Document 1091
 DOCN  M9471091
 TI    A Phase I study of an angiogenesis inhibitor, TNP-470 (AGM-1470),
       administered to patients (pts) with HIV-associated Kaposi's sarcoma (KS)
       (Meeting abstract).
 DT    9409
 AU    Pluda JM; Wyvill K; Figg WD; Whitcup SM; Lietzau J; Saville MW; Cohen R;
       Feigal E; Parks D; Foli A; et al; NCI, Bethesda, MD
 SO    Proc Annu Meet Am Soc Clin Oncol; 13:A8 1994. Unique Identifier :
       AIDSLINE ICDB/94600005
 AB    The fumagillin analogue TNP-470 is a potent inhibitor of angiogenesis in
       vitro (Ingber, et al Nature 348, 555, 1990). Anti-tumor inhibitory
       activity in animal models has been shown to be dose- but not
       schedule-dependent. We have found that TNP-470 inhibits in vitro
       KS-derived spindle cell proliferation (Saville, et al J Cell Biochem
       Suppl 17E:22, 1993 abstr) at a concentration that is well tolerated in
       animals and is not toxic to human lymphocytes. We therefore began a
       Phase I trial of TNP-470 administered iv over 1 hr every other day to
       pts with HIV-associated KS. 15 pts have been enrolled to date on 5 dose
       levels (4.6, 9.3, 15.4, 23.2, and 32.4 mg/m2). Preclinical toxicology
       studies revealed that at very high doses TNP-470 could cause seizures
       associated with cerebral and pulmonary bleeding. No dose-limiting
       toxicities have been noted in this study, although 2 pts developed
       asymptomatic, transient, small white-centered retinal hemorrhages after
       7 and 10 weeks of TNP-470 at 4.6 mg/m2 and 15.4 mg/m2 respectively that
       were felt to be probably related to HIV. No objective, measurable
       anti-KS responses have been seen although 4 pts have had stable disease
       lasting 4-14 wk. Interestingly, the pt receiving 32.4 mg/m2 had the
       disappearance of KS-associated, morphine-requiring foot pain after 6 wk
       of TNP-470, along with a significant reduction in tumor-associated leg
       edema and flattening and decrease in size in some KS lesions. A second
       pt receiving 15.4 mg/m2 also had reduced tumor edema. Preliminary
       pharmacokinetics suggest that TNP-470 has a rapid clearance (max 1164
       +/- 718 L/hr) and an extremely short plasma half life (range 5.5-10
       min). There have been no effects on CD4 cells or HIV p24 antigen. In
       summary, although TNP-470 has been well tolerated, no objective,
       measurable anti-KS responses have been noted to date. However, there has
       been a suggestion of biological activity noted in 2 pts. We will
       continue to accrue pts on successively higher dose levels, as tolerated.
 DE    Antibiotics, Antineoplastic/*ADMINISTRATION & DOSAGE/ADVERSE  EFFECTS
       Dose-Response Relationship, Drug  Drug Administration Schedule  HIV
       Infections/*DRUG THERAPY  Human  Infusions, Intravenous  Sarcoma,
       Kaposi's/*DRUG THERAPY  Sesquiterpenes/*ADMINISTRATION & DOSAGE/ADVERSE
       EFFECTS  Skin Neoplasms/*DRUG THERAPY  MEETING ABSTRACT  CLINICAL TRIAL
       CLINICAL TRIAL, PHASE I

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