A phase I study of the antimetabolite (E)-2'-fluoromethylene-2'-deoxycytidine (MDL 101,731) administered as a twice-weekly infusion.
OBJECTIVE
(E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite. Preclinical tests have shown antiproliferative activity in various human tumor xenograft models and have also indicated that efficacy is greatest with frequent dosing schedules. We conducted a phase I trial of MDL 101,731 infusion in humans with advanced cancer to determine the maximum tolerated dose and the dose-limiting toxicities of this drug when administered on a twice-weekly schedule.


METHODS
The drug was administered on a twice-weekly schedule for 3 weeks, followed by a 2-week rest. The initial dose was 16 mg/m2. This was reduced to 12 mg/m2 if persistent neutropenia occurred. All toxicity in the first six patients resolved by the end of the first rest week. The schedule was changed to 3 weeks of therapy followed by 1 rest week for the subsequent four patients.


RESULTS
Dose escalation beyond 16 mg/m2 was not feasible because of dose-limiting toxicities, principally hematologic. No irreversible or life-threatening toxicity was seen. Grade 2 noninfectious fever, mucositis, and anorexia were also seen. In patients with stable disease, there was a heavily pretreated patient with rectal cancer in whom a 38% reduction in indicator lesions of 7 months' duration occurred.


CONCLUSIONS
(E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite with evidence of anticancer activity in heavily pretreated patients. The maximum tolerated dose when the agent is given twice weekly is 16 mg/m2.
Burtness
B
B
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8032, USA.
Belker
M
M
Stoltz
M
M
Peccerillo
K M
KM
Lamb
L A
LA
Chmael
S E
SE
McKeon
A
A
Clark
M B
MB
Winship
J
J
Marsh
J C
JC
Pizzorno
G
G
DeVita
V T
VT
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D003841:Deoxycytidine; C086432:tezacitabine