Determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of AMG 994, in combination with AMG 404.

Participants will be administered with the MTD or RP2D of AMG 994 identified in the dose escalation part of the study, in combination with AMG 404.

Administered as an intravenous (IV) infusion.

AMG 994

AMG 404

The primary objective of this study is to evaluate the safety, tolerability, and maximum tolerated dose (MTD)/maximum tolerated combination dose (MTCD) or recommended phase 2 dose (RP2D) of AMG 994 as monotherapy and AMG 994 in combination with AMG 404 in participants with advanced solid tumors.

AMG 994 will be administered by short term intravenous (IV) infusion once weekly in each 28-day cycle and AMG 404 will be administered by short-term IV infusion once every 4 weeks (Q4W) in a 28 day cycle (on day 1 of cycle 2 and beyond). The study will be conducted in 2 parts: Part 1 - Dose Exploration and Part 2 - Dose Expansion.

Study of AMG 994 Monotherapy and AMG 994 and AMG 404 Combination Therapy in Participants With Advanced Solid Tumors

A Phase 1, Multicenter, Open-label, Dose Exploration and Dose Expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 994 Monotherapy and Combination of AMG 994 and AMG 404 in Subjects With Advanced Solid Tumors

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

Amgen

Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Adenocarcinoma

Cholangiocarcinoma

Mesothelioma

Mesothelioma, Malignant

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenoma

Neoplasms, Mesothelial

Bile Duct Cancer

Malignant Mesothelioma

All Drugs and Chemicals

Dermatologic Agents

Antibodies

Tofacitinib

Immunoglobulins

Coal Tar

LMB-100

Immunotoxins

Janus Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunoconjugates

Immunologic Factors

LMB-100 at escalating doses plus tofacitinib

Arms 1 and 2: Administered intravenous (IV) as an approximate 30-minute infusion of each 21-day cycle on days 4, 6 and 8 until disease progression, intolerance or withdrawal from study.

Arms 1 and 2: Administered orally twice daily on days 1-10 of each cycle until disease progression, intolerance or withdrawal from study.

Test for mesothelin expression in tumor tissues for study eligibility

Mesothelin Expression

Christine C Alewine, M.D.

Background:

The protein mesothelin is found on many kinds of tumors. The drug LMB-100 targets cancer cells that make this protein. Researchers want to see if LMB-100 combined with another drug can help people with these tumors.

Objective:

To find a safe dose of LMB-100 plus tofacitinib in people with pancreatic cancer, bile-duct cancer, and other solid tumors that make mesothelin.

Eligibility:

People ages 18 and older with pancreatic cancer, bile-duct cancer, or any other solid tumor with mesothelin that worsened after treatment or they could not receive standard treatment

Design:

Participants will be screened with:

* Medical history
* Tumor tissue sample. If they do not have a sample, they will have a biopsy.
* Physical exam
* Blood and heart tests
* Scans and x-rays: They may have a dye injected for the scans.

Participants will take the drugs in up to three 21-day cycles. They will take tofacitinib by mouth twice a day on days 1-10 of each cycle. They will have LMB-100 injected into the blood on days 4, 6, and 8 of every cycle. Patients that do not have a medi-port may need to have a central vein access line placed.

Participants will take other drugs on the days they receive LMB-100.

Participants will repeat screening tests during the study. They may have a biopsy at the start of the first 2 cycles.

If participants must stop the study, they will have a safety visit 3-6 weeks after their last dose of the study drug. Some participants may then have visits every 6 weeks.

After treatment, participants will be contacted about once a year. They will be asked about their cancer.

