Because tumor growth requires new blood vessel formation, agents that inhibit tumor-induced angiogenesis in preclinical models should be well tolerated by patients and could produce clinically relevant antitumor responses. We hypothesize: that interpatient pharmacokinetic (PK) and pharmacodynamic (PD) variability can be accounted for, at least in part, by determining a drug metabolism profile for each patient; that the results of agent-specific biological assays on tumor or plasma from patients will be predictive for clinical antitumor effect; and that metabolic and biologic data obtained in Phase I trails will be useful in the design of Phase II efficacy trials. We have extensive prior experience in the pharmacologic evaluation of new agents; determination of patient's metabolic profiles; biological characterization of agents that inhibit tumor angiogenesis; and the determination of growth factor expression in human tumors. We propose to combine these capabilities to conduct early clinical trials of agents that inhibit tumor-induced angiogenesis. During he first year an agent that inhibits endothelial cell growth, TNP-470, will be studied alone and then in combination with pentosan polysulfate (PPS), and agent that inhibits the activity of Heparin Binding Growth Factors (HBGFs). Because of promising antitumor and anti-angiogenic activity of TNP-470 in preclinical models of human CNS tumors, recommended Phase II doses (RP2Ds) for patients with CNS tumors will also be determined. An additional 10 patients with accessible tumor and measurable disease will be studied at the RP2D to obtain additional data on PK/PD, metabolic profiles and correlative biological assays on tumor and plasma. Accrual of additional female and minority patients at the RP2D will be permitted to explore differences in metabolic profiles and PK parameters in these populations. Detailed methodology is provided regarding the proposed clinical protocols; drug assays; metabolic characterization of patients; measures of tumor-induced endothelial cell growth and plasma anti-HBGF activity; and HBGF expression in human tumors specimens. Agents to be studied in subsequent years will be determined from our preclinical data in consultation with the NCI and could include recombinant human (rHu) Interferon-alfa, rHu platelet factor IV and third generation anti-HBGF polyanions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA062500-01
Application #
2103789
Study Section
Special Emphasis Panel (SRC (74))
Project Start
1994-03-01
Project End
1998-01-31
Budget Start
1994-03-01
Budget End
1995-01-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Marshall, John L; Rizvi, Naiyer; Kauh, John et al. (2002) A phase I trial of depsipeptide (FR901228) in patients with advanced cancer. J Exp Ther Oncol 2:325-32
Marshall, J L; Hawkins, M J; Tsang, K Y et al. (1999) Phase I study in cancer patients of a replication-defective avipox recombinant vaccine that expresses human carcinoembryonic antigen. J Clin Oncol 17:332-7
Wojtowicz-Praga, S; Torri, J; Johnson, M et al. (1998) Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer. J Clin Oncol 16:2150-6
Wojtowicz-Praga, S M; Dickson, R B; Hawkins, M J (1997) Matrix metalloproteinase inhibitors. Invest New Drugs 15:61-75
Marshall, J L; Wellstein, A; Rae, J et al. (1997) Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer. Clin Cancer Res 3:2347-54