Fumagillin analog in the treatment of Kaposi's sarcoma: a phase I AIDS Clinical Trial Group study. AIDS Clinical Trial Group No. 215 Team.
OBJECTIVE
Angiogenesis is a major component of Kaposi's sarcoma (KS) and a critical process in tumor growth. The present study was designed primarily to test the toxicity and pharmacokinetics (PK) of the angiogenesis inhibitor TNP-470 and secondarily to evaluate tumor response in patients with early AIDS-related KS.


METHODS
Patients with AIDS-related KS were required to have cutaneous disease with > or = 5 measurable lesions and no evidence of pulmonary, symptomatic gastrointestinal, or acutely life-threatening KS. Thirty-eight patients received TNP-470 by weekly intravenous infusion over 1 hour at one of six dose levels for up to 24 weeks.


RESULTS
The dose levels tested included 10, 20, 30, 40, 50 and 70 mg/m2. Median CD4 count was 24 cells/microl (range, 0 to 460). Fourteen patients (36%) had > or = 50 cutaneous lesions and 19 (49%) had oral lesions. Adverse events included neutropenia (n = 2), hemorrhage (n = 3), and urticaria (n = 1). PK studies showed wide interpatient and intrapatient variability. Elimination half-life values were short (range, 0.01 to 0.61 hours). Seven patients (18%) achieved a partial response. The median time to partial response was 4 weeks (range, 2 to 25), and the median duration of response was 11 weeks (range, 3 to 26+).


CONCLUSIONS
TNP-470, administered as a weekly, 1-hour infusion to patients with early AIDS-KS is well-tolerated at doses up to and including the highest dose tested. Tumor responses were observed in a substantial number of cases and occurred at various dose levels. TNP-470 should be evaluated further in patients with AIDS-KS as a single agent and in combination with other biologic response modifiers in early disease or after initial response to cytotoxic chemotherapy.
Dezube
B J
BJ
Beth Israel Deaconess Medical Center, Boston, MA, USA.
Von Roenn
J H
JH
Holden-Wiltse
J
J
Cheung
T W
TW
Remick
S C
SC
Cooley
T P
TP
Moore
J
J
Sommadossi
J P
JP
Shriver
S L
SL
Suckow
C W
CW
Gill
P S
PS
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy*; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D003510:Cyclohexanes; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012514:Sarcoma, Kaposi / Q000188:drug therapy*; D012717:Sesquiterpenes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy*
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol