Phase I clinical and pharmacokinetic trial of flavone acetic acid.
Flavone acetic acid is a synthetic benzopyrone derivative with an unknown mechanism of action. Thirty-eight patients (30 men and 8 women) were treated once a week for 4 weeks every 5 weeks with doses of flavone acetic acid ranging from 0.33 to 12.5 g/m2. At doses less than or equal to 3.9 g/m2, the drug was administered intravenously over 1 hour; at doses greater than or equal to 5.28 g/m2, the infusion period was lengthened to 6 hours. Treatment of all patients included hydration before and after treatment and alkalization to maintain urine pH at greater than or equal to 6.5. A dose-limiting toxic effect was hypotension at 10 g/m2. Pharmacokinetic studies revealed linear behavior in the eight patients studied, beginning at 3.9 g/m2. Peak plasma levels ranged from 125 to 630 micrograms/mL, with a mean terminal half-life of 22.4 hours. Immunologic monitoring was performed in three patients at 10 g/m2. A transient increase in CD16- and/or Leu-19-positive cells was noted in all three patients. In one patient, this increase correlated with a 10-fold increase in K562 cell killing. There were no objective tumor responses seen in this trial. The recommended phase II dose on this schedule is 8 g/m2. Further studies to elucidate the drug's mechanism of action and to define its immunologic properties are recommended.
Temple University Comprehensive Cancer Center, Philadelphia, PA 19140.
K A
KA
Havlin
J G
JG
Kuhn
J B
JB
Craig
D H
DH
Boldt
G R
GR
Weiss
J
J
Koeller
G
G
Harman
R
R
Schwartz
G N
GN
Clark
D D
DD
Von Hoff
D000328:Adult; D000368:Aged; D000943:Antigens, Differentiation / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019002:CD56 Antigen; D004341:Drug Evaluation; D005260:Female; D005419:Flavonoids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011961:Receptors, Fc / Q000032:analysis; D017452:Receptors, IgG
D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D019002:CD56 Antigen; D005419:Flavonoids; D011961:Receptors, Fc; D017452:Receptors, IgG; C049328:flavone acetic acid