untitled h1
3.3.1 lmb-100

Table 13 below provides a guideline on how to manage certain toxicities which are expected with LMB-100 based on preclinical studies and previous clinical experience with LMB-100 and molecules in the same class.  
| Table 13 - Guidelines for Managing Specific LMB-100 Adverse Events  Event Action to Be Taken IRR/hypersensitivity reaction during  short infusion of LMB-100  If an IRR/hypersensitivity develops, the infusion of LMB-100  should be temporarily interrupted. The participant should be  monitored until complete resolution of the symptoms and treated  as clinically indicated. Treatment or concomitant medication  may include IV saline, oxygen, bronchodilators, corticosteroids,  and vasopressors depending on the symptoms.  (Arms A1 and A2)  If the short infusion is interrupted (Arms A1 or A2):  o In the event of IRR CTCAE Grade1, upon resolution of  symptoms, the infusion will resume at the same rate (the  rate being used at the time that the IRR occurred).  o In the event of IRR Grade 2 or 3, upon resolution of  symptoms, the infusion will resume at one-half the  previous rate. The infusion can be re-escalated to initial rate  if considered well tolerated after 1 hour of infusion.  o In the event of IRR CTCAE Grade 3, or CTCAE Grade 4  (which may include pulmonary or cardiac events) or an  anaphylactic reaction:  ƒ The infusion must be stopped and the participant should  receive aggressive treatment  ƒ Participants experiencing IRR CTCAE Grade 4 or  anaphylaxis must be permanently discontinued from  study treatment  For participants receiving short infusion LMB-100 who  previously experienced IRR CTCAEtGrade 2, the infusion rate  for subsequent LMB-100 infusion should be reduced to one-half  of the previous rate and corticosteroids premedication should be  given 30 minutes prior to infusion in addition to standard premedications: o Dexamethasone (20 mg PO 6 -12hrs before infusion or 8  mg IV, 30 - 60 min [+ 30 minutes] before infusion) or  equivalent dose of another corticosteroid as clinically  indicated   |
|---|  
| Event                                                                | Action to Be Taken                                                                                                                                                                                                                                                                                                                                                       |
|----------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| IRR/hypersensitivity reaction during  continuous infusion of LMB-100 | If an IRR/hypersensitivity develops, the infusion of LMB-100  should be temporarily interrupted. The participant should be  monitored until complete resolution of the symptoms and treated  as clinically indicated. Treatment or concomitant medication  may include IV saline, oxygen, bronchodilators, corticosteroids,  and vasopressors depending on the symptoms. |
| (Arms B1 and B2)                                                     | In the event of IRR CTCAE Grade 4 (which may include  pulmonary or cardiac events) or an anaphylactic reaction: ƒ The participant should receive aggressive treatment ƒ Participants experiencing IRR CTCAE Grade 4 or  anaphylaxis must be permanently discontinued from  study treatment  In the event of IRR CTCAE Grade 1, 2, 3, upon resolution of  symptoms, o If the loading dose is interrupted, the remainder of the  loading dose should be omitted and the patient should  resume with the continuous infusion.  o If the continuous infusion is interrupted: ƒ Patients should be retreated with the standard premedications if the infusion has already proceeded for 6  hours or more  ƒ The infusion will resume at the same rate  ƒ Patients should receive repeated dosing of the standard  pre-medications and dexamethasone at the intervals  specified in Section 3.2.1.4.2 Participants receiving continuous infusion LMB-100 who have  experienced IRR CTCAEtGrade 2 infusion, should receive:  o Standard pre-medications 30-60 minutes prior to start of  infusion  o Standard corticosteroids premedication should be given 30  minutes prior to subsequent infusion in addition to standard  pre-medications:  ƒ Dexamethasone (20 mg PO 6 -12hrs before infusion or 8  mg IV, 30 - 60 min [+ 30 minutes] before infusion) or  equivalent dose of another corticosteroid as clinically  indicated  o Repeated dosing of standard pre-medications and  dexamethasone at the following intervals:  ƒ Dexamethasone, q12 hours  ƒ Diphenhydramine, q6 hours  ƒ Acetaminophen, q12 hours                                                                                                                                                                                                                                                                                                                                                                          |  
| Version Date: 12/11/2018  Event              | Action to Be Taken ƒ Ranitidine, q12 hours                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
|----------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Vascular leak syndrome                       | In the event of Grade ≥2 CTCAE vascular leak syndrome  (medical intervention indicated): o Vasopressor support (e.g., phenylephrine) if indicated to  stabilize blood pressure  o Administer colloidal solutions (e.g., albumin) if there is a  clinically significant, symptomatic and persistent systolic  blood pressure drop, urine output significantly declines or  serum albumin falls to 2.5 mg/dL or lower  o For pulmonary congestion provide diuretic and/or albumin  treatment as appropriate  o Progressive shortness of breath may require endotracheal  intubation or drainage of a pleural effusion  o For oliguria and /or rising serum creatinine level delay  LMB-100 if Grade 3 urine output (<10 mL/hr)  o Use dopamine if participant is unresponsive to or unable to  tolerate fluids.  o In the event of Grade ≥2 CTCAE pericardial effusion  (asymptomatic effusion small to moderate size), consider  delaying LMB-100 administration. In the event of Grade  ≥3 CTCAE pericardial effusion (effusion with physiologic  consequences) stop LMB-100 treatment until full  resolution  o Hydrocortisone (200 mg IV) or equivalent dose of another |
| Inflammatory reactions to serosal  membranes | corticosteroid as clinically indicated                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| o                                            | In the event of Grade 2 CTCAE pericardial effusion  (asymptomatic effusion small to moderate size), consider  delaying LMB-100 administration. In the event of Grade  ≥3 CTCAE pericardial effusion (effusion with physiologic  consequences) stop LMB-100 treatment until full  resolution                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| o                                            | In the event of pleuritis resulting in mild to severe pleuritic  pain, treat with analgesics or steroids as clinically indicated                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| o                                            | For participants who have previously experienced pleuritis  consider administration of dexamethasone 4 mg, PO bid  beginning with first LMB-100 infusion and completing 24  hours after the last LMB-100 infusion of the cycle. (If  participant is already receiving corticosteroids at dose and  schedule at or above this amount as part of the premedication regimen, do not give additional steroids for  pleuritis)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| Dehydration                                  | Encourage that participants maintain oral hydration (~1.5 L/ day)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |  
| Event                                                                                                      | Action to Be Taken                                                                                                                                                                                                                                                                                                                                                             |
|------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Nausea                                                                                                     | Ondansetron or another anti-emetic should be available as needed  during Days 1-6 of each cycle                                                                                                                                                                                                                                                                                |
| Renal toxicity                                                                                             | In the event of Grade 1 or greater renal toxicity consider  increasing oral or intravenous hydration, consider delaying  LMB-100 administration by up to 48hrs.  In the event of Grade 2 or great renal toxicity hold LMB-100  administration until recovery to Grade 1 or better. If this does  not occur within 48hrs, no further LMB-100 should be given  during the cycle. |
| IRR = infusion related reaction; IV = intravenous; CTCAE = Common Terminology Criteria for Adverse  Events |                                                                                                                                                                                                                                                                                                                                                                                |  
3.3.2 *Nab-paclitaxel* If nab-paclitaxel is withdrawn prior to completion of treatment, LMB-100 may still be continued in the absence of progressive disease. 3.3.2.1 Dose levels Dose modifications of nab-paclitaxel for myelosuppression and other chemotherapy related toxicities will be made as per package insert.  
| 3.4 STUDY CALENDARS   | 3.4.1 Calendar for patient receiving short infusion LMB-100 (Arms A1 and A2)   | 1 cycle = 21-days,   | Unless otherwise indicated, screening assessments must occur within 28 days prior to enrollment. Cycle 1, day 1 assessments with the exception of  imaging studies may occur up to 3 days prior to treatment initiation. Imaging studies must be completed ± 7 days from the indicated time. If screening  assessments are performed within the appropriate timeframe for Cycle 1 Day 1 assessments, they do not need to be repeated on that day.   | Beyond cycle 1, performance status and standard laboratory assessments may be performed up to 1 day prior to the indicated time.   | Dosing cycles after cycle 1 may be delayed for up to one week to accommodate schedule conflicts, Federal holidays and inclement weather, etc.  They may be delayed for up to two weeks due to toxicity.   | Cycle 1 -2   | Long Term  Follow Up   |
|-----------------------|--------------------------------------------------------------------------------|----------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|------------------------|
| Post Therapy          | Safety Follow  Up Visit6                                                       | X                    | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   | X                                                                                                                                  | X                                                                                                                                                                                                         |              |                        |
| Withdrawal            | visit5 Screening Day 1 Day 3 Day 5 Day 8                                       | X                    | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   | X                                                                                                                                  | X                                                                                                                                                                                                         | X            | X                      |
| X                     | X                                                                              | X                    | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                    |                                                                                                                                                                                                           |              |                        |
| X                     | X                                                                              | X                    | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                    |                                                                                                                                                                                                           |              |                        |
| X                     | X                                                                              | X                    | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                    |                                                                                                                                                                                                           |              |                        |
| X                     | X                                                                              | X                    | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   | X                                                                                                                                  | X                                                                                                                                                                                                         | X            | X                      |
| X                     | Vital signs1 X                                                                 | X                    | Labs2 X                                                                                                                                                                                                                                                                                                                                                                                                                                             | X                                                                                                                                  | X Hepatitis and HIV screening panel                                                                                                                                                                       |              |                        |
| 1,25-dihydroxy Vit D  |                                                                                |                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                    |                                                                                                                                                                                                           |              |                        |
| Nab-paclitaxel        | History and PE                                                                 |                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                    |                                                                                                                                                                                                           |              |                        |
| Procedure             | LMB-100                                                                        | Weight               | Height                                                                                                                                                                                                                                                                                                                                                                                                                                              | PS                                                                                                                                 |                                                                                                                                                                                                           |              |                        |  
51  
| Long Term  Follow Up         | Concomitant meds continuous              | 1 During the infusions of all study, vital signs (heart rate, blood pressure, oxygen saturation) have to be monitored pre-infusion and  every 15 minutes (± 5 minutes) during the infusion and then every 30 minutes (± 10 minutes) until 2 hours post-infusion.  2 CBC with differential, Acute Care Panel, Hepatic Panel, Mineral Panel, , C-reactive protein (CRP), creatine kinase (CK), PT, PTT,  LDH   |                     |    |                                 |     |    |                                                                  |
|------------------------------|------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|----|---------------------------------|-----|----|------------------------------------------------------------------|
| X6 X7                        | X                                        |                                                                                                                                                                                                                                                                                                                                                                                                              |                     |    |                                 |     |    |                                                                  |
| Post Therapy                 | Safety Follow  Up Visit6                 | X                                                                                                                                                                                                                                                                                                                                                                                                            | X                   | X  | X                               |     |    |                                                                  |
| Withdrawal                   | visit5 Screening Day 1 Day 3 Day 5 Day 8 | X                                                                                                                                                                                                                                                                                                                                                                                                            | X                   | X  | X                               | X   |    |                                                                  |
| X                            | Please refer to section 5.2.1            | Please refer to section 5.2.1                                                                                                                                                                                                                                                                                                                                                                                |                     |    |                                 |     |    |                                                                  |
| X                            |                                          |                                                                                                                                                                                                                                                                                                                                                                                                              |                     |    |                                 |     |    |                                                                  |
| Cycle 1 -2                   | Adverse events continuous                | 52                                                                                                                                                                                                                                                                                                                                                                                                           |                     |    |                                 |     |    |                                                                  |
| X X                          | X                                        | X                                                                                                                                                                                                                                                                                                                                                                                                            | X                   | X8 | NIH Advance Directives Form7 X9 | PKs |    |                                                                  |
| X                            | Pregnancy test3 X                        | Confirmation of Dx4 X                                                                                                                                                                                                                                                                                                                                                                                        | CT CAP and/or MRI X | X  | X                               | X   | X  | Annual phone call to monitor  survival and additional CA therapy |
| Ambulatory Oxygen Saturation | Correlative Studies                      |                                                                                                                                                                                                                                                                                                                                                                                                              |                     |    |                                 |     |    |                                                                  |
| Echocardiogram               | Chest X-ray                              |                                                                                                                                                                                                                                                                                                                                                                                                              |                     |    |                                 |     |    |                                                                  |
| Procedure                    | Urinalysis                               | CA 19-9                                                                                                                                                                                                                                                                                                                                                                                                      | ECG                 |    |                                 |     |    |                                                                  |  
Long Term Follow Up  
  
