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LMB-100

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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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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)

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