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Epithelial Ovarian Cancer Highest mortality rate of all gynecologic malignancies: 14,500 deaths/yr in the US 75% of women present with advanced disease (spread to upper abdomen) Predilection for peritoneal cavity

Recurrent Ovarian Cancer “While some patients will benefit from second-line therapy, less than 10% will achieve a clinical CR, and the median survival is less than 1 year.”

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Inclusion Criteria Must have persistent, recurrent or progressive ovarian cancer after prior treatment with platinum and taxol compounds The following laboratory values obtained £ 7 days prior to registration: ANC ³ 1500/µL PLT £ 100,000 µL Total bilirubin £ upper normal limit AST £ 3 x upper limit of normal (ULN) Creatinine £ 1.5 x ULN Hgb ³ 8.0 gm/dL

Inclusion Criteria (cont’d) Anti-measles immunity as demonstrated by IgG anti-measles antibody levels of ³ 20.0 EU/mL as determined by Enzyme Immunoassay (Diamedix, FL) Normal DTH (delayed type hypersensitivity) Normal serum CEA levels (<5 ng/mL)

Exclusion Criteria HIV-positive test result Intra-abdominal disease > 8 cm in diameter, intrahepatic disease, or disease beyond the abdominal cavity Treatment with oral/systemic corticosteroids, except if adrenal replacement doses are employed

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Issues raised by the reviewers Definition of protective immunity against measles virus in study eligibility criteria Statistical design (accelerated titration vs standard cohort of three design) Choice of animal model

Choice of animal model Ifnarko CD46 Ge CD46 transgenic-IFNa/b receptor knockout Susceptible to MV-Edmonston infection Inoculation via intranasal route: Acute lung inflammation and diffuse lung hemorrhage. Syncytia in lymphatic organs Intracerebral inoculation can be lethal Mice develop a brisk immune response against MV Mrkic et al, 1988, Singh et al, 1999, Mrkic et al, 2000

Choice of animal model Toxicology studies designed in consultation with FDA FDA supportive of using the Ifnarko CD46 Ge model in this setting

Toxicology studies to date Health Monitoring (regular observations) Bloodwork (Hematology/Chemistry) Histology (early and late)

Toxicology: Interim analysis (6-3-02) Health Monitoring: No evidence of acute or subacute toxicity. Bloodwork: No change in biochemical parameters. ALB, ALP, ALT, AMY, TBIL, BUN, CA, PHOS, CREAT, GLU, K+, TP, GLOB. No change in CBC or coagulation tests. No evidence of leukopenia, lymphopenia,  leukocytosis. CEA levels  (10,000-100,000 ng/ml) confirmed active virus infection 3 days after virus administration.

Toxicology: Interim analysis (6-3-02) cont’d Histology: No histological abnormalities detected in any organ. (brain, spleen, peritoneal wall, heart, lungs, pancreas, kidney, liver, muscle, ovaries) Peritonitis? NO apparent discomfort, NO ascites, NO evidence of inflammation at post-mortem, NO histological evidence of peritonitis after single or multiple dosing, NO abnormal neutrophilic infiltration in peritoneal lavages.

Biodistribution of MV-CEA

MV-CEA Biodistribution (QRT-PCR) Spleen>kidneys>liver (10/10 animals positive) Lungs (4/10 animals slightly above background) Brain=below detection limits

Issues raised by the reviewers Safety of the proposed approach Safety of high dose measles vaccines SSPE Monitoring of immunosuppresion Immunogenicity of circulating serum CEA

Safety of high dose measles vaccines High titer vaccines: 104.7-105.8 pfu HT-EZ, HT-SW: associated with increased mortality in 4 studies (girls>boys) in countries with high infant mortality; Guinea-Bissau, Senegal and Haiti

Safety of high dose measles vaccines HOWEVER: Increased mortality as compared to STD-SW, but NOT as compared to unvaccinated children No evidence of immune suppression as initially postulated No difference in mortality between HT and STD vaccines in countries with lower infant mortality ie Peru, Mexico, Philippines, US Routine use of HT-EZ in Senegal (2396 children):no difference in mortality

SSPE Rare complication of measles infection (1:106) Associated with wild type measles virus, but NOT with vaccine strains; Epidemiologic and sequence data Median time to onset: 5-10yr   Median survival of recurrent ovarian CA pts: 8-15 mo

Monitoring Immunosuppresion DTH :at baseline and prior to ReRx   - Nl DTH required for eligibility   - >6wk supression defines DLT Other immune monitoring: at baseline and prior to ReRx: WBC, lymphocyte count, CD4 count, CD8 count, CD4/CD8 ratio,total immunoglobulin levels, anti-MV IgG Ab (EIA), anti-MV lymphoproliferative assay

Immunogenicity of circulating serum CEA Self-antigen Routinely used for monitoring of colon cancer pts with advanced disease Little evidence exists for humoral or cell mediated immunity in cancer patients CEA vaccine trials: strong immunogens such as vaccinia virus or GMCSF required to generate an immune response against CEA