  
3 Pregnancy test required in women of childbearing potential; i.e. premenopausal women and women ≤ 2 years after menopause (menopause is defined as amenorrhea for > 2 years. 4 Assessment may occur at any time prior to enrollment 5 For participants who complete both cycles of therapy, the withdrawal visit should be scheduled for any time between Day 20 of and 7 days following the end of Cycle 2. For participants who do not complete both cycles of therapy, the withdrawal visit should be scheduled 3-6 weeks from last treatment. Imaging studies do not need to be repeated if most recent were performed within the prior 20 days. 6 Safety follow up will occur 3 - 6 weeks after last dose of study therapy in patients that have progressed. The safety assessment will occur 6 weeks +/-2 weeks after the previous scan in those that have stable disease, partial response or complete response. The assessments listed refer to those that will be performed if the patient is seen in clinic. If withdrawal visit occurred within this timeframe, it can be used as the safety follow up visit. If the patient is unable to return to the clinic for the follow up visit, an adverse event assessment will be performed by telephone. 7 Scans, every 6 weeks, will only be performed until disease progression. Note: for patients on long term follow up, scans may beperformed outside of NIH. 8 Chest x-ray to be done within 7 days prior to treatment on cycle 1 only. 9 As indicated in section 9.3, all subjects will be offered the opportunity to complete an NIH advanced directives form. This should be done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained. The completion of the form is strongly recommended, but is not required.  
3.4.2 *Calendars subjects in Arm B1 (single agent continuous infusion LMB-100)* 3.4.2.1 24 HOUR INFUSION (on Day 1 OR Day 1 & 4) 1 cycle = 21 days Unless otherwise indicated, screening assessments must occur within 28 days prior to enrollment. Cycle 1, day 1 assessments with the exception of imaging studies may occur up to 3 days prior to treatment initiation. Imaging studies must be completed ± 7 days from the indicated time. If screening assessments are performed within the appropriate timeframe for Cycle 1 Day 1 assessments, they do not need to be repeated on that day. Beyond cycle 1, performance status and standard laboratory assessments may be performed up to 1 day prior to the indicated time. Dosing cycles after cycle 1 may be delayed for up to one week to accommodate schedule conflicts, Federal holidays and inclementweather, etc. They may be delayed for up to two weeks due to toxicity. Cycle 1 & 2  
| Long  Term  Follow  Up  Safety  Follow  Up  Visit8   |                |            |         |    |      |                   |                       |
|------------------------------------------------------|----------------|------------|---------|----|------|-------------------|-----------------------|
| Post Therapy                                         | X              | X          | X       | X  | X    | X                 |                       |
| Screening Day 1 Day 2 Day 3                          |                |            |         |    |      |                   |                       |
| Day 4-5* Day 6* Day 8 Withdrawal visit7              | X              | X          | X1 X    | X  | X1 X | X                 | X1 X                  |
| X X                                                  | X              | X          | X       |    |      |                   |                       |
| X                                                    | X              | X          | X       | X  |      |                   |                       |
| X                                                    | X              | X          | X       |    |      |                   |                       |
| X                                                    | X              | X          | X       | X  |      |                   |                       |
| C1 only                                              |                |            |         |    |      |                   |                       |
| X                                                    | X              | X          | X       | X  | X    | X                 | X                     |
| X                                                    | Vital signs1 X | X          | Labs2 X | X  | X    | Pregnancy test3 X | Confirmation of Dx4 X |
| 1,25-dihydroxy Vit D                                 |                |            |         |    |      |                   |                       |
| History and PE                                       |                |            |         |    |      |                   |                       |
| Procedure                                            | LMB-100        | Urinalysis |         |    |      |                   |                       |
| Weight                                               | Height         | PS         |         |    |      |                   |                       |  
| Long  Term  Follow  Up  Safety  Follow  Up  Visit8                                                         | X9 X9                     | X                             |                                                  |    |                             |                                            |                       |
|------------------------------------------------------------------------------------------------------------|---------------------------|-------------------------------|--------------------------------------------------|----|-----------------------------|--------------------------------------------|-----------------------|
| Post Therapy                                                                                               | X                         | X                             |                                                  |    |                             |                                            |                       |
| Screening Day 1 Day 2 Day 3                                                                                |                           |                               |                                                  |    |                             |                                            |                       |
| Day 4-5* Day 6* Day 8 Withdrawal visit7                                                                    | X                         | X                             | X                                                | X  | Concomitant meds continuous |                                            |                       |
| * For the D1&4 continuous infusion level only (and not for participants just getting 24 hr infusion on D1) |                           |                               |                                                  |    |                             |                                            |                       |
| Please refer to section 5.2.2.1                                                                            |                           |                               |                                                  |    |                             |                                            |                       |
| Please refer to section 5.2.2.1                                                                            |                           |                               |                                                  |    |                             |                                            |                       |
| Cycle 1 & 2                                                                                                | Adverse events continuous |                               |                                                  |    |                             |                                            |                       |
| X                                                                                                          |                           |                               |                                                  |    |                             |                                            |                       |
| X                                                                                                          | X                         | X10                           | X6                                               |    |                             |                                            |                       |
| X                                                                                                          | X                         | CA 19-95 X                    | X                                                | X  | X                           | Annual phone call to  monitor survival and | additional CA therapy |
| Assessment of tumor  MSLN expression4,                                                                     | CT CAP and/or MRI         | Ambulatory Oxygen  Saturation | Correlative Studies,  including optional  biopsy |    |                             |                                            |                       |
| Echocardiogram                                                                                             | NIH Advance               | Directives Form6              |                                                  |    |                             |                                            |                       |
| Chest X-ray                                                                                                |                           |                               |                                                  |    |                             |                                            |                       |
| Procedure                                                                                                  | ECG                       | PKs                           |                                                  |    |                             |                                            |                       |  
  
