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

Brief summary public domain (ClinicalTrials.gov)

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.

Detailed description public domain (ClinicalTrials.gov)

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:

Detailed description public domain (ClinicalTrials.gov)

* 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).

Intervention public domain (ClinicalTrials.gov)

Drug: LMB-100. 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.

Intervention public domain (ClinicalTrials.gov)

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

Intervention public domain (ClinicalTrials.gov)

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

Arm public domain (ClinicalTrials.gov)

1. Dose escalation (experimental): LMB-100 at escalating doses plus tofacitinib

Arm public domain (ClinicalTrials.gov)

2. Dose expansion (experimental): LMB-100 at optimal dose plus tofacitinib

Primary outcome public domain (ClinicalTrials.gov)

Maximum Tolerated Dose (MTD) of LMB-100 With Tofacitinib. 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). Time frame: First cycle of treatment (21 days).

Primary outcome public domain (ClinicalTrials.gov)

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. 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. Time frame: Plasma LMB-100 levels during Cycle 2 treatment (each cycle = 21 days).

Primary outcome public domain (ClinicalTrials.gov)

Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Treated in the Dose Escalation Group. 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. Time frame: Throughout study treatment until 30 days post-completion, approximately 13 weeks.

Secondary outcome public domain (ClinicalTrials.gov)

Percentage of Participants With LMB-100 Plasma Drug Levels Above Threshold 600ng/mL During Cycle 2 in Dose Escalation. Time frame: Plasma LMB-100 levels during Cycle 2 of treatment (each cycle = 21 days).

Secondary outcome public domain (ClinicalTrials.gov)

Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100. Time frame: Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days).

Secondary outcome public domain (ClinicalTrials.gov)

Percentage of Participants Without Delayed Formation of Neutralizing Anti-LMB-100 Anti-drug Antibodies (ADAs). Time frame: Plasma LMB-100 levels during Cycle 3 treatment (each cycle = 21 days).

Secondary outcome public domain (ClinicalTrials.gov)

Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) of LMB-100. Time frame: Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days).

Secondary outcome public domain (ClinicalTrials.gov)

Plasma Half-Life (T1/2) of LMB-100. Time frame: Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days).

Secondary outcome public domain (ClinicalTrials.gov)

Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Who Have Pancreatobiliary Cancer. Time frame: Throughout study treatment until 30 days post-completion, approximately 13 weeks..

Eligibility public domain (ClinicalTrials.gov)

* INCLUSION CRITERIA: * Patients must have histologically confirmed solid tumor malignancy for which no curative therapy exists. * Pancreatic adenocarcinoma, extrahepatic cholangiocarcinoma or epithelioid subtype of mesothelioma, as determined by National Cancer Institute (NCI) Laboratory of Pathology, OR for all other tumor types, at least 20% of tumor cells must express mesothelin. Determination can be made using archival tumor tissue or fresh biopsy if archival tumor tissue is not available. * All patients must have evaluable disease (i.e., measurable per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. or by following carbohydrate antigen 19-9 (CA19-9) tumor marker). Patients in the expansion cohort must have measurable disease, per RECIST 1.1. evaluation of measurable disease. * Patients must have received at least one prior standard systemic treatment regimen for advanced disease OR be ineligible to receive available standards due to co-morbidities, prior toxicity, lack of standard options for tumor type, or having received all standards available for prior treatment of early-stage disease OR have refused first-line standard systemic treatment but have received prior anti-cancer treatments. * Patients with deficient Mismatch Repair (dMMR)/high levels of MicroSatellite Instability (MSI-H) disease must have received at least one prior anti-programmed cell death 1 (PD1) therapy, be ineligible to receive this treatment due to concurrent medical conditions or have refused this therapy. * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 * Age \>=18 years. Because no dosing or adverse event data are currently available on the use of LMB-100 alone or in combination with tofacitinib in persons with \<18 years of age, children are excluded from this study. * Patients must be more than 14 days removed from most recent minor surgical procedure (such as biliary stenting), 28 days from most recent major surgical procedure and 14 days from radiation therapy, systemic treatments (such as chemotherapy), or experimental drug treatment. All acute toxicities from prior treatment must have resolved to grade 1 or less except alopecia, anemia, peripheral neuropathy, or endocrinopathies corrected by replacement therapy. * Adequate hematological function: neutrophil count of \>= 1.5 x 10\^3 cells/micro liters, platelet count of \>= 85,000/micro liters, hemoglobin greater than or equal to 9 g/dL * Serum albumin \>= 2.5 mg/dL without intravenous …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 19 participants (actual).