Background:

* Pancreatic cancer is the fourth most common cause of cancer death in the United States, claiming more than 40,000 lives each year.
* Incidence nearly equals mortality with just 6% of participants living five years beyond their diagnosis. Most patients are diagnosed at an advanced stage, but even patients with early-stage disease have a long-term survival of less than 20%.
* Cholangiocarcinoma is a rare disease and just 3,000 patients are diagnosed with the extrahepatic form yearly. The median overall survival of patients with advanced disease receiving standard of care treatment is less than 1 year.
* Expression of mesothelin (MSLN) in pancreatic ductal adenocarcinoma (PDA) has been examined in several published studies and ranges from 86 to 100%. Similar incidence of expression has been observed in extrahepatic cholangiocarcinoma.
* In addition to pancreatobiliary tumors, many other solid tumor types also express MSLN such as mesothelioma, colorectal, lung adenocarcinomas, epithelial ovarian, gastric and triple negative breast cancers, as well as some tumors of squamous cell origin.
* LMB-100 and a closely related immunotoxin also targeting MSLN have been studied in previous Phase 1 clinical studies for mesothelioma and pancreatic cancer.
* Results from these studies showed that almost all patients formed anti-drug-antibodies (ADAs) that neutralized subsequent injection of the product making it ineffective.
* Tofacitinib is an oral Janus Kinase-1 and -3 (JAK) inhibitor approved by the FDA for the treatment of rheumatoid arthritis and ulcerative colitis.
* Pre-clinical studies have shown that tofacitinib can prevent the formation of ADAs against an immunotoxin closely related to LMB-100
* Co-administration of tofacitinib with immunotoxin increased immunotoxin serum half- life in mice and enhanced anti-tumor efficacy
* This clinical trial will investigate whether co-administration of tofacitinib with LMB- 100 can prevent or delay the formation of ADAs and thus allow patients to receive additional effective cycles of LMB-100.

Objectives:

* The primary objective of the dose escalation phase of this study is to assess the safety and tolerability of LMB-100 given in combination with tofacitinib to patients with pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma and other mesothelin-positive solid tumors
* The primary objective of the expansion phase of this study is to determine whether co-administration of tofacitinib delays formation of neutralizing anti-LMB-100 ADAs through cycle 2 of treatment (as measured by LMB-100 serum drug levels) in patients with pancreatobiliary cancers.

Eligibility:

* Age \>= 18 years
* Histologically confirmed solid tumor malignancy for which no curative therapy exists
* Participants must have received at least one prior systemic treatment regimen for their disease OR be ineligible to receive available standard treatments for their disease OR refused first-line standard systemic treatments but have been treated with other anti-cancer agents.

Design:

* This is a Phase I study which will accrue up to 45 subjects total, accounting for screen failure.
* Participants will be co-treated for 3 cycles with tofacitinib given orally for the first 10 days of each 21-day cycle, and LMB-100 given on days 4, 6 and 8.
* A 3+3 dose escalation schema will be used. Two dose levels are planned. One minus dose level could be utilized if dose de-escalation is necessary.
* Following identification of an optimal dose and schedule, an expansion phase of 15 participants will be initiated at the optimal dose for patients with pancreatic adenocarcinoma and extrahepatic cholangiocarcinoma. At least 8 participants in the expansion phase must have pancreatic adenocarcinoma.
* Participants on the Dose Escalation and Dose Expansion Arms who appear to be obtaining clinical benefit from LMB-100/tofacitinib after 3 cycles of treatment may elect to receive additional cycles of therapy at the discretion of the principal investigator (PI).

Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors

A Phase I Study of Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

A dose limiting toxicity is defined as any events occurring within the first cycle of treatment (21 days) such as any death not clearly due to the underlying disease or extraneous causes, transaminitis that meets criteria for Hy's Law: grade ≥2 elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) with simultaneous elevation of total bilirubin to ≥ 2x ULN while alkaline phosphatase remains \< 2x upper limit of normal (ULN). Some hematological toxicities, and Grade ≥3 non-hematological toxicities; and any other drug related toxicity considered significant enough to be qualifies as a DLT in the opinion of the principal investigator. Inability to start cycle 2 within 2 weeks after completing cycle 1 due to drug-related adverse events.

MTD is defined as the maximum dose at which less than 33% of participants experience a dose-limiting toxicity (defined as any events occurring within the first cycle of treatment (21 days) such as any death not clearly due to the underlying disease or extraneous causes).