1 During continuous infusion, vital signs including, if possible, supine diastolic and systolic blood pressure, pulse rate, and oxygen saturation) must be monitored pre-infusion, every 30 minutes (± 5 minutes) for the first two hours of the infusion beginning with the start of loading dose, and thereafter, every 6 hours (±60 minutes) until the infusion finishes. Vital signs during the first 2 hours of infusion are not required to be captured in the eCRF unless abnormalities are observed. 2 CBC with differential, Acute Care Panel, Hepatic Panel, Mineral Panel, C-reactive protein (CRP), Creatine Kinase (CK), CK, PT, PTT, LDH 3 Pregnancy test required in women of childbearing potential; i.e. premenopausal women and women ≤ 2 years after menopause (menopause is defined as amenorrhea for > 2 years 4 Assessment may occur at any time prior to enrollment 5 For patients with diagnosis pancreatic or biliary cancers (cholangiocarcinoma) only 6 As indicated in section 9.3, all subjects will be offered the opportunity to complete an NIH advanced directives form. This should be done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained. The completion of the form is strongly recommended, but is not required. 7 For participants who complete both cycles of therapy, the withdrawal visit should be scheduled for any time between Day 20 of and 7 days following the end of Cycle 2. For participants who do not complete both cycles of therapy, the withdrawal visit should be scheduled 3-6 weeks from last treatment. Imaging studies do not need to be repeated if most recent were performed within the prior 20 days. 8 Safety follow up will occur 3 - 6 weeks after last dose of study therapy in patients that have progressed. The safety assessment will occur 6 weeks +/-2 weeks after the previous scan in those that have stable disease, partial response or complete response. The assessments listed refer to those that will be performed if the patient is seen in clinic. If withdrawal visit occurred within this timeframe, it can be used as the safety follow up visit. If the patient is unable to return to the clinic for the follow up visit, an adverse event assessment will be performed by telephone. 9 Scans, every 6 weeks, will only be performed until disease progression. Note: for patients on long term follow up, scans may be performed outside of NIH. 10 Chest x-ray to be done within 7 days prior to treatment on cycle 1 only  
| 3.4.2.2 48 HOUR INFUSION            | Unless otherwise indicated, screening assessments must occur within 28 days prior to enrollment. Cycle 1, day 1 assessments with the exception of  imaging studies may occur up to 3 days prior to treatment initiation. Imaging studies must be completed ± 7 days from the indicated time. If  screening assessments are performed within the appropriate timeframe for Cycle 1 Day 1 assessments, they do not need to be repeated on that day.   | Beyond cycle 1, performance status and standard laboratory assessments may be performed up to 1 day prior to the indicated time.   | Dosing cycles after cycle 1 may be delayed for up to one week to accommodate schedule conflicts, Federal holidays and inclement weather, etc.  They may be delayed for up to two weeks due to toxicity.   | Cycle 1 & 2   | Long  Term  Follow  Up  Safety  Follow  Up Visit8   |                       |    |      |
|-------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|-----------------------------------------------------|-----------------------|----|------|
| Post Therapy                        | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   | X                                                                                                                                  | X                                                                                                                                                                                                         | X             | X                                                   | X                     |    |      |
| Withdraw                            | al visit7 Day 8                                                                                                                                                                                                                                                                                                                                                                                                                                     | X                                                                                                                                  | X                                                                                                                                                                                                         | X1 X          | X                                                   | X1 X                  | X  | X1 X |
| X                                   |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                    |                                                                                                                                                                                                           |               |                                                     |                       |    |      |
| Day 5 Screening Day 1 Day 2-3 Day 4 | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   | X                                                                                                                                  | X                                                                                                                                                                                                         | X             |                                                     |                       |    |      |
| X                                   | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   | X                                                                                                                                  | X                                                                                                                                                                                                         | X             |                                                     |                       |    |      |
| Height C1 only                      | Vital signs1 X                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                    |                                                                                                                                                                                                           |               |                                                     |                       |    |      |
| X                                   | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   | X                                                                                                                                  | X                                                                                                                                                                                                         | X             | X                                                   | X                     | X  |      |
| X                                   | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Labs2 X                                                                                                                            | X                                                                                                                                                                                                         | X             | Pregnancy test3 X                                   | Confirmation of Dx4 X |    |      |
| 1,25-dihydroxy Vit D                |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                    |                                                                                                                                                                                                           |               |                                                     |                       |    |      |
| History and PE                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                    |                                                                                                                                                                                                           |               |                                                     |                       |    |      |
| Procedure                           | LMB-100                                                                                                                                                                                                                                                                                                                                                                                                                                             | Urinalysis                                                                                                                         |                                                                                                                                                                                                           |               |                                                     |                       |    |      |
| Weight                              | PS                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                    |                                                                                                                                                                                                           |               |                                                     |                       |    |      |  
57  
| Long  Term  Follow  Up  Safety  Follow  Up Visit8   | X9 X9                           | X                                |            |    |    |    |                                                 |                                            |                       |
|-----------------------------------------------------|---------------------------------|----------------------------------|------------|----|----|----|-------------------------------------------------|--------------------------------------------|-----------------------|
| Post Therapy                                        | X                               | X                                |            |    |    |    |                                                 |                                            |                       |
| Withdraw                                            | al visit7 Day 8                 | X                                | X          | X  | X  |    |                                                 |                                            |                       |
| Day 5                                               | Please refer to section 5.2.2.2 | Please refer to section 5.2.2.2  |            |    |    |    |                                                 |                                            |                       |
| Cycle 1 & 2                                         | Adverse events continuous       |                                  |            |    |    |    |                                                 |                                            |                       |
| Screening Day 1 Day 2-3 Day 4                       | Day 3  only                     | X10                              |            |    |    |    |                                                 |                                            |                       |
| X                                                   | X                               | NIH Advance Directives  Form6 X6 | PKs        |    |    |    |                                                 |                                            |                       |
| Assessment of tumor MSLN                            | expression4, X                  | CT CAP and/or MRI X              | CA 19-95 X | X  | X  | X  | Correlative Studies,  including optional biopsy | Annual phone call to  monitor survival and | additional CA therapy |
| Ambulatory Oxygen  Saturation                       |                                 |                                  |            |    |    |    |                                                 |                                            |                       |
| Echocardiogram                                      |                                 |                                  |            |    |    |    |                                                 |                                            |                       |
| Procedure                                           | Chest X-ray                     |                                  |            |    |    |    |                                                 |                                            |                       |
| ECG                                                 |                                 |                                  |            |    |    |    |                                                 |                                            |                       |  
  
