Intra-pleural Administration of GL-ONC1, a Genetically Modified Vaccinia Virus, in Patients With Malignant Pleural Effusion: Primary, Metastases and Mesothelioma

Primary Outcome Measures:

Maximum Tolerated Dose (MTD) [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Three patients will be enrolled in each cohort at the dose levels shown in the table below in order to determine the Maximum Tolerated Dose (MTD). At the beginning of a new dose level, only one patient will be treated. The first patient in each cohort must be treated and complete 14 days of post-treatment evaluation prior to the treatment of the remaining two patients in that cohort.

Secondary Outcome Measures:

safety [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

The safety, tolerability and feasibility of GL-ONC1 will be assessed by the evaluation of the type, frequency, and severity of adverse events (AEs), changes in clinical laboratory tests (hematological and chemistry), immunogenicity and physical examination. All AEs and laboratory toxicities will be graded on the CTCAE (version 4).

detection of virus in body fluids [ Time Frame: days 2 and 3 after treatment ] [ Designated as safety issue: No ]

Patients will undergo serial sampling of blood, sputum, urine samples and pleural drainage for evaluation of viral particles by VPA immediately before treatment, and on days 2 and 3 after treatment.

evaluation of viral appearance in tumor [ Time Frame: 2-7 days after intrapleural instillation of virus ] [ Designated as safety issue: No ]

Unless medically contraindicated, patients will undergo Video-Assisted Thoracic Surgery (VATS) with pleural biopsies to assess for green fluorescent protein (GFP) viral expression in tumor and surrounding tissues, and if appropriate, to perform pleurodesis at 2-7 days after intrapleural instillation of virus. Random pleural biopsies and GFPdirected biopsies will be performed to allow for assessment of viral presence. Viral plaque assays (VPA) will be performed in tumor biopsies and pleural drainage to confirm viral titers. Immunohistochemical (IHC) staining for GL-ONC1 will be performed on both GFP (-) and (+) areas at videothoracoscopy

Therapeutic efficacy [ Time Frame: day 60 post treatment ] [ Designated as safety issue: No ]

Therapeutic efficacy will be investigated with CT scans pretreatment and at Day 60 posttreatment. Response by RECIST criteria (and by modified RECIST – for mesothelioma tumors) will be summarized for each dose level using descriptive statistics.

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of histologically or cytologically documented, malignant pleural effusions (primary non-small-cell lung carcinoma, mesothelioma, and other histologies), who have free pleural space (partial or total) that permits the intrapleural drug instillation.
• Age must be ≥ 18 years.
• All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedures must have resolved to Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0) Grade ≤ 1. Any surgery, where anesthesia was administered, must have occurred at least 28 days prior to study enrolment.
• Chemotherapy, radiotherapy or immunotherapy must have stopped more than 14 days prior to receiving study drug; however, small field palliative radiotherapy is allowed.
• ECOG ≤ 2.
• Required baseline laboratory data include:
  • Absolute neutrophil count (ANC) ≥ 1.5 × 109 [SI units 109/L],
  • Platelets ≥ 100 ×109 [SI units 109/L],
  • Hemoglobin ≥ 9.0 g/dL [SI units gm/L],
  • Serum creatinine ≤ 1.5 × upper limit of normal (ULN),
  • Bilirubin ≤ 1.5 × ULN,
  • AST/ALT ≤ 2.5 × ULN (≤ 5 × ULN in the presence of liver metastases)
  • Negative pregnancy test for females of childbearing potential.

Exclusion Criteria:

• Pregnant or breast-feeding women.
• Patients with fever or any active systemic infections, including known HIV, hepatitis B or C.
• Patients on immunosuppressive therapy or with immune system disorders, including autoimmune diseases.
• Concurrent steroid use of more than an equivalent of 20 mg/day prednisone (or equivalent).
• Prior splenectomy.
• Previous organ transplant.
• Patients with clinically significant dermatological disorders, e.g., eczema or psoriasis, as judged by the principal investigator, or any unhealed skin wounds or ulcers.
• Patients with symptomatic brain metastases requiring treatment.
• Clinically significant cardiac disease (New York Heart Association, Class III or IV).
• Dementia or altered mental status that would prohibit informed consent.
• Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality, that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results and, in the judgment of the principal investigator, would make the patient inappropriate for this study.
• Known allergy to ovalbumin or other egg products.
• Prior gene therapy treatments or prior therapy with cytolytic virus of any type.
• Concurrent therapy with any other investigational anticancer agent.
• Concurrent antiviral agent active against vaccinia virus (e.g. cidofovir, vaccinia immunoglobulin) during the study.