IV, PRN severe infusion related reaction (should be available on unit) -Ondansetron 8 mg PO q8h, PRN nausea Please encourage oral hydration of 1.5 to 2L daily while receiving LMB-100.