Procedure  
Concomitant meds continuous 1 During continuous infusion, vital signs including, if possible, supine diastolic and systolic blood pressure, pulse rate, and oxygen saturation) must be monitored pre-infusion, every 30 minutes (± 5 minutes) for the first two hours of the infusion beginning with the start of loading dose, and thereafter, every 6 hours (±60 minutes) until the infusion finishes. Vital signs during the first 2 hours of infusion are not required to be captured in the eCRF unless abnormalities are observed. 2 CBC with differential, Acute Care Panel, Hepatic Panel, Mineral Panel, , C-reactive protein (CRP), Creatine Kinase (CK), PT, PTT, LDH 3 Pregnancy test required in women of childbearing potential; i.e. premenopausal women and women ≤ 2 years after menopause (menopause is defined as amenorrhea for > 2 years 4 Assessment may occur at any time prior to enrollment 5 For patients with diagnosis pancreatic or biliary cancers (cholangiocarcinoma) only 6 As indicated in section 9.3, all subjects will be offered the opportunity to complete an NIH advanced directives form. This should be done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained. The completion of the form is strongly recommended, but is not required. 7 For participants who complete both cycles of therapy, the withdrawal visit should be scheduled for any time between Day 20 of and 7 days following the end of Cycle 2. For participants who do not complete both cycles of therapy, the withdrawal visit should be scheduled 3-6 weeks from last treatment. Imaging studies do not need to be repeated if most recent were performed within the prior 20 days. 8 Safety follow up will occur 3 - 6 weeks after last dose of study therapy in patients that have progressed. The safety assessment will occur 6 weeks +/-2 weeks after the previous scan in those that have stable disease, partial response or complete response. The assessments listed refer to those that will be performed if the patient is seen in clinic. If withdrawal visit occurred within this timeframe, it can be used as the safety follow up visit. If the patient is unable to return to the clinic for the follow up visit, an adverse event assessment will be performed by telephone. 9 Scans, every 6 weeks, will only be performed until disease progression. Note: for patients on long term follow up, scans may be performed outside of NIH. 10 Chest x-ray to be done within 7 days prior to treatment on cycle 1 only  
59  
| 3.4.3 Calendar for Subjects in Arm B2 (LMB-100 24-hour continuous infusion combination therapy)   | 1 cycle = 14 days   | Unless otherwise indicated, screening assessments must occur within 28 days prior to enrollment. Cycle 1, day 1 assessments with the exception of  imaging studies may occur up to 3 days prior to treatment initiation. Imaging studies must be completed ± 7 days from the indicated time. If  screening assessments are performed within the appropriate timeframe for Cycle 1 Day 1 assessments, they do not need to be repeated on that day.   | Beyond cycle 1, performance status and standard laboratory assessments may be performed up to 1 day prior to the indicated time.   | Dosing cycles after cycle 1 may be delayed for up to one week to accommodate schedule conflicts, Federal holidays and inclement weather, etc. They may be delayed for up to two weeks due to toxicity.   | All cycles   | Safety Follow Up Visit8 Long Term Follow Up   |    |    |
|---------------------------------------------------------------------------------------------------|---------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|-----------------------------------------------|----|----|
| Post Therapy                                                                                      | X                   | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   | X                                                                                                                                  | X                                                                                                                                                                                                        | X            |                                               |    |    |
| Withdrawal                                                                                        | visit7              | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   | X                                                                                                                                  | X                                                                                                                                                                                                        | X            | X                                             | X  | X  |
| C1 only                                                                                           | C1 only             | C1 only                                                                                                                                                                                                                                                                                                                                                                                                                                             | C1 only                                                                                                                            |                                                                                                                                                                                                          |              |                                               |    |    |
| Day 3 Day 2                                                                                       | X                   | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   | X                                                                                                                                  | X                                                                                                                                                                                                        | X            | 60                                            |    |    |
| C1 only                                                                                           |                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                    |                                                                                                                                                                                                          |              |                                               |    |    |
| Day 1                                                                                             | X                   | X                                                                                                                                                                                                                                                                                                                                                                                                                                                   | X                                                                                                                                  | X                                                                                                                                                                                                        | X            | X                                             | X  | X  |
| Screening                                                                                         | X                   | Vital signs1 X                                                                                                                                                                                                                                                                                                                                                                                                                                      | X                                                                                                                                  | Labs2 X                                                                                                                                                                                                  | X            | X                                             | X  |    |
| Hepatitis and HIV screening  panel                                                                |                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                    |                                                                                                                                                                                                          |              |                                               |    |    |
| 1,25-dihydroxy Vit D                                                                              |                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                    |                                                                                                                                                                                                          |              |                                               |    |    |
| Nab-paclitaxel                                                                                    | History and PE      |                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                    |                                                                                                                                                                                                          |              |                                               |    |    |
| Procedure                                                                                         | LMB-100             | Urinalysis                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                    |                                                                                                                                                                                                          |              |                                               |    |    |
| Weight                                                                                            | Height              | PS                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                    |                                                                                                                                                                                                          |              |                                               |    |    |  
| Safety Follow Up Visit8 Long Term Follow Up   | Concomitant meds continuous     | 1 During continuous infusion, vital signs including, if possible, supine diastolic and systolic blood pressure, pulse rate, and oxygen saturation)  must be monitored pre-infusion, every 30 minutes (± 5 minutes) for the first two hours of the infusion beginning with the start of loading   |                                 |            |    |    |                                 |                                                 |                                                                   |
|-----------------------------------------------|---------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|------------|----|----|---------------------------------|-------------------------------------------------|-------------------------------------------------------------------|
| X9 X9                                         | X                               |                                                                                                                                                                                                                                                                                                  |                                 |            |    |    |                                 |                                                 |                                                                   |
| Post Therapy                                  | X                               | X                                                                                                                                                                                                                                                                                                | X                               |            |    |    |                                 |                                                 |                                                                   |
| Withdrawal                                    | visit7                          | X                                                                                                                                                                                                                                                                                                | X                               | X          | X  |    |                                 |                                                 |                                                                   |
| Day 3                                         | Please refer to section 5.2.2.1 | Please refer to section 5.2.2.1                                                                                                                                                                                                                                                                  |                                 |            |    |    |                                 |                                                 |                                                                   |
| All cycles                                    | 61                              |                                                                                                                                                                                                                                                                                                  |                                 |            |    |    |                                 |                                                 |                                                                   |
| Adverse events continuous                     |                                 |                                                                                                                                                                                                                                                                                                  |                                 |            |    |    |                                 |                                                 |                                                                   |
| Day 2                                         | X                               |                                                                                                                                                                                                                                                                                                  |                                 |            |    |    |                                 |                                                 |                                                                   |
| Day 1                                         | X10                             |                                                                                                                                                                                                                                                                                                  |                                 |            |    |    |                                 |                                                 |                                                                   |
| X                                             | X                               | X                                                                                                                                                                                                                                                                                                | NIH Advance Directives Form6 X6 | PKs        |    |    |                                 |                                                 |                                                                   |
| Screening                                     | Pregnancy test3 X               | Confirmation of Dx4 X                                                                                                                                                                                                                                                                            | CT CAP and/or MRI X             | CA 19-95 X | X  | X  | X  Ambulatory Oxygen Saturation | Correlative Studies, including  optional biopsy | Annual phone call to monitor  survival and additional CA  therapy |
| Echocardiogram                                | Chest X-ray                     |                                                                                                                                                                                                                                                                                                  |                                 |            |    |    |                                 |                                                 |                                                                   |
| Procedure                                     | ECG                             |                                                                                                                                                                                                                                                                                                  |                                 |            |    |    |                                 |                                                 |                                                                   |  
dose, and thereafter, every 6 hours (±60 minutes) until the infusion finishes. Vital signs during the first 2 hours of infusion are not required to be captured in the eCRF unless abnormalities are observed.  
| 2 CBC with differential, Acute Care Panel, Hepatic Panel, Mineral Panel, C-reactive protein (CRP), Creatine Kinase (CK), CK, PT, PTT,  LDH   | 3 Pregnancy test required in women of childbearing potential; i.e. premenopausal women and women ≤ 2 years after menopause (menopause  is defined as amenorrhea for > 2 years  4 Assessment may occur at any time prior to enrollment  5 For patients with diagnosis pancreatic or biliary cancers (cholangiocarcinoma) only  6 As indicated in section 9.3, all subjects will be offered the opportunity to complete an NIH advanced directives form. This should be done  preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained. The completion of the form  is strongly recommended, but is not required.  7 For participants who complete all cycles of therapy, the withdrawal visit should be scheduled for any time between Day 20 of and 7 days  following the end of Cycle 2. For participants who do not complete all cycles of therapy, the withdrawal visit should be scheduled 3-6  weeks from last treatment. Imaging studies do not need to be repeated if most recent were performed within the prior 20 days.  8 Safety follow up will occur 3 - 6 weeks after last dose of study therapy in patients that have progressed. The safety assessment will occur 6  weeks +/-2 weeks after the previous scan in those that have stable disease, partial response or complete response. The assessments listed  refer to those that will be performed if the patient is seen in clinic. If withdrawal visit occurred within this timeframe, it can be used as the  safety follow up visit. If the patient is unable to return to the clinic for the follow up visit, an adverse event assessment will be performed  by telephone.  9 Scans, every 6 weeks, will only be performed until disease progression. Note: for patients on long term follow up, scans may be performed  outside of NIH.   | 10 Chest x-ray to be done within 7 days prior to treatment on cycle 1 only   |
|----------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|
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3.5 criteria for removal from

Prior to removal from study, effort must be made to have all subjects complete a safety visit as indicated in the Study Calendar following the last dose of study therapy. 3.5.1 *Criteria for removal from protocol therapy*  
x Progressive disease
x Participant has completed planned number of cycles of study therapy x Participant requests to be withdrawn from active therapy  
x Pregnancy
x Unacceptable Toxicity as defined in sections 3.1.2 and 3.3 x Investigator discretion 3.5.2 *Off-Study Criteria* x Screen failure x Participant lost to follow-up  
x Participant requests to be withdrawn from study x Death
3.5.2.1 Off Protocol Therapy and Off-Study Procedure Authorized staff must notify Central Registration Office (CRO) when a subject is taken off protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from the website (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and sent via encrypted email to: NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.
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4 concomitant medications/measures 4.1.1 permitted

Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter (OTC) drugs, approved dietary and herbal supplements, nutritional supplements) used by a participant from the screening period until the follow-up visit. If any treatment is given within 4 weeks prior to screening this should be reported to the investigator and recorded in the eCRF. All therapy and/or medication administered to manage adverse events should be recorded on the Adverse Event eCRF.
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4.1.2 prohibited therapy

Participants should be treated for all concomitant conditions and adverse events according to accepted standards of medical care at the discretion of the investigator. The following treatments are not permitted during the study:  
x Any other investigational therapy x Cytotoxic chemotherapy agents other than *nab-*paclitaxel x Radiotherapy. Note: palliative 8Gy radiotherapy is allowed. x Immunosuppressive therapy and chronically administered glucocorticoids (high dose is considered as !20 mg of dexamethasone a day [or equivalent)] for !7 consecutive days)
x Other systemic anti-neoplastic agents and targeted therapies
If any anti-neoplastic or investigational therapies listed above are needed, the participant will be considered to have evidence of progressive neoplastic disease and have experienced treatment failure with study treatment and should be withdrawn from study treatment. Caution should be exercised when drugs that are known to be substrates (e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4 are to be co-administered with paclitaxel. Caution should also be exercised when paclitaxel is concomitantly administered with known substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., rifampin) of CYP2C8. All concomitant treatments must be documented in the eCRF.
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5 biospecimen collection 5.1 correlative

