Mesothelin-Targeted Immunotoxin LMB-100 in Combination With SEL-110 in Subjects With Malignant Pleural or Peritoneal Mesothelioma

Background:

- LMB-100 and a closely related immunotoxin also targeting mesothelin have been studied in
previous Phase 1 clinical studies for mesothelioma and pancreatic cancer.

- Results from these studies showed that the majority of patients formed
anti-drug-antibodies (ADAs) that neutralized subsequent injection of the product making
it ineffective.

- In a small subset of patients that did not form ADAs to the product, good response and
regression of tumors was seen.

- In a different application SEL-110, a biodegradable nanoparticle containing rapamycin,
has been shown in clinical trials to prevent the formation of ADAs to an immunogenic
enzyme when co-administered. Preclinical data show that SEL-110 also prevents the
formation of ADAs to LMB-100.

- This clinical trial will investigate whether SEL-110 when administered with LMB-100 is
able to prevent the formation of ADAs and thus allow patients to receive multiple,
effective injections of LMB-100.

Objectives:

-The primary objective of the study is to assess the safety and tolerability of LMB-100 in
combination with SEL-110.

Eligibility:

Primary Inclusion Criteria

- Greater than or equal to 18 years of age

- Histologically confirmed epithelial or biphasic pleural or peritoneal mesothelioma not
amenable to potentially curative surgical resection.

- Patients must have measurable disease per 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.

- Patients for whom no standard curative therapy exists

Primary Exclusion Criteria:

- Known or clinically suspected CNS primary tumors or metastases including leptomeningeal
metastases.

- Evidence of significant, uncontrolled concomitant diseases which could affect compliance
with the protocol or interpretation of results.

- Evidence of active or uncontrolled infections.

- Live attenuated vaccinations 14 days prior to treatment

- Pregnant women are excluded from this study

Design:

- This is a Phase I, single center, dose escalation study of LMB-100 in combination with
SEL-110

- Patients will receive the combination using a dose escalation scheme in which different
doses of LMB100 and SEL-110 will be evaluated.

- Patients will receive 4 cycles of LMB-100 with SEL-110. A cycle will consist of i.v.
infusion of SEL-110 on Day 1 of the cycle followed immediately by an i.v. infusion of
LMB-100, then on Days 3 and 5 of the cycle patients will receive an i.v. infusion of
LMB-100 only. Treatment cycles will be separated by 21 days.

- 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, CCR, NCI.

- Archival sample or fresh biopsy or tumor effusion must be available for confirmation
of diagnosis.

- Patients must have measurable disease per 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.

- ECOG performance status (PS) 0 or1

- 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 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 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.

- 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

- 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 PEGylated 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 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