Phase I study of adozelesin administered by 24-hour continuous intravenous infusion.
BACKGROUND
Adozelesin, a synthetic analogue of the antitumor antibiotic CC-1065, is the first of a class of potent sequence-specific alkylating agents to be brought to clinical trial. In preclinical in vitro testing, it has demonstrated antitumor activity at picomolar concentrations.


OBJECTIVE
We conducted a phase I study of adozelesin to (a) determine a recommended dose for phase II testing using a 24-hour intravenous infusion, (b) characterize the toxic effects of the drug using this schedule, and (c) document any antitumor activity observed.


METHODS
Adozelesin was given as a 24-hour continuous intravenous infusion. Treatments were initially scheduled every 3 weeks, but the prolonged myelosuppression observed necessitated a final dosing interval of every 6 weeks. The starting dose of 30 micrograms/m2 was escalated using a modified Fibonacci scheme until dose-limiting toxicity was encountered.


RESULTS
Twenty-nine patients were entered in the study. Successive dose levels used were 30, 60, 100, 150, 120, and 100 micrograms/m2. Prolonged thrombocytopenia and granulocytopenia were dose limiting. No antitumor responses were observed.


CONCLUSIONS
We recommend that the phase II dose of adozelesin given as a continuous 24-hour intravenous infusion be 100 micrograms/m2, repeated every 6 weeks. Other potentially less myelosuppressive schedules could be pursued.
Fleming
G F
GF
Department of Medicine, University of Chicago Medical Center, IL 60637-1470.
Ratain
M J
MJ
O'Brien
S M
SM
Schilsky
R L
RL
Hoffman
P C
PC
Richards
J M
JM
Vogelzang
N J
NJ
Kasunic
D A
DA
Earhart
R H
RH
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001572:Benzofurans; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D053138:Cyclohexenes; D004334:Drug Administration Schedule; D000080890:Duocarmycins; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007211:Indoles; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001572:Benzofurans; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D000080890:Duocarmycins; D007211:Indoles; C060090:adozelesin