All blood samples for PK assessment will be collected from an IV line different to that receiving the infusion to measure free and total concentrations for LMB-100 for all patients. The date and time of each sample collection will be recorded. If multiple samples are drawn at a given time point, the PK sample should take precedence. Free and total plasma concentrations of LMB-100 will be measured using validated ligand-binding assays.  
5.1.1.1 Sample collection:
Blood will be collected in 2 mL K2EDTA tubes (purple top) at the times defined in section 5.2.  
Samples should be inverted 8 to 10 times after collection. Store on wet ice or at 4°C. Processing within 60 minutes of blood collection is highly preferred. 5.1.1.2 Sample processing Samples will be processed in the Clinical Pharmacology Program. Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. Upon arrival in the CPP the following procedures should be followed:  
1. Store on wet ice until centrifugation. 2. Centrifuge 1500xg for 10 minutes at 4°C within 60 minutes of blood collection. 3. Transfer plasma specimen to 2mL cryovials and store at -70°C.  
The analyses will be performed retrospectively in batched samples or at the end of the trial.
5.1.1.3 Sample Shipping Samples will be shipped by the CPP on dry ice to Ms. Yanyu Wang in Frederick for analysis.  
Leidos Biomedical, Inc. Attention: Ms. Yanyu Wang and Dr. Jon Inglefield.  
Building 469, Room 200 Miller Drive Frederick, MD 21702 Phone: 301-846-6905/301-846-6865 5.1.1.4 Sample storage Samples will be stored in the CPP until shipment to the Leidos Biomedical Inc. Lab in Frederick. 5.1.2 *Nab-Paclitaxel Pharmacokinetic Assessments* Blood samples for the determination of plasma levels of abraxane (nab-paclitaxel) will be obtained from each patient receiving nab-paclitaxel as directed in section 5.2. Bioanalytical measurements will be conducted on an ultra HPLC-MSMS system using an assay developed and validated by the Clinical Pharmacology Program. This data will be used to monitor nab-paclitaxel plasma concentrations both in the absence and presence of LMB-100 to assess any drug interactions as well as correlate to pharmacodynamic endpoints, clinical response, toxicity, and pharmacogenetic analyses. 5.1.2.1 Sample Collection See section 5.2 for schedule, volumes and tube types. Blood samples will be inverted 4-5x then placed on wet ice until a member of the Blood Processing Core can pick them up and process into plasma for database entry, aliquoting and storage. Paclitaxel is stable in blood on wet ice overnight, if needed. 5.1.2.2 Sample processing Samples will be processed in the Clinical Pharmacology Program. Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. 5.1.2.3 Sample storage Samples will be stored in the CPP. 5.1.3 *Pharmacogenetic Studies* Pharmacogenetic studies will be performed to analyze the genomic DNA and assess the genotype of the most relevant drug metabolizing enzymes and transporters (DMET). DNA will be analyzed on a DMET Plus (Affymatrix) genotyping platform that tests for 1,936 genetic variations in 225 drug disposition genes, including 47 CYP (phase I metabolism) genes, 13 non-CYP (phase I metabolism) genes, 78 phase II metabolizing genes (including UGTs), 63 transporters, 4 genes involved in facilitation of drug transporters, 9 genes involved in global regulation of drug metabolizing/transporting proteins, 4 drug binding proteins, and 4 drug targets. Of specific interest to nab-paclitaxel are polymorphisms in CYP2C8, CYP3A4/5, and ABCB1, all of which are included in the DMET analysis. Studies will be performed by the Clinical Pharmacology Program. 5.1.3.1 Sample Collection One blood sample will be collected per patient. See section 5.2 for timing, volume and tube type. 5.1.3.2 Sample processing Samples will be processed in the Clinical Pharmacology Program. Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.  
5.1.3.3 Sample storage Samples will be stored in the CPP. 5.1.4 *Assessment of anti-drug antibodies (ADAs)* 5.1.4.1 Sample Collection Samples will be collected before the first dose of LMB-100 administration during each cycle. (See section 5.2)
Draw 2mL into K2EDTA tube (purple top). Samples should be inverted 8 to 10 times after collection. Store on wet ice or at 4°C. Processing within 60 minutes of blood collection is highly preferred. 5.1.4.2 Sample Processing Samples will be processed in the Clinical Pharmacology Program. Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. Upon arrival in the CPP, each sample should be processed in the following manner:
1. Store on wet ice until centrifugation. 2. Centrifuge 1500xg for 10 minutes at 4°C within 60 minutes of blood collection. 3. Transfer plasma specimen to 2mL cryovials and store at -70°C.  
Autoantibody levels will be retrospectively assessed.  
5.1.4.3 Sample Shipping Samples will be shipped by the CPP on dry ice to Ms. Yanyu Wang in Frederick for analysis.  
Leidos Biomedical, Inc. Attention: Ms. Yanyu Wang and Dr. Jon Inglefield. Building 469, Room 200 Miller Drive Frederick, MD 21702 Phone: 301-846-6905/301-846-6865 5.1.4.4 Sample Storage Samples will be stored in the CPP until shipment to the Leidos Biomedical Inc. Lab in Frederick. 5.1.5 *Retrospective Analysis of Mesothelin Expression in tumor tissue* IHC analysis will be performed by the Laboratory of Pathology at NCI to determine mesothelin expression within the tumor at any time after study enrollment. Leftover tissue from archival specimens or tumor biopsies obtained at screening will be used for analysis. Specimens will be used to correlate treatment with response with mesothelin expression in an exploratory analysis. 5.1.6 *Cytokines for identification of mechanism for PE-mediated capillary leak syndrome* PE-based RITs cause dose-limiting CLS. At low doses CLS manifests as mild and transient weight gain, hypoalbuminemia, and peripheral or facial edema. At higher doses it can cause lifethreatening cardiopulmonary compromise. Previous studies in rats have indicated that pathological changes indicative of CLS onset occur within just two hours of toxin administration and even when the PE fragment lacks a targeting domain.[41] In vitro studies with cultured endothelial cells have demonstrated that super-physiologic doses of PE-based RITs cannot induce endothelial cell toxicity unless the cells express the RIT target.[42] Together these data suggest the hypothesis that PE-based RITs cause CLS by triggering release of vasoactive cytokines by specific immune cells rather than through direct damage to endothelial cells. To test this hypothesis, we will collect additional serum from participants during the first hours of standard PK measurements on Cycle 1 Day 1 of treatment (see section 5.2 for specific time points). Samples will be stored for later analysis. 5.1.6.1 Specimen collection To test this hypothesis, we will collect additional serum from participants on the days and timepoints shown in sections 5.2.1 and 5.2.2 respectively for short infusion and continuous infusion cohorts. 5.1.6.2 Sample processing Serum collected at some time points will also be used for serum MPF measurements (see Section 5.1.11) and must be aliquoted appropriately to complete both assays. Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred).  
For sample pickup, page 102-11964.  
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. Cytokine levels will be retrospectively assessed.  
5.1.7 *Circulating endothelial cells (CEP and CEC) for identification of mechanism for PEmediated capillary leak syndrome*
Circulating endothelial progenitor cells (CEP) and mature circulating endothelial cells (CEC) will be assessed by multiparameter flow cytometry. Cells will be analyzed for forward and side scatter, and cells expressing hematopoietic markers will be excluded. Endothelial cells will be identified using co-expression of markers, such as CD31 and CD146 for CEC, and CD31 and CD133 for CEP. The cell populations will also be analyzed for viability using scatter profiles and a vital stain, such as Hoechst 33258. Percentages of stained cells will be determined and compared with appropriate negative controls. Multiparameter flow cytometric analysis will be performed with a Miltenyi Quant equipped with FlowJo software, using a minimum of 100,000 events per analysis.
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5.1.7.1 sample collection

Draw blood into one 8-cc CPT citrate (BD) tube at (1) baseline, just prior to beginning therapy, (2) cycle 1 at 16 to 30 hours following end of last infusion as specified in sections 5.2.1 and 5.2.2, and (3) cycle 2 day 1, prior to therapy.
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5.1.7.2 sample processing

Contact the Trepel Lab, Developmental Therapeutics Branch, NCI by email (Jane Trepeltrepel@helix.nih.gov; and Sunmin Lee- lees@pop.nci.nih.gov) when the patient is scheduled and by phone as soon as the blood is drawn at 240 760 6330and a lab member will pick up the sample.
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5.1.8 immune subset analysis

Peripheral blood mononuclear cells (PBMC) will be assessed using multiparameter flow cytometry for immune subsets including but not necessarily limited to CD8+ T-cells, CD4+Foxp3- T-cells, Tregs, Th1, Th2 and Th17+ CD4+ T-cells, monocyte subsets, MDSC subsets. Assessment will include functional markers, i.e. PD-1, Tim-3, CTLA-4, PD-L1, HLA-DR and/or CD40.
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5.1.8.1 sample collection

Draw blood into two 8-cc CPT citrate (BD) tubes at (1) baseline, just prior to beginning therapy, (2) cycle 1 following end of last infusion as specified in sections 5.2.1 and 5.2.2 , and (3) cycle 2 day 1, prior to therapy.
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5.1.8.2 sample processing

Contact the Trepel Lab, Developmental Therapeutics Branch, NCI by email (Jane Trepeltrepel@helix.nih.gov; Yusuke Tomita- yusuke.tomita@nih.gov and Sunmin Leelees@pop.nci.nih.gov) when the patient is scheduled and by phone as soon as the blood is drawn at 240 760 6330. Please phone the lab as soon as it is drawn and a lab member will come to pick up the blood. Please keep blood at ambient temperature.  
Members of the lab will enter the samples in a secure patient database, process the samples for viable cell storage, label each sample with a unique 2D barcode, and viably store the samples. They will prepare the samples for staining, stain and run the samples by multiparametric flow cytometry (MACSQuant, Miltenyi Biotec, Bergisch Gladbach, DE), and analyze the data using FlowJo (FlowJo LLC, Ashland, OR) software.
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5.1.9 peripheral blood immune gene

Peripheral blood immune gene expression will be evaluated by the Trepel Lab using the NanoString nCounter® platform (NanoString Technologies, Seattle, WA). Collect peripheral blood in a PAXgene Blood RNA tube (PreAnalytix; 2.5 cc peripheral blood per tube) per the manufacturer's instructions. After the blood is drawn, the tube should be inverted several times and placed at room temperature. RNA will be isolated using the PAXgene Blood RNA Kit according to the manufacturer's instructions. Peripheral immune gene expression will be evaluated using the PanCancer Immune Profiling codeset of 730 immune genes and 40 control genes at baseline and post-therapy by the Trepel Lab to look for correlates of clinical response with innate or adaptive immunity.
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5.1.9.1 sample collection

Draw blood into one 2.5 ml PAXgene RNA tube at (1) baseline, just prior to beginning therapy, (2) cycle 1 following end of last infusion as specified in sections 5.2.1 and 5.2.2, and (3) cycle 2 day 1, prior to therapy.
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5.1.9.2 sample processing

