) The purpose of this project is to optimize effective therapy for patients with peritoneal involvement of ovarian cancer using regional radioimmunotherapy. These studies will utilize a newly designed recombinant monoclonal antibody with a deleted CH2 region (HuCC49 delta CH2) radiolabeled with 188Re and administered by the intraperitoneal route (IP). Our prior phase I studies with 177Lu-CC49 have shown evidence of anti-tumor effects (objective responses and prolonged disease-free survival) but the trials were limited by the immunogenicity of the murine monoclonal antibody and dose-limiting marrow suppression. The newly designed molecule should have little or no immunogenicity allowing repeated courses of therapy. Also, animal studies have confirmed the predicted improved tumor penetration and short plasma half-life due to the small size of the antibody construct. The construct will be radiolabeled with 188Re, which have shown superior results in animal studies and is predicted to reduce marrow radiation in analysis of clinical data. This new radiolabeled product 188Re-HuCC49 delta CH2 will be possible due to availability of 188Re from a generator and a stable trisuccin chelator synthesized and tested by our team. Our initial phase I trial will establish the maximum tolerated dose (MTD) of 188Re-HuCC49 delta CH2 administered by IP route and include studies of immune response, imaging, dosimetry, pharmacokinetics, tumor response, and tumor markers. Dr. Donald Buchsbaum will concurrently analyze repeat dose schedules and integration of radiosensitizing agents in animal models. The animal model results will be utilized in the details of designing two subsequent clinical trials aimed to further improve the tumor to normal tissue ratios of IP radioimmunotherapy with 188Re-HuCC49 delta CH2. These studies should provide effective new therapy for ovarian cancer patients who have relapsed after standard therapy or possibly as an adjuvant strategy in first-line therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA083591-04
Application #
6660933
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2002-09-30
Project End
2003-09-29
Budget Start
Budget End
Support Year
4
Fiscal Year
2002
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Skates, Steven J; Greene, Mark H; Buys, Saundra S et al. (2017) Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk - Combined Results from Two Screening Trials. Clin Cancer Res 23:3628-3637
Ren, Yi A; Mullany, Lisa K; Liu, Zhilin et al. (2016) Mutant p53 Promotes Epithelial Ovarian Cancer by Regulating Tumor Differentiation, Metastasis, and Responsiveness to Steroid Hormones. Cancer Res 76:2206-18
Nelson, Carol A; Azure, Michael T; Adams, Christopher T et al. (2014) The somatostatin analog 188Re-P2045 inhibits the growth of AR42J pancreatic tumor xenografts. J Nucl Med 55:2020-5
Kim, Kenneth H; Dmitriev, Igor; O'Malley, Janis P et al. (2012) A phase I clinical trial of Ad5.SSTR/TK.RGD, a novel infectivity-enhanced bicistronic adenovirus, in patients with recurrent gynecologic cancer. Clin Cancer Res 18:3440-51
Kimball, Kristopher J; Preuss, Meredith A; Barnes, Mack N et al. (2010) A phase I study of a tropism-modified conditionally replicative adenovirus for recurrent malignant gynecologic diseases. Clin Cancer Res 16:5277-87
Borovjagin, Anton V; McNally, Lacey R; Wang, Minghui et al. (2010) Noninvasive monitoring of mRFP1- and mCherry-labeled oncolytic adenoviruses in an orthotopic breast cancer model by spectral imaging. Mol Imaging 9:59-75
Szafran, April Adams; Folks, Karri; Warram, Jason et al. (2009) Death receptor 5 agonist TRA8 in combination with the bisphosphonate zoledronic acid attenuated the growth of breast cancer metastasis. Cancer Biol Ther 8:1109-16
Matsumura, Noriomi; Huang, Zhiqing; Baba, Tsukasa et al. (2009) Yin yang 1 modulates taxane response in epithelial ovarian cancer. Mol Cancer Res 7:210-20
Bell, Walter C; Sexton, Katherine C; Grizzle, William E (2009) How to efficiently obtain human tissues to support specific biomedical research projects. Cancer Epidemiol Biomarkers Prev 18:1676-9
Meredith, Ruby F; Shen, Sui; Forero, Andres et al. (2008) A method to correct for radioactivity in large vessels that overlap the spine in imaging-based marrow dosimetry of lumbar vertebrae. J Nucl Med 49:279-84

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