Phase I study with the DNA sequence-specific agent adozelesin.
Adozelesin, a synthetic analog of the antitumor antibiotic CC-1065, is a novel cytotoxic agent which inhibits DNA synthesis by binding to the minor groove of the DNA helix. Preclinical studies have shown a broad spectrum of activity against a variety of murine and human tumor xenograft models. We conducted a phase I study of adozelesin to (i) determine a recommended dose for phase II testing using a 10 min i.v. infusion, (ii) characterize the toxic effects of the drug using this schedule and (iii) document any antitumor activity observed. Adozelesin was administered as an i.v. infusion every 6 weeks. CBC and biological parameters were performed weekly. The starting dose of 10 microg/m2, corresponding to 1/30 the mouse equivalent lethal dose, was escalated, according to a modified Fibonacci scheme, until dose-limiting toxicity was encountered. Forty-seven adult patients with solid malignancies were entered in the study. Successive dose levels used were 10, 20, 33, 50, 70, 105, 120, 150 and 180 microg/m2. The main toxic effect was myelosuppression, which was dose limiting. The maximally tolerated dose was defined as 180 microg/m2. A minor response with a 4 month duration was reported in one previously treated patient with melanoma. We conclude that the recommended phase II dose of adozelesin given as a 10 min infusion is 150 microg/m2, repeated every 4 weeks.
Burris
H A
HA
University of Texas Health Science Center at San Antonio, 78229, USA.
Dieras
V C
VC
Tunca
M
M
Earhart
R H
RH
Eckardt
J R
JR
Rodriguez
G I
GI
Shaffer
D S
DS
Fields
S M
SM
Campbell
E
E
Schaaf
L
L
Kasunic
D
D
Von Hoff
D D
DD
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D001572:Benzofurans; D001769:Blood / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D053138:Cyclohexenes; D004305:Dose-Response Relationship, Drug; D000080890:Duocarmycins; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D007211:Indoles; D007262:Infusions, Intravenous; D008099:Liver / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D001572:Benzofurans; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D000080890:Duocarmycins; D007211:Indoles; C060090:adozelesin