Intrapleural Measles Virus Therapy in Patients With Malignant Pleural Mesothelioma

PRIMARY OBJECTIVES:

Maximum tolerated dose (MTD) for the intrapleural administration of a modified vaccine strain
measles virus (MV) genetically engineered to produce human thyroidal sodium iodine symporter
(NIS) (MV-NIS [oncolytic measles virus encoding thyroidal sodium iodide symporter])in
patients with MPM.

SECONDARY OBJECTIVES:

Safety and toxicity of the repeated (up to 6 cycles) intrapleural administration of MV-NIS in
patients with malignant pleural mesothelioma.

TERTIARY OBJECTIVES:

I. Time course of viral infection, dissemination and elimination by non-invasive measurements
of NIS gene expression using radioactive iodine and single-photon emission computed
tomography (SPECT)/ computed tomography (CT) imaging with.

II. Viremia, viral replication, and viral shedding following intrapleural administration.

III. Changes in humoral and cellular anti-MV immunity following the intrapleural
administration of MV-NIS.

IV. Antitumor efficacy of this approach by serial measurements of radioiodine uptake by
SPECT/CT, radiographic response, and time to disease progression.

V. Changes in both local and systemic innate and adaptive anti-tumor immunity following the
intrapleural administration of MV-NIS.

VI. Effect of MV-NIS administration on the eukaryotic initiation factor (eIF) 4F translation
complex in mesothelioma cells.

OUTLINE: This is a dose-escalation study.

Patients receive the oncolytic measles virus encoding thyroidal sodium iodide symporter
(MV-NIS) intrapleurally. In the absence of unacceptable side effects or disease progression
treatment can be repeated every 28 days for up to 6 courses.

After completion of study treatment, patients are followed up every 3 to 6 months for up to 5
years.

Inclusion Criteria:

PRE-REGISTRATION:

- Diagnosis of MPM, confined to single pleural cavity, with histologic confirmation of
the primary tumor

- Measurable disease per modified Response Evaluation Criteria in Solid Tumors (RECIST)
criteria for mesothelioma

- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1, or 2

- Ability to provide informed consent

- Willingness to return to Mayo Clinic Rochester or the University of Minnesota Cancer
Center for follow up

- Life expectancy >= 12 weeks (in the opinion of the enrolling investigator)

- Willingness to provide the biologic specimens and participate in the SPECT/CT imaging
as required by the protocol

- Presence of a pleural effusion with the ability to safely place an intrapleural
catheter or have pre-existing intrapleural catheter

- Absolute neutrophil count (ANC) >= 1500/μL

- Platelet count >= 100,000/μL

- Total bilirubin =< 1.5 x upper limit of institutional normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2
x upper limit of institutional normal

- Serum Creatinine =< 1.5 x upper limit of institutional normal

- Hemoglobin >= 9.0 g/dL

- Must be willing to implement contraception throughout study and for the 4 weeks
following last viral administration

REGISTRATION:

- Anti-measles immunity as demonstrated by serum IgG anti-measles antibody levels of ≥
1.1 EU/ml as determined by BioPlex Measles IgG multiplex flow immunoassay.

- Hepatitis B and C negative

- Human immunodeficiency virus (HIV) negative

- CD4 count >= 200/μL

- CT imaging review submission to confirm unilateral pleural involvement; this review
for CT imaging is mandatory prior to registration to confirm eligibility; it should be
initiated as soon as possible after pre-registration

- Negative pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

Exclusion Criteria:

PRE-REGISTRATION

- Uncontrolled intercurrent illness including, but not limited to:

- Active infection =< 5 days prior to pre-registration

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Symptomatic congestive heart failure New York Heart Association classification
III or IV

- Symptomatic coronary artery disease (CAD)

- Symptoms of CAD on systems review

- Cardiac arrhythmias

Any of the following therapies prior to pre-registration:

- Chemotherapy =< 4 weeks

- Immunotherapy =< 4 weeks

- Biologic therapy =< 4 weeks; Note exception: prior viral and/or gene therapy are
exclusion criteria

- Radiotherapy =< 4 weeks Failure to fully recover from acute, reversible effects of
prior anti-cancer therapy regardless of interval since last treatment; NOTE: patients
must have fully recovered from all acute, reversible toxicities (defined as Common
Terminology Criteria for Adverse Events [CTCAE] 4.0 =< grade 1) associated with
previous treatment

Any of the following because this study involves an investigational agent whose genotoxic,
mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Any ancillary therapy considered investigational (utilized for a non-Food and
Drug Administration [FDA] approved indication and in the context of a research
investigation) or any other treatment specifically for treating the current
malignancy

- Immunocompromised patients, including patients known to be HIV positive

- Other active malignancy =< 2 years prior to pre-registration; EXCEPTIONS:
non-melanotic skin cancer or carcinoma-in-situ of the cervix

- History of organ transplantation

- Known hepatitis B or C

- Treatment with oral/systemic corticosteroids; NOTE: with the exception of topical
or inhaled steroids

- Exposure to household contacts =<15 months old or household contact with a person
with known immunodeficiency

- Allergy to measles vaccine or history of severe reaction to prior measles
vaccination

- Allergy to iodine; NOTE: this does not include reactions to intravenous contrast
materials

- History of tuberculosis or purified protein derivative (PPD) skin test positivity

- Inability or unwillingness to have pleural catheter placed

- Requiring ongoing blood product support at time of pre-registration