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Maximum Tolerated Dose (MTD) of LMB-100 With Tofacitinib [First cycle of treatment (21 days)]. Number, mcg/kg given days 4, 6, 8 every cycle. All Participants in Dose Escalation Dose Level 1, and Dose Level 2 (n=10): 100.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

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 [Plasma LMB-100 levels during Cycle 2 treatment (each cycle = 21 days)]. Number, Percentage of participants. Dose Expansion LMB-100, 100 mcg/kg (n=6): 33.3.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Treated in the Dose Escalation Group [Throughout study treatment until 30 days post-completion, approximately 13 weeks]. Count Of Participants, Participants. Dose Escalation Dose Level 1 LMB-100 100 mcg/kg (n=7): 1; Dose Escalation Dose Level 2 LMB-100 140 mcg/kg (n=3): 2.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Percentage of Participants With LMB-100 Plasma Drug Levels Above Threshold 600ng/mL During Cycle 2 in Dose Escalation [Plasma LMB-100 levels during Cycle 2 of treatment (each cycle = 21 days)]. Number, Percentage of participants. Dose Escalation Dose Level 1 LMB-100 100 mcg/kg (n=4): 75.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Maximum Observed (Peak) Plasma Concentration (Cmax) of LMB-100 [Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days)]. Mean, ng/mL (Standard Deviation). Dose Escalation Dose Level 1 LMB-100 100 mcg/kg (n=7): 1644.43 (343.08); Dose Escalation Dose Level 2 LMB-100 140 mcg/kg (n=3): 2160.67 (797.9); Dose Expansion LMB-100, 100 mcg/kg (n=5): 1466.4 (257.25).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Percentage of Participants Without Delayed Formation of Neutralizing Anti-LMB-100 Anti-drug Antibodies (ADAs) [Plasma LMB-100 levels during Cycle 3 treatment (each cycle = 21 days)]. Number, Percentage of participants. Dose Escalation Dose Level 1 LMB-100 100 mcg/kg (n=2): 100; Dose Escalation Dose Level 2 LMB-100 140 mcg/kg (n=1): 0; Dose Expansion LMB-100, 100 mcg/kg (n=1): 0.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) of LMB-100 [Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days)]. Mean, h*ng/mL (Standard Deviation). Dose Escalation Dose Level 1 LMB-100 100 mcg/kg (n=6): 2415.9 (1041.2); Dose Escalation Dose Level 2 LMB-100 140 mcg/kg (n=2): 2918.5 (2434.6); Dose Expansion LMB-100, 100 mcg/kg (n=5): 2804.1 (190.14).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Plasma Half-Life (T1/2) of LMB-100 [Pre-administration, end-of-infusion, then 1, 2, 4, 8-10, 12-16 hours post- LMB-100 during cycle 1 (each cycle = 21 days)]. Mean, hour (h) (Standard Deviation). Dose Escalation Dose Level 1 LMB-100 100 mcg/kg (n=6): 1.0 (0.39); Dose Escalation Dose Level 2 LMB-100 140 mcg/kg (n=2): 0.8 (0.22); Dose Expansion LMB-100, 100 mcg/kg (n=5): 1.2 (0.25).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Number of Participants With Serious Adverse Events Possibly, Probably, and/or Definitely Related to LMB-100 Who Have Pancreatobiliary Cancer [Throughout study treatment until 30 days post-completion, approximately 13 weeks.]. Count Of Participants, Participants. Dose Expansion LMB-100, 100 mcg/kg (n=6): 4.