Mesothelin-Targeted Immunotoxin LMB-100 in Combination With SEL-110 in Subjects With Malignant Pleural or Peritoneal Mesothelioma
Condition: Mesothelioma
MeSH terms: Mesothelioma; Mesothelioma, Malignant
Intervention: LMB-100; SEL-110
Intervention description: administered on days 1, 3 and 5 of each 21 day cycle for up to 4 cycles; administered on day 1 of each cycle for up to 4 cycles
Intervention MeSH terms: LMB-100
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Immunotoxin; Rapamycin; Targeted Therapy; Mesothelin

Summary:

      Background:

      Mesothelioma is cancer of the tissue that lines some organs. A new drug, LMB-100, may bind to
      a protein on mesothelioma tumors and kill cancer cells. But sometimes the body makes
      antibodies that reduce how well LMB-100 works. Researchers want to see if adding the drug
      SEL-110 to LMB-100 will prevent these antibodies from forming.

      Objective:

      To learn how safe and tolerable LMB-100 plus SEL-110 is in people with advanced mesothelioma.

      Eligibility:

      Adults ages 18 and older who have pleural or peritoneal mesothelioma that has not responded
      to prior platinum-based therapy

      Design:

      Participants will be screened with

        -  Medical history

        -  Physical exam

        -  Blood and urine tests

        -  Sample of tumor tissue. This can be from a previous procedure.

        -  Scan of the chest, abdomen, and pelvis. Participants will lie on a table in a scanner
           that takes pictures. A special dye may be injected in a vein.

        -  Positron emission tomography (fludeoxyglucose positron emission tomography (FDG-PET))
           scan. A sugar attached to a chemical that gives off a signal will be injected before the
           scan.

        -  Heart function tests

      The study will be done in 21-day cycles. Participants will get the study drugs for up to 4
      cycles. They will get them through an intravenous (IV) catheter (a tube inserted in a vein,
      usually in the arm):

        -  LMB-100 for about 30 minutes on day 1, day 3, and day 5 of each cycle

        -  SEL-110 for about 1 hour on day 1 of each cycle

      Participants will get standard medicines to help prevent side effects.

      Participants will repeat some screening tests during each cycle and about 5 weeks after the
      last dose of study drug.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Histologically confirmed epithelial or biphasic pleural or peritoneal mesothelioma not
             amenable to potentially curative surgical resection. However, patients with biphasic
             tumors that have a more than or equal to 50% sarcomatoid component will be excluded.

        The diagnosis will be confirmed by the Laboratory of Pathology, Center for Cancer Research
        (CCR), National Cancer Institute (NCI).

          -  Archival sample or fresh biopsy or tumor effusion must be available for confirmation
             of diagnosis.

          -  Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors
             (RECIST) 1.1.

          -  Patients must have had at least one prior chemotherapy regimen that includes
             pemetrexed and cisplatin or carboplatin. There is no limit to the number of prior
             chemotherapy regimens received.

          -  The last dose of previous therapy must have occurred at least 3 weeks prior to the
             start of study therapy. Palliative radiotherapy is allowed up to 2 weeks before the
             first LMB-100 infusion.

          -  Patients for whom no standard curative therapy exists

          -  Age greater than or equal to 18 years. Because no dosing or adverse event data are
             currently available on the use of LMB-100 + SEL-110 in patients <18 years of age,
             children are excluded from this study

          -  All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure
             must have resolved to Grade less than or equal to 1, except alopecia (any grade) and
             Grade 2 peripheral neuropathy.

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

          -  Adequate hematological function: neutrophil count of more than or equal to 1.0 times
             10(9) cells/L, platelet count of greater than or equal to 100,000/mcL, hemoglobin more
             than or equal to 9 g/dL

          -  Adequate liver function: Bilirubin less than or equal to 2.5 times the upper limit of
             normal (ULN) (excluding Gilbert's Syndrome, see below).

          -  Patients with Gilbert's syndrome will be eligible for the study. The diagnosis of
             Gilbert's syndrome is suspected in people who have persistent, slightly elevated
             levels of unconjugated bilirubin without any other apparent cause. A diagnosis of
             Gilbert's syndrome will be based on the exclusion of other diseases based on the
             following criteria:

               1. Unconjugated hyperbilirubinemia noted on several occasions

               2. No evidence of hemolysis (normal hemoglobin, reticulocyte count, and lactate
                  dehydrogenase (LDH))

               3. Normal liver function tests

               4. Absence of other diseases associated with unconjugated hyperbilirubinemia

          -  Adequate renal function: creatinine clearance (by Cockcroft Gault formula) greater
             than or equal to 50 mL/min.

          -  Must have serum albumin > 2.5 g/dL without intravenous supplementation

          -  Must have left ventricular ejection fraction > 50%

          -  Must have an ambulatory oxygen saturation of > 90% on room air

          -  The effects of LMB-100 in combination with SEL-110 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 after 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 subject 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. History or clinical evidence of CNS
             metastases unless 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 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, uncontrolled
             arrhythmias, unstable angina, non-compensative congestive heart failure, or clinically
             significant pericardial effusion)

          -  Active or uncontrolled infections.

          -  Human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C
             virus (HCV) infection. HIV positive patients will be excluded due to a theoretical
             concern that the degree of immune suppression associated with the treatment may result
             in progression of HIV infection.

          -  Patients with prior pneumonectomy

          -  Prior therapy with LMB-100

          -  Any other diseases, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that would
             contraindicate the use of an investigational drug

          -  Major surgery or significant traumatic injury greater than or equal to 28 days prior
             to the first LMB-100 infusion (excluding biopsies) or anticipation of the need for
             major surgery during study treatment

          -  Dementia or altered mental status that would prohibit informed consent

          -  Live attenuated vaccinations 14 days prior to treatment

          -  Pregnant women are excluded from this study because it is unknown whether LMB-100 +
             SEL 100 has the potential for 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+SEL-110, breastfeeding should be discontinued if
             the mother is treated with LMB-100+SEL-110. These potential risks may also apply to
             other agents used in this study.

          -  Known hypersensitivity to any of the components of LMB-100 and/or SEL-110

          -  Presence of immunosuppressive conditions, including administration of any medications
             or treatments that may adversely affect the immune system such as allergy injections,
             immune globulin, interferon, immunomodulators, cytotoxic drugs, or systemic
             corticosteroids (oral or injectable) during 3 months prior to enrollment.

        Inhaled and topical corticosteroids allowed.

          -  Known allergy to polyethylene glycol (PEG)ylated products.

          -  History of anaphylactic reaction to a recombinant protein or hypersensitivity to PEG.

          -  Taken an investigational drug within 4 weeks prior to study drug administration or
             plans to take an investigational agent during the study.

          -  Taken a strong inhibitor or inducer of cytochrome P450 3A4 (CYP3A4) within 14 days
             prior to enrollment (see Flockhart Table or similarly updated source for a list of
             such agents)

          -  Taken drugs known to interact with Rapamune such as cyclosporine, diltiazem,
             erythromycin, ketoconazole (and other antifungals), nicardipine (and other calcium
             channel blockers), rifampin, verapamil within 14 days prior to enrollment

          -  Uncontrolled hypertension (above 150/95 mm Hg).

          -  History of end-stage renal disease requiring dialysis.

          -  Serum phosphorus less than 2.0 mg/dL

          -  Organ transplant recipient