Contact the Trepel Lab, Developmental Therapeutics Branch, NCI by email (Jane Trepeltrepel@helix.nih.gov; Yusuke Tomita- yusuke.tomita@nih.gov and Sunmin Leelees@pop.nci.nih.gov) when the patient is scheduled and by phone as soon as the blood is drawn at 240-760-6330. Please phone the lab as soon as it is drawn and a lab member will come to pick up the blood.
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5.1.10 circulating tumor cells

Peripheral blood will be collected to correlate changes in circulating tumor cells with clinical response as well as to assess immune-mediated cell death. CTCs will be assessed using ferrofluidic enrichment and multi-parameter flow cytometric detection. CTCs are identified by positive expression of epithelial markers and a viability marker and negative expression of hematopoietic markers.
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5.1.10.1 sample collection

Draw blood into two 7.5 ml Veridex CellSave tubes at (1) baseline, just prior to beginning therapy, (2) cycle 1 following end of last infusion as specified in sections 5.2.1 and 5.2.2 and (3) cycle 2 day 1, prior to therapy.
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5.1.10.2 sample processing

Contact the Trepel Lab, Developmental Therapeutics Branch, NCI by email (Jane Trepeltrepel@helix.nih.gov; Yusuke Tomita- yusuke.tomita@nih.gov and Sunmin Leelees@pop.nci.nih.gov) when the patient is scheduled and by phone as soon as the blood is drawn at 240-760-6330 and a lab member will come to pick up the blood. Please keep blood at ambient temperature. Members of the lab will enter the samples in a secure patient database, and process the samples for immediate CTC assessment. They will prepare the samples for staining, stain and run the samples by multiparametric flow cytometry (MACSQuant, Miltenyi Biotec, Bergisch Gladbach, DE), and analyze the data using FlowJo (FloJo LLC, Ashland, OR) software.
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5.1.11 treatment effect on tumor

An optional biopsy may be collected in Arm B1 on day 8 of cycle 2 and in arm B2on day 3 of cycle 2 in order to analyze any changes in the tumor microenvironment, pre and post. The C2 D8 samples will be collected in Interventional Radiology, using image guidance techniques, including CT guidance, as required. Biopsies will be obtained from primary tumor sites and/or metastatic sites
(if applicable). No more than 4 cores may be obtained per site. The biopsies collected post-treatment will be compared to those collected at the time of enrollment (section 5.1.5). The samples will be assessed by immunohistochemistry in the NCI Laboratory of Pathology.
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5.1.12 serum megakaryocyte potentiating factor

MPF is a second protein product produced by the *MSLN* gene. This product is secreted by the cell and can be detected in the circulation in some patients. We hypothesize that serum MPF level may be used as a marker of tumor response in patients with MSLN-producing tumors like pancreatic cancer. Also, because LMB-100 halts tumor cell protein synthesis, we hypothesize that during the time of treatment serum MPF levels may also decline due to LMB-100 effect on tumor cells. To test our first hypothesis, we will collect serum from participants pre-dose for C1 and C2 as well as at the conclusion of the study. To address our second hypothesis, we will collect serum at the end of infusion (see section 5.2 for specific time points). Samples will be stored for later analysis in the Cao lab.
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5.1.12.1 specimen collection

