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

 -  Patients for whom no standard curative therapy exists

 Primary Exclusion Criteria:

 -  Known or clinically suspected central nervous system (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
 intravenous (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, 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