This measure assessed how many participants have LMB-100 plasma drug levels higher than threshold (600 ng/mL) during Cycle 2 pharmacokinetics (PK) measurements, a sign of effective prevention of anti-LMB-100 antibodies. The validated enzyme-linked immunosorbent assay (ELISA) test was used to measure plasma LMB-100 concentration. Below 600ng/mL is considered a bad outcome and above 600ng/mL is considered a good outcome.

Grade 1-5 adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 observed in participants with pancreatic cancer. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant. Grade 4 is life-threatening consequences. Grade 5 is death related to adverse events.

This measure assessed how many participants in the dose escalation have LMB-100 plasma drug levels higher than threshold (600 ng/mL) during Cycle 2 pharmacokinetics (PK) measurements, a sign of effective prevention of anti-LMB-100 antibodies. The validated enzyme-linked immunosorbent assay (ELISA) test was used to measure plasma LMB-100 concentration. Below 600ng/mL is considered a bad outcome and above 600ng/mL is considered a good outcome.

The maximum observed analyte concentration in plasma was reported.

This measure assessed how many participants have no LMB-100 plasma drug levels higher than threshold (600 ng/mL) during Cycle 3 pharmacokinetics (PK) measurements, a sign of effective prevention of anti-LMB-100 antibodies. The validated enzyme-linked immunosorbent assay (ELISA) test was used to measure plasma LMB-100 concentration. Below 600ng/mL is considered a bad outcome and above 600ng/mL is considered a good outcome.

AUC is a measure of the serum concentration of LMB-100 over time. It is used to characterize drug absorption.

Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.

Grade 1-4 adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 observed in participants with pancreatic cancer. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant. Grade 4 is life-threatening consequences. Grade 5 is death related to adverse event.

National Cancer Institute (NCI)

Principla Investigator

LMB-100 100 mcg/kg

LMB-100: Arms 1: Administered intravenous (IV) as an approximate 30-minute infusion of each 21-day cycle on days 4, 6 and 8 until disease progression, intolerance or withdrawal from study.

Tofacitinib: Arms 1: Administered orally twice daily on days 1-10 of each cycle until disease progression, intolerance or withdrawal from study.

Dose Escalation Dose Level 1 LMB-100 100 mcg/kg

LMB-100 140 mcg/kg

LMB-100: Arms 2: Administered intravenous (IV) as an approximate 30-minute infusion of each 21-day cycle on days 4, 6 and 8 until disease progression, intolerance or withdrawal from study.

Tofacitinib: Arms 2: Administered orally twice daily on days 1-10 of each cycle until disease progression, intolerance or withdrawal from study.

Dose Escalation Dose Level 2 LMB-100 140 mcg/kg

LMB-100 at optimal dose plus tofacitinib - 100 mcg/kg

LMB-100 at optimal dose plus tofacitinib LMB-100: Arms 1: Administered intravenous (IV) as an approximate 30-minute infusion of each 21-day cycle on days 4, 6 and 8 until disease progression, intolerance or withdrawal from study.

Tofacitinib: Arms 1: Administered orally twice daily on days 1-10 of each cycle until disease progression, intolerance or withdrawal from study.

Dose Expansion LMB-100, 100 mcg/kg

LMB-100 at escalating doses plus tofacitinib

LMB-100: Arms 1: Administered intravenous (IV) as an approximate 30-minute infusion of each 21-day cycle on days 4, 6 and 8 until disease progression, intolerance or withdrawal from study.

Tofacitinib: Arms 1: Administered orally twice daily on days 1-10 of each cycle until disease progression, intolerance or withdrawal from study.

Mesothelin Expression: Test for mesothelin expression in tumor tissues for study eligibility

LMB-100 at escalating doses plus tofacitinib

LMB-100: Arms 2: Administered intravenous (IV) as an approximate 30-minute infusion of each 21-day cycle on days 4, 6 and 8 until disease progression, intolerance or withdrawal from study.