To test this hypothesis, we will collect additional serum from participants in 4 mL red SST tubes at the following time-points: Cycle 1 Day 1 pre-dose, Cycle 1 at end of infusion, Cycle 2 Day 1 pre-dose, and at the time of progression or withdrawal from study. 5.1.12.2 Sample processing Serum collected at some time points will also be used for serum cytokine analysis (see Section 5.1.6). For serum MPF analysis, aliquot 100 μL each into two cryovials with printed labels and a sample identifier and store at -80°C. Coded, linked samples will be provided to the laboratory of Liang Cao upon request of the PI. Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred).  
For sample pickup, page 102-11964.  
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.  
| 5.2 SAMPLE COLLECTION SCHEDULE                                                                                    | 5.2.1 Sample Collection for Patients receiving short infusion LMB-100 (Arms A1 and A2)   | Timed samples should be collected within +/- 15 minutes of indicted time, except for nab-paclitaxel PKs collections drawn at 5 or more hours after  the end of infusion. For these, samples should be collected with + / - 60 minutes of indicated time.   | Cycle   |    |    |
|-------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|----|----|
| Tumor  Sample                                                                                                     | (5.1.5)                                                                                  | NA                                                                                                                                                                                                                                                         | Xa      |    |    |
| expression                                                                                                        | (5.1.9)                                                                                  |                                                                                                                                                                                                                                                            |         |    |    |
| Immune                                                                                                            | gene                                                                                     | PAXgene  RNA tube                                                                                                                                                                                                                                          |         |    |    |
| 2.5 mL                                                                                                            | Pre-dose                                                                                 | Xd Xd                                                                                                                                                                                                                                                      |         |    |    |
| CellSave & three  8 mL CPT citrate  tubes                                                                         |                                                                                          |                                                                                                                                                                                                                                                            |         |    |    |
| Two 7.5 mL  Veridex                                                                                               |                                                                                          |                                                                                                                                                                                                                                                            |         |    |    |
| CECs, Immune  Subsets,                                                                                            | CTCs                                                                                     | (5.1.7, 5.1.8,  5.1.10)                                                                                                                                                                                                                                    |         |    |    |
| PE mediated  CLS  (Cytokines)  and serum  MPF level                                                               | (5.1.6, 5.1.12)                                                                          |                                                                                                                                                                                                                                                            |         |    |    |
| (5.1.2)                                                                                                           |                                                                                          |                                                                                                                                                                                                                                                            |         |    |    |
| ADA                                                                                                               | Pre-dose                                                                                 |                                                                                                                                                                                                                                                            |         |    |    |
| 4 mL red SST  tube                                                                                                | Pre-dose, EOI,  1, 2 and 4 hours  after EOI  Xb Pre-dose                                 | EOI                                                                                                                                                                                                                                                        |         |    |    |
| K2EDTA  tube                                                                                                      |                                                                                          |                                                                                                                                                                                                                                                            |         |    |    |
| 2 mL                                                                                                              |                                                                                          |                                                                                                                                                                                                                                                            |         |    |    |
| Pharmacogenetic  studies                                                                                          | (5.1.3)                                                                                  | 4-6 mL in purple  top tube                                                                                                                                                                                                                                 | 72      |    |    |
| infusion (15-min),  2-5min prior to  EOI (25-28min),  EOI, and 0.5, 1, 2,  5, 8, 12, 24, 48 and  72 hr post dose. |                                                                                          |                                                                                                                                                                                                                                                            |         |    |    |
| pre-infusion, half  way through                                                                                   |                                                                                          |                                                                                                                                                                                                                                                            |         |    |    |
| Nab-paclitaxel  PKs                                                                                               | (5.1.2)                                                                                  | sodium heparin  tube                                                                                                                                                                                                                                       |         |    |    |
| 4 mL in 6 mL                                                                                                      | Pre-dose,  EOI, 1, 2,  and 4  hours after  EOI                                           |                                                                                                                                                                                                                                                            |         |    |    |
| LMB-100  PKs                                                                                                      | (5.1.1)                                                                                  | K2EDTA  tube                                                                                                                                                                                                                                               |         |    |    |
| 2 mL                                                                                                              | Pre-dose,  EOIc                                                                          |                                                                                                                                                                                                                                                            |         |    |    |
| Screening                                                                                                         |                                                                                          |                                                                                                                                                                                                                                                            |         |    |    |
| Day                                                                                                               | 1                                                                                        | 2                                                                                                                                                                                                                                                          | 3       | 5  | 6  |
| Screening                                                                                                         | 1                                                                                        |                                                                                                                                                                                                                                                            |         |    |    |  
| Tumor  Sample                                       | (5.1.5)                 | NA                                                                                                                               |                                                                                                                                                                     |                                                                                                                                                                                     |
|-----------------------------------------------------|-------------------------|----------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| expression                                          | (5.1.9)                 |                                                                                                                                  |                                                                                                                                                                     |                                                                                                                                                                                     |
| Immune                                              | gene                    | PAXgene  RNA tube                                                                                                                |                                                                                                                                                                     |                                                                                                                                                                                     |
| 2.5 mL                                              | Pre-dose                |                                                                                                                                  |                                                                                                                                                                     |                                                                                                                                                                                     |
| CellSave & three  8 mL CPT citrate  tubes           |                         |                                                                                                                                  |                                                                                                                                                                     |                                                                                                                                                                                     |
| Two 7.5 mL  Veridex                                 |                         |                                                                                                                                  |                                                                                                                                                                     |                                                                                                                                                                                     |
| CECs, Immune  Subsets,                              | CTCs                    | (5.1.7, 5.1.8,  5.1.10)                                                                                                          |                                                                                                                                                                     |                                                                                                                                                                                     |
| PE mediated  CLS  (Cytokines)  and serum  MPF level | (5.1.6, 5.1.12)         |                                                                                                                                  |                                                                                                                                                                     |                                                                                                                                                                                     |
| (5.1.2)                                             |                         |                                                                                                                                  |                                                                                                                                                                     |                                                                                                                                                                                     |
| ADA                                                 | Pre-dose                | ADA =anti-drug antibody; EOI =End of infusion; PK =pharmacokinetic; CTC=circulating tumor cell; CEC=circulating endothelial cell | a. Archival tissue collection or biopsy if no tissue available (mandatory). b. Collected preferably at baseline, but may be collected at any time during the study. | c. Required only for patients on Arm A1. May alternatively be drawn on day 5 to avoid a weekend draw.  d. May alternatively be drawn post treatment on C1D5 to avoid a weekend draw |
| 4 mL red SST  tube                                  | Pre-dose                | X                                                                                                                                | X                                                                                                                                                                   | X                                                                                                                                                                                   |
| K2EDTA  tube                                        |                         |                                                                                                                                  |                                                                                                                                                                     |                                                                                                                                                                                     |
| 2 mL                                                | Pre-dose                | X                                                                                                                                | X                                                                                                                                                                   | X                                                                                                                                                                                   |
| Pharmacogenetic  studies                            | (5.1.3)                 | 4-6 mL in purple  top tube                                                                                                       |                                                                                                                                                                     |                                                                                                                                                                                     |
| Nab-paclitaxel  PKs                                 | (5.1.2)                 | sodium heparin  tube                                                                                                             |                                                                                                                                                                     |                                                                                                                                                                                     |
| 4 mL in 6 mL                                        |                         |                                                                                                                                  |                                                                                                                                                                     |                                                                                                                                                                                     |
| LMB-100  PKs                                        | (5.1.1)                 | K2EDTA  tube                                                                                                                     |                                                                                                                                                                     |                                                                                                                                                                                     |
| 2 mL                                                | Pre-dose, EOI           | Pre-dose, EOIc                                                                                                                   |                                                                                                                                                                     |                                                                                                                                                                                     |
| Day                                                 | 1                       | 3                                                                                                                                | Safety Follow-up  Visit                                                                                                                                             |                                                                                                                                                                                     |
| Withdrawal Visit                                    |                         |                                                                                                                                  |                                                                                                                                                                     |                                                                                                                                                                                     |
| Cycle                                               | At time of  Progression |                                                                                                                                  |                                                                                                                                                                     |                                                                                                                                                                                     |
| 2                                                   |                         |                                                                                                                                  |                                                                                                                                                                     |                                                                                                                                                                                     |  
| 5.2.2 Sample Collection for Patients receiving continuous infusion of LMB-100 (Arms B1 and B2)                                                                                                                                     | 5.2.2.1 24-hour continuous infusion                                                            | Timed samples scheduled for within 4 hours after reference point (start of infusion or end of infusion) should be collected within +/- 15 minutes of  indicted time. Those collected 4 or more hours after reference point (start of infusion or end of infusion) may be collected within +/- 60 minutes of  indicated time.   | Cycle   |                      |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|----------------------|
| (5.1.5, 5.1.11)                                                                                                                                                                                                                    |                                                                                                |                                                                                                                                                                                                                                                                                                                                |         |                      |
| Tumor  Sample                                                                                                                                                                                                                      | NA                                                                                             | Xb                                                                                                                                                                                                                                                                                                                             |         |                      |
| expression  (5.1.9)                                                                                                                                                                                                                |                                                                                                |                                                                                                                                                                                                                                                                                                                                |         |                      |
| Immune                                                                                                                                                                                                                             | gene                                                                                           | PAXgene  RNA tube                                                                                                                                                                                                                                                                                                              |         |                      |
| 2.5 mL                                                                                                                                                                                                                             | Pre-dose                                                                                       |                                                                                                                                                                                                                                                                                                                                |         |                      |
| Two 7.5 mL  Veridex CellSave  & three 8 mL CPT                                                                                                                                                                                     | citrate tubes                                                                                  |                                                                                                                                                                                                                                                                                                                                |         |                      |
| CECs, Immune  Subsets, CTCs  (5.1.7, 5.1.8,  5.1.10)  CLS (Cytokines)  and serum MPF  level   (5.1.6, 5.1.12)  PE mediated  ADA  (5.1.2)  Pharmacogenetic  studies (5.1.3)  Nab-paclitaxel  PKsa (5.1.2) LMB-100  PKs (5.1.1)  Day | Pre-dose                                                                                       |                                                                                                                                                                                                                                                                                                                                |         |                      |
| Pre-dose, 1, 2, 4  and 6 hours after                                                                                                                                                                                               | start of continuous  infusion                                                                  |                                                                                                                                                                                                                                                                                                                                |         |                      |
| Pre- dose                                                                                                                                                                                                                          |                                                                                                |                                                                                                                                                                                                                                                                                                                                |         |                      |
| 4 mL red SST  tube                                                                                                                                                                                                                 | EOI                                                                                            |                                                                                                                                                                                                                                                                                                                                |         |                      |
| 2 mL  K2ED TA  tube 4-6 mL in purple  top tube                                                                                                                                                                                     | Xc                                                                                             |                                                                                                                                                                                                                                                                                                                                |         |                      |
| sodium heparin  tube                                                                                                                                                                                                               |                                                                                                |                                                                                                                                                                                                                                                                                                                                |         |                      |
| 4mL in 6 mL                                                                                                                                                                                                                        | (~15-min), 2-5  min prior to  EOI(~25- 28min), EOI,  and 0.5, 1, 2, 5,  8, 12 hours  post-dose |                                                                                                                                                                                                                                                                                                                                |         |                      |
| Pre-infusion,  half way  through dose                                                                                                                                                                                              | and 6 hours                                                                                    | after start                                                                                                                                                                                                                                                                                                                    | of      | continuous  infusion |
| Pre-dose,  End of  loading  dose, 2,                                                                                                                                                                                               | 24 hr post-dose                                                                                |                                                                                                                                                                                                                                                                                                                                |         |                      |
| EOI then 2  hours after  EOI                                                                                                                                                                                                       |                                                                                                |                                                                                                                                                                                                                                                                                                                                |         |                      |
| Abbreviated Title: LMB-100 + Abrx in PDA  Version Date: 12/11/2018                                                                                                                                                                 | K2EDTA  tube                                                                                   |                                                                                                                                                                                                                                                                                                                                |         |                      |
