Mesothelin-Targeted Immunotoxin LMB-100 in People With Malignant Mesothelioma
Condition: Mesothelioma
MeSH terms: Mesothelioma; Mesothelioma, Malignant
Intervention: LMB-100; nab-paclitaxel
Intervention description: Administered intravenous (IV) on days 1, 3 and 5 of a 21 day cycle for up to 4 cycles (Arms A1 and A2) or 2 cycles (Arms B1 and B2); Arms B1 and B2 only. Administered intravenous (IV) on days 1 and 8 of each 21 day cycle for up to 6 cycles
Intervention MeSH terms: Paclitaxel; LMB-100
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Immunotoxin; Mesothelin; Targeted Therapy

Summary:

      Background:

      LMB-100 is a man-made protein. It is attracted to the mesothelin protein. This is found in
      many tumors, including mesothelioma. But it is found in only a very small number of normal
      tissues. After binding to mesothelin on tumors, LMB-100 attacks and kills cancer cells.
      Researchers want to test LMB-100 in people with advanced mesothelioma.

      Objective:

      To find a safe dose and anti-tumor activity of LMB-100 for people with advanced mesothelioma.

      Eligibility:

      Adults ages 18 and older with:

      Advanced pleural or peritoneal mesothelioma that has not responded to platinum-based

      therapy

      Adequate organ function

      Design:

      Participants will be screened with:

      Samples of tumor tissue or tumor fluid. These can be new or from a previous procedure.

      Medical history

      Physical exam

      Blood, urine, and heart tests

      Chest x-rays

      Computed tomography (CT) or magnetic resonance imaging (MRI) scans

      Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans

      Participants will get LMB-100 on days 1, 3, and 5 of each 21-day cycle. It will be given
      through an intravenous (IV) catheter, a tube inserted in an arm vein. They will get standard
      medicines before each infusion to help prevent side effects. Each infusion lasts about 30
      minutes. They will be monitored for up to 2 hours after.

      During each cycle, participants will repeat the screening tests.

      Participants will get the study drug for up to 4 cycles or until their disease worsens or
      they have intolerable side effects.

      About 4-6 weeks after their last infusion, participants will have a follow-up visit. They
      will repeat the study tests.

      Participants will have follow-up scans every 6 weeks until their disease gets worse.

      Participants will be called about once a year to see how they are doing.
    

Eligibility criteria:

        -  INCLUSION CRITERIA (All Cohorts):

          -  Histologically confirmed epithelial or biphasic 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, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as greater than or equal to 20 mm
             with conventional techniques or as greater than or equal to10 mm with spiral computed
             tomography (CT) scan.

          -  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 curable 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 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 (ECOG) performance status (PS) 0 or1

          -  Adequate hematological function: neutrophil count of more than of equal to 1.5x10^9
             cells/L, platelet count of greater than or equal to 100,000/microl, (transfusion
             independent, defined as not receiving platelet transfusions within 7 days prior to
             laboratory sample) hemoglobin more than or equal to 9 g/dL

          -  Adequate Liver function: aspartate aminotransferase (AST) and alanine aminotransferase
             (ALT) less than 2.5 X upper limit of normal alkaline phosphate less than 2.5 X upper
             limit of normal unless bone metastasis is present (less than 5 X upper limit of
             normal) in the absence of liver metastasis.

          -  Bilirubin less than or equal to 1.5 mg/dL (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:

               -  Unconjugated hyperbilirubinemia noted on several occasions

               -  No evidence of hemolysis (normal hemoglobin, reticulocyte count, and lactate
                  dehydrogenase (LDH)

               -  Normal liver function tests

               -  Absence of other diseases associated with unconjugated hyperbilirubinemia

          -  Adequate renal function: creatinine less than 1.5 mg/dL OR creatinine clearance (by
             Cockcroft Gault formula) greater than or equal to 50 mL/min.

          -  Must have serum albumin > 2.5 mg/dL without intravenous supplementation

          -  Must have left ventricular ejection fraction > 50%

          -  Must have an ambulatory oxygen saturation of > 90% on room air

          -  Women of child-bearing potential (defined as a sexually mature woman who (1) has not
             undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy
             [the surgical removal of both ovaries] or; (2) has not been naturally postmenopausal
             for at least 24 consecutive months [i.e., has had menses at any time during the
             preceding 24 consecutive months]) must:

               -  Either commit to true abstinence* from heterosexual contact (which must be
                  reviewed on a monthly basis), or agree to use, and be able to comply with,
                  effective contraception without interruption, 28 days prior to starting study
                  therapy (including dose interruptions), while on study medication and for 3
                  months after the last dose of study therapy; and

               -  Have a negative serum pregnancy test (<= -human chorionic gonadotropin (hCG)
                  result at screening and agree to ongoing pregnancy testing during the course of
                  the study, and after the end of study therapy. This applies even if the subject
                  practices true abstinence* from heterosexual contact.

          -  Men must agree to practice true abstinence or agree to use a condom during sexual
             contact with a pregnant female or a female of childbearing potential while
             participating in the study, during dose interruptions and for 6 months following
             discontinuation of study therapy, even if he has undergone a successful vasectomy.

          -  Ability of subject to understand and the willingness to sign a written informed
             consent document.

        EXCLUSION CRITERIA (All Cohorts):

        -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, unstable arrhythmias, unstable angina, 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

          -  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

          -  Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with LMB-100, breastfeeding should be
             discontinued if the mother is treated with LMB-100. These potential risks may also
             apply to other agents used in this study.

          -  Known hypersensitivity to any of the components of LMB-100

          -  High doses of systemic corticosteroids within 7 days prior to first dosing. High dose
             is considered as > 20 mg of dexamethasone a day (or equivalent) for > 7 consecutive
             days.

        EXCLUSION CRITERIA (Cohort B only)

          -  Subjects must not have received paclitaxel nor nab-paclitaxel within 4 months prior to
             initiation of study therapy.

          -  Participants with contra-indication and/or history of sever hypersensitivity reactions
             to nab-paclitaxel.