Tofacitinib: Arms 2: Administered orally twice daily on days 1-10 of each cycle until disease progression, intolerance or withdrawal from study.

Mesothelin Expression: Test for mesothelin expression in tumor tissues for study eligibility

LMB-100 at optimal dose plus tofacitinib

LMB-100: Arms 1: Administered intravenous (IV) as an approximate 30-minute infusion of each 21-day cycle on days 4, 6 and 8 until disease progression, intolerance or withdrawal from study.

Tofacitinib: Arms 1: Administered orally twice daily on days 1-10 of each cycle until disease progression, intolerance or withdrawal from study.

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Christine C. Alewine

All Participants in Dose Escalation Dose Level 1, and Dose Level 2 administered LMB-100: Both Arms intravenous (IV) as an approximate 30-minute infusion of each 21-day cycle on days 4, 6 and 8 and Tofacitinib orally twice daily on days 1-10 of each cycle, and LMB-100.

All Participants in Dose Escalation Dose Level 1, and Dose Level 2

Maximum Tolerated Dose (MTD) of LMB-100 With Tofacitinib

LMB-100 at optimal dose plus tofacitinib - 100 mcg/kg LMB-100: Arms 1: Administered intravenous (IV) as an approximate 30-minute infusion of each 21-day cycle on days 4, 6 and 8 until disease progression, intolerance or withdrawal from study.

Tofacitinib: Arms 1: Administered orally twice daily on days 1-10 of each cycle until disease progression, intolerance or withdrawal from study.

Per protocol, this measure includes all participants who meet eligibility criteria for the dose expansion (pancreatobiliary diagnosis) and received LMB-100 at the Maximum Tolerated Dose (Dose Escalation-Dose Level 1 (DL1) and Dose expansion, n =11). Only participants who have pharmacokinetics results during Cycle 2 are evaluable. Five more participants were not evaluable due to not receiving Cycle 2 treatment or not having pharmacokinetics results.

Percentage of Participants With Pancreatobiliary Cancer and LMB-100 Plasma Drug Levels Above Threshold 600ng/mL During Cycle 2 Who Received LMB-100 at Maximum Tolerated Dose

Per protocol, this outcome measure was only assessed in the dose escalation dose level 1 and dose escalation dose level 2 groups.

Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Treated in the Dose Escalation Group

6/10 participants were not evaluable for this endpoint because they did not receive the second cycle of treatment.

Percentage of Participants With LMB-100 Plasma Drug Levels Above Threshold 600ng/mL During Cycle 2 in Dose Escalation

1/6 participants from the expansion cohort were not evaluable because they discontinued treatment before receiving LMB-100 during their 1st cycle.

Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100

12/16 participants were not evaluable because they did not receive a 3rd cycle of treatment.

Percentage of Participants Without Delayed Formation of Neutralizing Anti-LMB-100 Anti-drug Antibodies (ADAs)

3/16 participants from both cohorts were not analyzed they did not have AUC(INF) of LMB-100 measured during the 1st cycle (i.e., Not evaluable)

Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) of LMB-100

3/16 participants were not analyzed because they did not have Plasma Half-life (T1/2) of LMB-100 measured during the 1st cycle (i.e., Not evaluable).

Plasma Half-Life (T1/2) of LMB-100

Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Who Have Pancreatobiliary Cancer

Dose Escalation- Dose Level 1 LMB-100 100 mcg/kg

Number of Participants With Serious and/or Non-serious Adverse Events Regardless of Attribution Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

1 of 7 participants in Dose Escalation-Dose Level 1 is not evaluable due to withdrawal from the study with loss of follow-up before the conclusion of the DLT period.

Number of Participants With a Dose-Limiting Toxicity (DLT)

Dose Escalation- Dose Level 2 - LMB -100 140 mcg/kg

Dose Expansion LMB-100 100 mcg/kg

Participants were enrolled but not treated.

