Phase I trial of intravenous vinzolidine (LY 104208) given on a biweekly dosing schedule.
Vinzolidine (VZL) is a semisynthetic vinca alkaloid with broad antitumor activity in animal models of malignancy but had unpredictable toxic effects when given orally to humans. To minimize the toxic effects due to potential erratic gastrointestinal absorption, this drug was restudied in man as an intravenous preparation given as a rapid injection every two weeks. The maximum tolerated dose (MTD) on this schedule was 9.0 mg/m2 with unpredictable leukopenia (usually occurring 5-14 days post treatment but appearing erratically), constipation, paralytic ileus, and inappropriate ADH syndrome as major toxicities. Nonhematologic toxicities were dose-limiting. Repetitive dosing at two week intervals was associated with leukopenia at D 14-15 in some but not all patients treated above 5.0 mg/m2 precluding further treatment on schedule. In contrast, the oral MTD of this agent in our prior studies was 45 mg/m2 with no evidence of delayed leukopenia. Intrapatient variability of toxicity was small; interpatient variability of toxicity was substantial and did not correlate with prior therapy. Because of the presence of delayed hematologic toxicity on repetitive dosing schedules, intravenous VZL should be given on a dosing schedule longer than 14 days. No antitumor activity was seen in this study.
Budman
D R
DR
Department of Medicine, North Shore University Hospital, Cornell Medical College, Manhasset, NY 11030.
Kreis
W
W
Behr
J
J
Schulman
P
P
Lichtman
S
S
Allen
S L
SL
Weiselberg
L
L
Satterlee
W G
WG
Nelson
R L
RL
Vinciguerra
V
V
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D014748:Vinca Alkaloids / Q000008:administration & dosage / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D014748:Vinca Alkaloids; C042392:vinzolidine