Mesothelin-Targeted Immunotoxin LMB-100 in Combination With Tofacitinib in Persons With Previously Treated Pancreatic Adenocarcinoma, Cholangiocarcinoma and Other Mesothelin Expressing Solid Tumors
Condition: Neoplasms With Mesothelin Expression; Epithelioid Mesothelioma; Cholangiocarcinoma, Extrahepatic; Adenocarcinoma, Pancreatic
MeSH terms: Adenocarcinoma; Cholangiocarcinoma; Mesothelioma
Intervention: LMB-100; Tofacitinib; Mesothelin Expression
Intervention description: 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
Intervention MeSH terms: Tofacitinib; LMB-100
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced Cancer; Immunotoxin; Antibody Based Therapeutics; Mesothelin

Summary:

      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.
    

Eligibility criteria:

        -  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 supplementation

          -  Adequate liver function: Bilirubin <2.5 x upper limit of normal (ULN) for all,
             aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN except
             for patients with significant tumor burden in their liver where AST and ALT < 5x ULN
             is acceptable in the absence of other etiologies for transaminitis

          -  Adequate renal function: creatinine clearance [Estimating glomerular filtration rate
             (EGFR) method or measured] >= 50 mL/min. Measured clearance will be used if both
             numbers are available.

          -  Must have left ventricular ejection fraction >= 50%

          -  Must have an ambulatory oxygen saturation of > 88% on room air

          -  The expansion phase patients must meet all eligibility criteria above AND must have
             diagnosis of pancreatic adenocarcinoma or extrahepatic cholangiocarcinoma with
             pathology confirmed to be consistent with one of these diagnoses by NCI Laboratory of
             Pathology.

          -  The effects of LMB-100 alone or in combination with tofacitinib on the developing
             human fetus are unknown. For this reason, women of child-bearing potential and men
             must agree to use adequate contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry until 3 months the last dose of study therapy. Should
             a woman become pregnant or suspect she is pregnant while she or her partner is
             participating in this study, she should inform her treating physician immediately.

          -  Ability of participant to understand and the willingness to sign a written informed
             consent document.

        EXCLUSION CRITERIA:

          -  Known or clinically suspected central nervous system (CNS) primary tumors or
             metastases including leptomeningeal metastases as CNS penetration of LMB-100 is
             expected to be poor. CNS metastases are permitted if they have been previously
             treated, are asymptomatic, and have had no requirement for steroids or enzyme-inducing
             anticonvulsants in the last 14 days.

          -  Evidence of significant, uncontrolled concomitant diseases which could affect
             compliance with the protocol or interpretation of results, including significant
             pulmonary disease other than that related to the primary cancer, uncontrolled diabetes
             mellitus, and/or significant cardiovascular disease (such as New York Heart
             Association Class III or IV cardiac disease, myocardial infarction within the last 6
             months, unstable arrhythmias, unstable angina, or clinically significant pericardial
             effusion).

          -  Any known diagnoses, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition (other than
             mesothelin [+] cancer diagnosis) that would contraindicate the use of an
             investigational drug, interfere with tumor measurement or lead to a life expectancy of
             less than 6 months as judged by the investigator.

          -  Contraindication to receiving prophylactic doses of low-molecular weight heparin
             (LMWH) or direct oral anticoagulants (DOAC) such as current active bleeding (except
             for grade 1 hematuria or epistaxis), recent history of significant bleeding without
             subsequent effective medical or surgical intervention, known history of gastric
             varices, uncontrolled malignant hypertension, history of coagulopathy that confers
             increased risk of bleeding. Patients on concurrent treatment with anti-platelet agents
             such as aspirin or clopidogrel are eligible if deemed to have acceptable risk of
             bleeding in consultation with Hematologist. Patients already receiving prophylactic or
             therapeutic doses of anticoagulant (heparin-based, or DOAC) for at least 4 weeks with
             no indication of significant bleeding while on therapy are considered NOT to have a
             contraindication to this therapy.

          -  Inability to administer or unwillingness to comply with recommended venous
             thromboembolism (VTE) prophylaxis for the duration of study treatment.

          -  Prior diagnosis of hematologic malignancy

          -  Active or uncontrolled infections (including tuberculosis, human immunodeficiency
             virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) or reasonable
             clinical suspicion of an active infection (such as cholangitis) as tofacitinib
             suppresses lymphocyte signaling and will impair host response to infection

          -  Latent tuberculosis (TB) infection as identified by interferon-gamma release assay
             (IGRA). If IGRA is indeterminate, tuberculin skin test (TST) may be used to determine
             status.

          -  Live attenuated vaccinations within 14 days prior to treatment.

          -  Use of a strong inhibitor or inducer of cytochrome P450 3A4 (CYP3A4) within 14 days
             prior to enrollment or similarly updated source for a list of such agents)

          -  Inability to take or digest oral medication.

          -  Dementia or altered mental status that would prohibit informed consent.

          -  Pregnant women are excluded from this study because the effects of LMB-100 and/or
             tofacitinib on the developing fetus are unknown and may have the potential to cause
             teratogenic or abortifacient effects. Because there is an unknown but potential risk
             for adverse events in nursing infants secondary to treatment of the mother with
             LMB-100 and/or tofacitinib, breastfeeding should be discontinued if the mother is
             treated with either of these agents.

          -  Baseline corrected QT interval by Fredericia (QTcF) interval of > 470 ms, participants
             with baseline resting bradycardia < 45 beats per minute, or baseline resting
             tachycardia >100 beats per minute.

          -  Participants with contra-indication and/or history of severe hypersensitivity
             reactions to any components related to LMB-100 and tofacitinib.

          -  Patients who have previously received LMB-100 (and therefore have high-levels of
             preexisting anti-drug antibodies (ADAs) to drug)