| 2 mL                                                                                                                                                                                                                               | Screening Screening                                                                            | 2                                                                                                                                                                                                                                                                                                                              |         |                      |
| 1 1                                                                                                                                                                                                                                |                                                                                                |                                                                                                                                                                                                                                                                                                                                |         |                      |  
74  
| (5.1.5, 5.1.11)                                                                                                                                                                                                                    |                    |                                     |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|-------------------------------------|
| Tumor  Sample                                                                                                                                                                                                                      | NA                 |                                     |
| expression  (5.1.9)                                                                                                                                                                                                                |                    |                                     |
| Immune                                                                                                                                                                                                                             | gene               | 24 hrs after EOId 24 hrs after EOId |
| PAXgene  RNA tube                                                                                                                                                                                                                  |                    |                                     |
| 2.5 mL  Two 7.5 mL  Veridex CellSave  & three 8 mL CPT                                                                                                                                                                             | citrate tubes      |                                     |
| CECs, Immune  Subsets, CTCs  (5.1.7, 5.1.8,  5.1.10)  CLS (Cytokines)  and serum MPF  level   (5.1.6, 5.1.12)  PE mediated  ADA  (5.1.2)  Pharmacogenetic  studies (5.1.3)  Nab-paclitaxel  PKsa (5.1.2) LMB-100  PKs (5.1.1)  Day | 4 mL red SST  tube |                                     |
| 2 mL  K2ED TA  tube 4-6 mL in purple  top tube  sodium heparin  tube  4mL in 6 mL                                                                                                                                                  | 48 hr post-dose    | 72 hr post-dose                     |
| K2EDTA  tube                                                                                                                                                                                                                       |                    |                                     |
| 2 mL                                                                                                                                                                                                                               | 3                  | 4                                   |
| Cycle                                                                                                                                                                                                                              |                    |                                     |  
| (5.1.5, 5.1.11)                                                                                                                                                                                                                    |                   |                           |          |                           |                         |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|---------------------------|----------|---------------------------|-------------------------|
| Tumor  Sample                                                                                                                                                                                                                      | NA                | Xe                        | Xe       |                           |                         |
| expression  (5.1.9)                                                                                                                                                                                                                |                   |                           |          |                           |                         |
| Immune                                                                                                                                                                                                                             | gene              | PAXgene  RNA tube         |          |                           |                         |
| 2.5 mL                                                                                                                                                                                                                             | Pre-dose          |                           |          |                           |                         |
| Two 7.5 mL  Veridex CellSave  & three 8 mL CPT                                                                                                                                                                                     | citrate tubes     |                           |          |                           |                         |
| CECs, Immune  Subsets, CTCs  (5.1.7, 5.1.8,  5.1.10)  CLS (Cytokines)  and serum MPF  level   (5.1.6, 5.1.12)  PE mediated  ADA  (5.1.2)  Pharmacogenetic  studies (5.1.3)  Nab-paclitaxel  PKsa (5.1.2) LMB-100  PKs (5.1.1)  Day | Pre-dose          |                           |          |                           |                         |
| 4 mL red SST  tube                                                                                                                                                                                                                 | Pre-dose          | X                         |          |                           |                         |
| X                                                                                                                                                                                                                                  |                   |                           |          |                           |                         |
| 2 mL  K2ED TA  tube                                                                                                                                                                                                                | Predose                   | Predose                           | X        | X                         | 76                      |
| 4-6 mL in purple  top tube  sodium heparin  tube  4mL in 6 mL  K2EDTA  tube 2 mL                                                                                                                                                   | Pre-dose          | and end of  loading  dose | Pre-dose | and end of  loading  dose |                         |
| EOI                                                                                                                                                                                                                                | EOI               |                           |          |                           |                         |
| (Arms A1,  A2, B1)                                                                                                                                                                                                                 |                   |                           |          |                           |                         |
| 8                                                                                                                                                                                                                                  |                   |                           |          |                           |                         |
| (Arm B2  only)                                                                                                                                                                                                                     |                   |                           |          |                           |                         |
| 1                                                                                                                                                                                                                                  | 2                 | 3                         | 1        | 2                         | At time of  Progression |
| (Arm B2  only)                                                                                                                                                                                                                     | Withdrawal  Visit |                           |          |                           |                         |
| Cycle                                                                                                                                                                                                                              | 2                 | 3                         |          |                           |                         |  
| (5.1.5, 5.1.11)                                                                                                                                                                                                                    |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                        |             |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|
| Tumor  Sample                                                                                                                                                                                                                      | NA                                                                                                                               |                                                                                                                                                                                   |                                                                                                                                                                                        |             |
| expression  (5.1.9)                                                                                                                                                                                                                |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                        |             |
| Immune                                                                                                                                                                                                                             | gene                                                                                                                             | PAXgene  RNA tube                                                                                                                                                                 |                                                                                                                                                                                        |             |
| 2.5 mL  Two 7.5 mL  Veridex CellSave  & three 8 mL CPT                                                                                                                                                                             | citrate tubes                                                                                                                    |                                                                                                                                                                                   |                                                                                                                                                                                        |             |
| CECs, Immune  Subsets, CTCs  (5.1.7, 5.1.8,  5.1.10)  CLS (Cytokines)  and serum MPF  level   (5.1.6, 5.1.12)  PE mediated  ADA  (5.1.2)  Pharmacogenetic  studies (5.1.3)  Nab-paclitaxel  PKsa (5.1.2) LMB-100  PKs (5.1.1)  Day | ADA =anti-drug antibody; EOI =End of infusion; PK =pharmacokinetic; CTC=circulating tumor cell; CEC=circulating endothelial cell | a. Performed only in subjects receiving nab-paclitaxel (i.e., not performed in single agent lead in)  b. Archival tissue collection or biopsy if no tissue available (mandatory). | c. Collected preferably at baseline, but may be collected at any time during the study. d. May alternatively be drawn on day prior (at least 2 hours post-EOI) to avoid a weekend draw | e. Optional |
| 4 mL red SST  tube                                                                                                                                                                                                                 | X                                                                                                                                |                                                                                                                                                                                   |                                                                                                                                                                                        |             |
| 2 mL  K2ED TA  tube                                                                                                                                                                                                                | X                                                                                                                                |                                                                                                                                                                                   |                                                                                                                                                                                        |             |
| 4-6 mL in purple  top tube  sodium heparin  tube  4mL in 6 mL  K2EDTA  tube 2 mL                                                                                                                                                   |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                        |             |
| Cycle                                                                                                                                                                                                                              | Safety  Follow-up  Visit                                                                                                         |                                                                                                                                                                                   |                                                                                                                                                                                        |             |  
| 5.2.2.2 48-hour continuous infusion               | Timed samples scheduled for within 4 hours after reference point (start of infusion or end of infusion) should be collected within +/- 15 minutes of  indicted time. Those collected 4 or more hours after reference point (start of infusion or end of infusion) may be collected within +/- 60 minutes of  indicated time.   | Cycle                               |                                                                                                                                                                                                                                                 |                |                   |
|---------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|-------------------|
| Tumor  Sample                                     | (5.1.5,  5.1.11)  expression  (5.1.9)                                                                                                                                                                                                                                                                                          |                                     |                                                                                                                                                                                                                                                 |                |                   |
| Immune                                            | gene                                                                                                                                                                                                                                                                                                                           | NA  PAXgene  RNA tube               |                                                                                                                                                                                                                                                 |                |                   |
| 2.5 mL                                            | Xb                                                                                                                                                                                                                                                                                                                             | 24 hrs after EOId 24 hrs after EOId |                                                                                                                                                                                                                                                 |                |                   |
| Pre-dose                                          |                                                                                                                                                                                                                                                                                                                                |                                     |                                                                                                                                                                                                                                                 |                |                   |
| Veridex CellSave  & three 8 mL CPT                | citrate tubes                                                                                                                                                                                                                                                                                                                  |                                     |                                                                                                                                                                                                                                                 |                |                   |
| Two 7.5 mL                                        | 4 mL red SST tube                                                                                                                                                                                                                                                                                                              |                                     |                                                                                                                                                                                                                                                 |                |                   |
| 2 mL K2EDTA  tube                                 |                                                                                                                                                                                                                                                                                                                                |                                     |                                                                                                                                                                                                                                                 |                |                   |
| CECs, Immune  Subsets,                            | CTCs                                                                                                                                                                                                                                                                                                                           | (5.1.7, 5.1.8,  5.1.10)             | Pre-dose                                                                                                                                                                                                                                        |                |                   |
| PE mediated CLS  (Cytokines) and  serum MPF level | (5.1.6, 5.1.12)                                                                                                                                                                                                                                                                                                                |                                     |                                                                                                                                                                                                                                                 |                |                   |
| (5.1.2)                                           |                                                                                                                                                                                                                                                                                                                                |                                     |                                                                                                                                                                                                                                                 |                |                   |
| ADA                                               | 24 hours after start                                                                                                                                                                                                                                                                                                           | of infusion                         |                                                                                                                                                                                                                                                 |                |                   |
| Pre-dose, 1, 2, 4  and 6 hours after              | start of infusion                                                                                                                                                                                                                                                                                                              |                                     |                                                                                                                                                                                                                                                 |                |                   |
| Xc Pre-dose                                       | EOI                                                                                                                                                                                                                                                                                                                            |                                     |                                                                                                                                                                                                                                                 |                |                   |
| Pharmacogenetic  studies                          | (5.1.3)                                                                                                                                                                                                                                                                                                                        | 4-6 mL in purple  top tube          | pre-infusion, half way  through loading dose  (15-min), 2-5min prior  to end of loading dose  (25-28min), EOI, and  0.5, 1, 2, 5, 8, 12, 24,  48 and 72 hr post dose.  Pre-dose, End of  loading dose, 2,  and 6 hours after  start of infusion |                |                   |
| Nab-paclitaxel PKsa                               | (5.1.2)                                                                                                                                                                                                                                                                                                                        | 4mL in 6 mL sodium  heparin tube    | EOI then 2 hours                                                                                                                                                                                                                                | after EOI      |                   |
| LMB-100 PKs                                       | (5.1.1)                                                                                                                                                                                                                                                                                                                        | Day                                 | 2 mL K2EDTA  tube                                                                                                                                                                                                                               | 24 hours after | start of infusion |
| Screening Screening                               | 1                                                                                                                                                                                                                                                                                                                              | 2                                   | 3                                                                                                                                                                                                                                               | 4              |                   |
| 1                                                 |                                                                                                                                                                                                                                                                                                                                |                                     |                                                                                                                                                                                                                                                 |                |                   |  
78  
| Tumor  Sample                                     | (5.1.5,  5.1.11)  expression  (5.1.9)   |                                  |                                                   |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
|---------------------------------------------------|-----------------------------------------|----------------------------------|---------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|
| Immune                                            | gene                                    | NA  PAXgene  RNA tube            |                                                   |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
| 2.5 mL                                            | Xe                                      |                                  |                                                   |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
| Pre-dose                                          |                                         |                                  |                                                   |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
| Veridex CellSave  & three 8 mL CPT                | citrate tubes                           |                                  |                                                   |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
| Two 7.5 mL                                        | 4 mL red SST tube                       |                                  |                                                   |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
| 2 mL K2EDTA  tube                                 |                                         |                                  |                                                   |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
| CECs, Immune  Subsets,                            | CTCs                                    | (5.1.7, 5.1.8,  5.1.10)          | Pre-dose                                          | ADA =anti-drug antibody; EOI =End of infusion; PK =pharmacokinetic; CTC=circulating tumor cell; CEC=circulating endothelial cell | a. Performed only in subjects receiving nab-paclitaxel (i.e., not performed in single agent lead in)  b. Archival tissue collection or biopsy if no tissue available (mandatory). | c. Collected preferably at baseline, but may be collected at any time during the study.  d. May alternatively be drawn on day prior (at least 2 hours post-EOI) to avoid a weekend draw | e. Optional |
| PE mediated CLS  (Cytokines) and  serum MPF level | (5.1.6, 5.1.12)                         |                                  |                                                   |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
| (5.1.2)                                           |                                         |                                  |                                                   |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
| ADA                                               | Pre-dose                                | X                                | X                                                 | X                                                                                                                                |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
| Pre-dose                                          | X                                       | X                                | X                                                 |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
| Pharmacogenetic  studies                          | (5.1.3)                                 | 4-6 mL in purple  top tube       |                                                   |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
| Nab-paclitaxel PKsa                               | (5.1.2)                                 | 4mL in 6 mL sodium  heparin tube | Pre-dose, end of  loading dose and  2 hours after | start of infusion                                                                                                                |                                                                                                                                                                                   |                                                                                                                                                                                         |             |
| LMB-100 PKs                                       | (5.1.1)                                 | Day                              | 2 mL K2EDTA  tube                                 | 24 hours after                                                                                                                   | start of infusion                                                                                                                                                                 | EOI                                                                                                                                                                                     |             |
| 1                                                 | 2                                       | 3                                | 8                                                 | At time of  Progression                                                                                                          | Withdrawal  Visit                                                                                                                                                                 | Safety  Follow-up  Visit                                                                                                                                                                |             |
| Cycle                                             | 2                                       |                                  |                                                   |                                                                                                                                  |                                                                                                                                                                                   |                                                                                                                                                                                         |             |  
79