Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.
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).
Proc Annu Meet Am Soc Clin Oncol; 13:A8 1994. Unique Identifier : AIDSLINE ICDB/94600005 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
Abstract:
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.
Keywords: Antibiotics, Antineoplastic/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS Dose-Response Relationship, Drug Drug Administration Schedule Human HIV Infections/*DRUG THERAPY Infusions, Intravenous Sarcoma, Kaposi's/*DRUG THERAPY Sesquiterpenes/*ADMINISTRATION & DOSAGE/ADVERSE EFFECTS Skin Neoplasms/*DRUG THERAPY ABSTRACT CLINICAL TRIAL CLINICAL TRIAL, PHASE I
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Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.
