Notes
Outline
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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