Enrolled But Not Treated

Dose Escalation Phase

Dose Expansion Phase

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Adenocarcinoma of Lung

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Lung Adenocarcinoma

Antineoplastic Agents

Antibodies, Monoclonal

Pembrolizumab

Immunomodulating Agents

Mitogens

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Participants will receive LMB-100 on days 1, 3 and 5 of a 21-day cycle for up to 2 cycles.

Participants will receive pembrolizumab on day 1 of each subsequent 21-day cycle.

pembrolizumab

Testing for mesothelin expression performed at screening

Testing for ROS oncogene 1 (ROS1) gene, anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) variations performed at screening.

TrueSight Oncology 500

Azam Ghafoor, M.D.

Background:

Over 230,000 new lung cancer cases are diagnosed every year in the United States (U.S.) About 80% of lung cancers are non- small cell lung cancer (NSCLC). Most people have a more advanced stage of the disease that doesn't respond well to standard treatment. Researchers want to see if a combination of drugs may be able to help.

Objective:

To find out if LMB-100 followed by pembrolizumab can help tumors to shrink in people with NSCLC.

Eligibility:

People ages 18 and older with NSCLC that has not responded to standard therapies

Design:

Participants will be screened with:

* Medical history
* Physical exam
* Tumor sample. If one is not available, they will have a biopsy.
* Assessments of ability to perform normal activities
* Lung function tests
* Blood, heart, and urine tests
* Computed tomography (CT) and positron emission tomography (PET). They will lie in a machine that takes pictures of the body.

Participants will take LMB-100 in 21-day cycles for up to 2 cycles. They will take the drug by injection into an arm vein on days 1, 3, and 5 of each cycle. They will stay in the hospital 7-10 days each cycle. Then they will get pembrolizumab by injection into an arm vein every 3 weeks for up to 2 years. They may be able to take pembrolizumab an additional year if their cancer gets worse.

Participants will have repeats of the screening tests throughout the study.

About 30 days and 90 days after they stop treatment, participants will have follow-up visits. Then they will have visits every 6-12 weeks. They will be followed for the rest of their life through phone calls and emails.

Background:

* Mesothelin is expressed in approximately half of all lung adenocarcinomas.
* LMB-100 has demonstrated anti-tumor efficacy against several mesothelin expressing tumor models including non-small cell lung cancer (NSCLC). Programmed death ligand 1 (PD-1) is an Ig superfamily member related to cluster of differentiation (CD28) and cluster of differentiation 152 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands.
* Pembrolizumab, an immunoglobulin G4 (IgG4) monoclonal antagonist antibody to PD-1, is Food and Drug Administration (FDA) approved in the frontline for advanced non-squamous NSCLC as a single agent with high programmed death-ligand 1 (PD-L1) expression \[tumor proportion score (TPS) \>=50%\] or in combination with platinum-based doublet chemotherapy (PD-L1 unselected). It also approved in the second-line for high PDL1 expressing tumors (TPS \>=1%).
* Combination treatment with LMB-100 plus pembrolizumab results in greater anti-tumor efficacy in murine lung cancer model.

Objectives:

-To determine the objective response rate of LMB-100 followed by pembrolizumab in the treatment of subjects with mesothelin-expressing non-squamous non-small cell lung cancer (NSCLC) previously treated with immune checkpoint inhibitors.

Eligibility:

* Histologically confirmed locally advanced or metastatic non-squamous, non-small cell lung cancer lacking an EGFR sensitizing mutation, anaplastic lymphoma kinase (ALK) or ROS oncogene 1 (ROS1) gene rearrangement and not amenable to potentially curative surgical resection or chemoradiation.
* Tumor mesothelin expression of at least 25% of tumor cells as determined by the Laboratory of Pathology at the NCI.
* Subjects must have at least progressed after one prior platinum-based doublet chemotherapy AND standard immune checkpoint inhibitor (ICI) with either frontline single-agent pembrolizumab, or in combination with platinum-based doublet chemotherapy, or second-line single-agent nivolumab, pembrolizumab, or atezolizumab.
* Age \>= 18 years.

