Reduced Immunogenicity Mesothelin-Targeted Immunotoxin LMB-100 in People With Malignant Mesothelioma

Primary Outcome Measures

• • maximum tolerated dose [ Time Frame: 3 weeks after initial dose ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures

• • proportion of patients at MTD with paartial or complete response per RECIST [ Time Frame: end of treatment ] [ Designated as safety issue: No ]
  • average time from treatment initiaition to disease progression or death [ Time Frame: progression ] [ Designated as safety issue: No ]
  • average time from start of treatment to death [ Time Frame: death ] [ Designated as safety issue: No ]
  • pharmacokenetic characteristics [ Time Frame: end of treatment ] [ Designated as safety issue: No ]
  • number of cycles LMB-100 can be given before ADAs develop [ Time Frame: end of treatment ] [ Designated as safety issue: No ]
  • listing and frequency of treatment related adverse events [ Time Frame: 30 days after treatment ] [ Designated as safety issue: Yes ]
  • Detailed Description:

    Background

    Although mesothelioma patients with a limited tumor burden may benefit from surgical resection, most patients have advanced disease at diagnosis and are not candidates for cytoreductive surgery.

    For mesothelioma patients who are not eligible for curative surgery, the median survival with supportive care alone is 6 months whereas with the current standard treatment, a combination of cisplatin and pemetrexed, the median survival is 12 months.

    Mesothelin, a tumor differentiation antigen, is expressed in over 95% of epitheloid mesothelioma. Mesothelin is a suitable candidate for targeted therapy due to its very limited expression in normal human tissue and its high expression in several tumors including mesothelioma.

    LMB-100 is a novel recombinant anti-mesothelin immunotoxin developed for the treatment of patients with solid tumors that express mesothelin. Mesothelin is targeted by linking a humanized fragment of the anti-mesothelin Fab to a de-immunized Pseudomonas exotoxin (PE).

    The clinical use of first generation immunotoxins such as SS1P was hampered mainly by their high immunogenicity. LMB-100 is a next generation PE-fusion protein that has been protein-engineered to maximally reduce its immunogenicity. LMB-100 has shown broad activity against different mesothelinexpressing cancer cell lines and tumor xenograft models.

    Objectives

    Phase 1: To determine the recommended phase 2 dose (RP2D) of LMB-100 in patients with treatment refractory advanced epithelioid or biphasic mesothelioma.

    Phase 2:To determine the efficacy of LMB-100 with respect to objective response rate in patients with treatment refractory advanced epithelioid or biphasic mesothelioma.

    Design

    This is a Phase I, open-label study to evaluate the safety, pharmacokinetics, and activity of LMB-100 in patients with treatment refractory advanced epithelioid or biphasic mesothelioma.

    LMB-100 will be administered intravenously on days 1, 3 and 5 of each 21 day cycle for up to 4 cycles

    Tumor response will be assessed after every 2 cycles

    Optional tumor biopsies may be collected at baseline and after 2 cycles of therapy

    The accrual ceiling will be set at 30

    Eligibility

    Criteria

    Inclusion Criteria

    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, CCR, 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 nonnodal lesions and short axis for nodal lesions) as greater than or equal to 20 mm with conventional techniques or as > 10 mm with spiral 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.

    ECOG performance status (PS) 0 or1

    Adequate hematological function: neutrophil count of more than or equal to 1.0 (SqrRoot) 10(9) cells/microL, platelet count of greater than or equal to 100,000/microl, hemoglobin more than or equal to 9 g/dL

    Adequate liver function: Bilirubin less than or equal to 2.5 (SqrRoot) 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 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 mg/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 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 4 months (female) or two months (male) 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 CriteriaKnown or clinically suspected 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.

    HIV or active HBV or 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

    Pregnant women are excluded from this study because it is unknown whether LMB-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, 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.