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

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 identify the recommended phase 2 dose (RP2D) of LMB-100 in patients with treatment
refractory advanced epithelioid or biphasic mesothelioma and evaluate potential efficacy of
the identified PP2D.

-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.

Eligibility:

- Age greater than or equal to 18 years

- Histologically confirmed advanced pleural or peritoneal mesothelioma

- Subjects must have had at least 1 prior chemotherapy regimen with last dose of previous
therapy occurring at 3 weeks before the start of study treatment

- Adequate organ function

- Participants with CNS metastases or prior pneumonectomy are excluded

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

- 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, 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
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 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 of equal to 1.5
(SqrRoot) 10^9 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: AST and 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 metastsis.

- 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 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 ( <= -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 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

- 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.