Design:

* This is an open-label, single center phase II study of LMB-100 followed by pembrolizumab in subjects with mesothelin expressing NSCLC who have progressed on standard therapies
* Subjects will receive LMB-100 at the single agent maximum tolerated dose (MTD) (140mg/kg) on days 1, 3 and 5 of a 21-day cycle for up to 2 cycles and pembrolizumab 200 mg on day 1 of cycle 3 of a 21- day cycle (or cycle 2 if disease progression is observed after 1 cycle) onwards until disease progression (on or after pembrolizumab) or intolerable toxicity for a maximum of 2 years (unless second course initiated).
* The total accrual ceiling for the screening will be set at 100 total patients in order to treat 23 subjects.

LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

A Phase II Study of LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Participants with a partial response or complete response is reported with an 80% confidence interval. Response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

Participants with a partial response or complete response is reported with an 95% confidence interval. Response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The participant's best response assignment will depend on the achievement of both measurement and confirmation criteria. Response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Progression free survival (PFS) is defined as the duration of time from start of treatment to time of progression (on or after pembrolizumab) or death, whichever occurs first, calculated from the on-study date using the Kaplan-Meier method.

Overall survival is defined as the duration of time from start of treatment to death from any cause.

Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 3 is severe. Grade 4 is life-threatening.

Participants who are treated who are unable to tolerate the treatment other than development of adverse events

Principal Investigator

3/6 participants were analyzed because 3 were screen failures. There were 3 deaths due to progression and not related to the study.

LMB-100 + Pembrolizumab

LMB-100: Participants will receive LMB-100 140mcg/kg on days 1, 3 and 5 of a 21-day cycle for up to 2 cycles.

Pembrolizumab: Participants will receive 200 mg pembrolizumab on day 1 of each subsequent 21-day cycle for up to 2 years or until disease progression.

Mesothelin Expression: Testing for mesothelin expression performed at screening.

TrueSight Oncology 500: Testing for ROS oncogene 1 (ROS1) gene, anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) variations performed at screening.

Mesothelin Expressing Non-Small Cell Lung Cancer Participants

Although 3 participants were screen failures, data collected for all (6) participants enrolled is shown here.

Dr. Azam Ghafoor

3/6 participants were analyzed because 3 were screen failures.

Proportion of Participants With Partial Response or Complete Response Reported With an 80% Confidence Interval

Proportion of Participants With Partial Response or Complete Response Reported With an 95% Confidence Interval

Complete Response

Partial Response

Stable Disease

Progressive Disease

Overall Response (OR)

Number of Participants With a Response

Progression Free Survival (PFS)

LMB-100 + Pembrolizumab

LMB-100: Participants will receive LMB-100 on days 1, 3 and 5 of a 21-day cycle for up to 2 cycles.

pembrolizumab: Participants will receive pembrolizumab on day 1 of each subsequent 21-day cycle.

Mesothelin Expression: Testing for mesothelin expression performed at screening

TrueSight Oncology 500: Testing for ROS oncogene 1 (ROS1) gene, anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) variations performed at screening.

Overall Survival

Grade 3 Possibly Related

Grade 3 Probably Related

Grade 3 Definitely Related

Grade 4 Possibly Related

Grade 4 Probably Related

Grade 4 Definitely Related

Proportion of Participants With Grade 3 and Grade 4 Adverse Events Possibly, Probably, and Definitely Related to LMB-100

Proportion of Participants With Grade 3 and Grade 4 Adverse Events Possibly, Probably, and Definitely Related to Pembrolizumab

Number of Participants Who Are Treated Who Are Unable to Tolerate the Treatment Other Than Development of Adverse Events

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

Overall Study

Digestive System Diseases

Gland and Hormone Related Diseases

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Paclitaxel

Albumin-Bound Paclitaxel

Tubulin Modulators

Antimitotic Agents

Arm A1, Dose Level 1, Phase I Short Infusion 100µg/kg LMB-100 +125mg/m\^2 nab-paclitaxel

