A Study of GL-ONC1, an Oncolytic Vaccinia Virus, in Patients With Advanced Peritoneal Carcinomatosis

• Dose Level and Dose Schedule [ Time Frame: End of Phase I (at 18 mo.), at monthly treatments, and after study completion (expected at 36 mo.) ] [ Designated as safety issue: Yes ]
  Determination of recommended dose and schedule for phase II portion of trial and future investigations by analysis of safety and efficacy data
• Detection of Anti-tumor Activity [ Time Frame: Tumor imaging [pre-study, mid-term (Day 43), after last treatment (Day 106), for 1 year @ 12-week intervals for patients with stable disease/better); Tumor markers and peritoneal cytologies collected on average over 4 months ] [ Designated as safety issue: No ]
  Sampling of evidence of anti-tumor activity via standard imaging practices, viral delivery to tumor and normal cells, and immune response activity.

The purpose of this study is to determine whether GL-ONC1, an attenuated vaccinia virus, is safe when administered to patients with peritoneal carcinomatosis via an infusion within the abdominal cavity through an implanted catheter. The study seeks also to arrive at a recommended dose and schedule for future investigations, evidence of anti-tumor activity, detection of virus in body fluids, analysis of viral delivery to tumor and normal cells, and to evaluate if there is an antibody response to vaccinia virus.

Peritoneal carcinomatosis includes a variety of tumors with extensive metastasis throughout the peritoneal cavity (inside surface of the abdomen) and can be found with gall bladder, liver, colon, appendix, ovarian, pancreas, mesothelioma, pseudomyxoma peritonei, rectal, small bowel and stomach cancers. It broadly includes multiple tumors that develop in and line the peritoneal abdominal cavity and linings. These tumors may be difficult to completely remove surgically and may recur despite conventional systemic chemotherapy, thereby resulting in poor patient outcomes. In preclinical studies, GL-ONC1, an oncolytic vaccinia virus, has shown the ability to preferentially locate, colonize and destroy tumor cells in more than 30 different human tumors. A Phase I clinical study focusing on the safety and tolerability of GL-ONC1 intravenously administered to patients with a variety of solid tumor entities has shown that GL-ONC1 is well-tolerated at therapeutic dose levels, with documented evidence of antitumor activity. This additional Phase I/II study seeks to evaluate GL-ONC1 administered repetitively every 4 weeks up to 4 cycles via infusion using an implanted catheter in the peritoneal cavity. In Phase I, patients will be individually assessed for safety and dose limiting toxicity. The study aims of Phase II portion are continued collection of safety information to better define the tolerability of GL-ONC1, as well as viral replication and the action or effect of GL-ONC1 in humans at the selected dose level and dosing schedule for future trials. Throughout both phases of the study, anti-tumor effects will be evaluated.

Inclusion Criteria:

1. Diagnosis of histologically or cytologically documented, advanced stage of peritoneal carcinomatosis that is refractory to standard therapy, exhibiting a likely survival of > 4 months as being judged clinically.
2. Evidence of measurable disease.
3. Age ≥ 18 years.
4. ECOG (Eastern Cooperative Oncology Group Performance Status) ≤ 2.

5. Required baseline laboratory data include:

   • Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.
   • Platelets ≥ 75 ×109/L
   • Haemoglobin ≥ 9.5 g/dL
   • Serum creatinine ≤ 2 × upper limit of normal(ULN)
   • Total Bilirubin ≤ 5 × ULN
   • AST/ALT ≤ 7.5 × ULN
   • Negative pregnancy test for females of childbearing potential
   • Serum albumin ≥ 2.5 g/dL.
   • If serum albumin level is < 2.5/dL,albumin substitution should take place until the threshold of ≥ 2.5 g/dL.
6. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, implantation of the indwelling peritoneal catheter, as well as the respective drainage procedures.
7. All patients must agree to use highly effective contraception.

Exclusion Criteria:

1. Patients exhibiting objective evidence at baseline of brain metastases are excluded from participating.
2. Pregnant or breast-feeding women.
3. Primary tumors and metastases to tissues/organs which, under clinical judgment, will likely hinder survival for at least the next 4 months.
4. Patients with fever, any active immunosuppressive systemic infection or a suppressed immune system, including known HIV, as assessed within 14 days prior to study enrolment.
5. Concurrent vaccination or immunotherapy for 28 days before study therapy and during study treatment.
6. Patients on immunosuppressive therapy or with immune system disorders, including autoimmune diseases. Concurrent steroid use of not more than an equivalent of 20 mg/day prednisolone is allowed.
7. Prior splenectomy.
8. Previous organ transplantation.
9. Fully therapeutic coagulation therapy that does not allow the intraperitoneal insertion of a permanent catheter.
10. Patients with clinically significant dermatological disorders(e.g., eczema or psoriasis), any skin lesions or ulcers, any history of atopic dermatitis, or any history of Darier's disease (Keratosis Follicularis).
11. Clinically significant cardiac disease (New York Heart Association, Class III or IV: see Appendix 10)
12. Known allergy to ovalbumin or other egg products.
13. Concurrent use of antiviral agents active against vaccinia virus.
14. Prior gene therapy treatment or prior therapy with cytolytic virus of any type.