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Highest mortality rate of all gynecologic
malignancies: 14,500 deaths/yr in the US |
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75% of women present with advanced disease
(spread to upper abdomen) |
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Predilection for peritoneal cavity |
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“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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Must have persistent, recurrent or progressive
ovarian cancer after prior treatment with platinum and taxol compounds |
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The following laboratory values obtained £ 7 days prior to
registration: |
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ANC ³ 1500/µL |
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PLT £ 100,000 µL |
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Total bilirubin £ upper normal limit |
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AST £ 3 x upper limit of normal (ULN) |
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Creatinine £ 1.5 x ULN |
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Hgb ³ 8.0 gm/dL |
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Anti-measles immunity as demonstrated by IgG
anti-measles antibody levels of ³ 20.0 EU/mL as determined by Enzyme Immunoassay
(Diamedix, FL) |
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Normal DTH (delayed type hypersensitivity) |
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Normal serum CEA levels (<5 ng/mL) |
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HIV-positive test result |
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Intra-abdominal disease > 8 cm in diameter,
intrahepatic disease, or disease beyond the abdominal cavity |
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Treatment with oral/systemic corticosteroids,
except if adrenal replacement doses are employed |
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Definition of protective immunity against
measles virus in study eligibility criteria |
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Statistical design (accelerated titration vs
standard cohort of three design) |
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Choice of animal model |
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Ifnarko CD46 Ge |
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CD46 transgenic-IFNa/b receptor knockout |
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Susceptible to MV-Edmonston infection |
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Inoculation via intranasal route: Acute lung
inflammation and diffuse lung hemorrhage. Syncytia in lymphatic organs |
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Intracerebral inoculation can be lethal |
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Mice develop a brisk immune response against MV |
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Mrkic et al, 1988, Singh et al, 1999, Mrkic et
al, 2000 |
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Toxicology studies designed in consultation with
FDA |
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FDA supportive of using the Ifnarko
CD46 Ge model in this setting |
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Health Monitoring
(regular observations) |
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Bloodwork
(Hematology/Chemistry) |
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Histology
(early and late) |
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Health Monitoring: No evidence of acute or
subacute toxicity. |
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Bloodwork: No change in biochemical parameters. |
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ALB, ALP, ALT, AMY, TBIL, BUN, CA, PHOS, CREAT,
GLU, K+, TP, GLOB. |
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No change in CBC or coagulation tests. |
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No evidence of leukopenia, lymphopenia, leukocytosis. |
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CEA levels
(10,000-100,000 ng/ml) confirmed active virus infection 3 days after
virus administration. |
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Histology: No histological abnormalities
detected in any organ. |
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(brain, spleen, peritoneal wall, heart, lungs,
pancreas, kidney, liver, muscle, ovaries) |
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Peritonitis? |
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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. |
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Spleen>kidneys>liver (10/10 animals
positive) |
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Lungs (4/10 animals slightly above background) |
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Brain=below detection limits |
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Safety of the proposed approach |
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Safety of high dose measles vaccines |
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SSPE |
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Monitoring of immunosuppresion |
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Immunogenicity of circulating serum CEA |
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High titer vaccines: 104.7-105.8
pfu |
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HT-EZ, HT-SW: associated with increased
mortality in 4 studies (girls>boys) in countries with high infant
mortality; Guinea-Bissau, Senegal and Haiti |
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HOWEVER: |
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Increased mortality as compared to STD-SW, but
NOT as compared to unvaccinated children |
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No evidence of immune suppression as initially
postulated |
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No difference in mortality between HT and STD
vaccines in countries with lower infant mortality ie Peru, Mexico,
Philippines, US |
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Routine use of HT-EZ in Senegal (2396
children):no difference in mortality |
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Rare complication of measles infection (1:106) |
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Associated with wild type measles virus, but NOT
with vaccine strains; Epidemiologic and sequence data |
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Median time to onset: 5-10yr |
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Median
survival of recurrent ovarian CA pts: 8-15 mo |
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DTH :at baseline and prior to ReRx |
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- Nl
DTH required for eligibility |
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>6wk supression defines DLT |
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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 |
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Self-antigen |
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Routinely used for monitoring of colon cancer
pts with advanced disease |
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Little evidence exists for humoral or cell
mediated immunity in cancer patients |
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CEA vaccine trials: strong immunogens such as
vaccinia virus or GMCSF required to generate an immune response against CEA |
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