Dose level 1 (DL1) Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving short infusion LMB-100+nabpaclitaxel

Arm A1, DL-1, Ph I Short Infusion 65µg/kg LMB-100 +125mg/m\^2 nab-paclitaxel

Arm A2, Phase 2 Short Infusion 65µg/kg LMB-100 +125mg/m\^2 nab-paclitaxel

Efficacy determination in patients with pancreatic cancer receiving short infusion LMB-100 + nabpaclitaxel

Arm B1, DL2, 48-hr Continuous Infusion Single Agent Lead-in 100µg/kg/day LMB-100 Maximum tolerated dose (MTD) determination in patients with pancreatic cancer receiving continuous infusion LMB-100 as single agent

Arm B1, DL1, 48-hr Continuous Infusion Single Agent Lead-in 65µg/kg/day LMB-100

Arm B1, DL3R, 24-hr Continuous Infusion Single Agent Lead-in 100µg/kg LMB-100

Subjects with pancreatic cancer receiving continuous infusion LMB-100 combination therapy

Arms A1 and A2 (short infusion): Administered intravenously (IV) on days 1, 3 and 5 of a 21 day cycle for a maximum of 2 cycles Arm B1 (continuous infusion): Administered IV for 24, 48, 72 or 96 hours continuously on the first 1 - 4 days or 24 hour infusions on days 1 and 4 (depending on dose level) of each 21 day cycle for a maximum of 2 cycles. Arm B2 (continuous infusion): Administered IV for 24,48, 72 or 96 hours continuously on the first 1 - 4 days or 24 hour infusions on days 1 and 4 (depending on dose level) of each 14 day cycle for a maximum of 3 cycles.

Administered intravenously (IV) on days 1 and for Arms A1, A2 and B1 on day 8 of each 14-21 day cycle for a maximum of 2 (Arms A1, A2 and B1) or 3 (Arm B2) cycles

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study of AMG 994 Monotherapy and AMG 994 and AMG 404 Combination Therapy in Participants With Advanced Solid Tumors	NCT04727554	Advanced Solid ...	AMG 994 AMG 404	18 Years - 100 Years	Amgen
Study of AMG 994 Monotherapy and AMG 994 and AMG 404 Combination Therapy in Participants With Advanced Solid Tumors	NCT04727554	Advanced Solid ...	AMG 994 AMG 404	18 Years - 100 Years	Amgen
Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors	NCT04034238	Neoplasms With ... Epithelioid Mes... Cholangiocarcin... Adenocarcinoma,...	LMB-100 Tofacitinib Mesothelin Expr...	18 Years -	National Institutes of Health Clinical Center (CC)
Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors	NCT04034238	Neoplasms With ... Epithelioid Mes... Cholangiocarcin... Adenocarcinoma,...	LMB-100 Tofacitinib Mesothelin Expr...	18 Years -	National Institutes of Health Clinical Center (CC)
Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors	NCT04034238	Neoplasms With ... Epithelioid Mes... Cholangiocarcin... Adenocarcinoma,...	LMB-100 Tofacitinib Mesothelin Expr...	18 Years -	National Institutes of Health Clinical Center (CC)
LMB-100 Followed by Pembrolizumab in the Treatment of Adults With Mesothelin-Expressing Non-Squamous Non-Small Cell Lung Cancer (NSCLC)	NCT04027946	Lung Cancer Non-Small Cell ... Adenocarcinoma ...	LMB-100 pembrolizumab Mesothelin Expr... TrueSight Oncol...	18 Years -	National Institutes of Health Clinical Center (CC)
Mesothelin-Targeted Immunotoxin LMB-100 Alone or in Combination With Nab-Paclitaxel in People With Previously Treated Metastatic and/or Locally Advanced Pancreatic Ductal Adenocarcinoma and Mesothelin Expressing Solid Tumors	NCT02810418	Neoplasms Pancreatic Neop...	LMB-100 Nab-Paclitaxel Mesothelin Expr... LMB-100	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for mesothelin expression