Phase I study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, combined with cytarabine in patients with refractory leukemia.
OBJECTIVE
Cloretazine (VNP40101M) is a novel sulfonylhydrazine alkylating agent with significant antileukemia activity. A phase I study of cloretazine combined with cytarabine (1-beta-d-arabinofuranosylcytosine, ara-C) was conducted in patients with refractory disease.


METHODS
Ara-C was given i.v. at a fixed dose of 1.5 gm/m(2)/d by continuous infusion for 4 days (patients ages <65 years at time of diagnosis) or 3 days (patients ages > or =65 years). Cloretazine was given i.v. over 15 to 60 minutes on day 2 at a starting dose of 200 mg/m(2), with escalation in 100 mg/m(2) increments in cohorts of three to six patients until a maximum tolerated dose was established. The DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT) was measured at baseline.


RESULTS
Forty patients, including 32 with acute myeloid leukemia, received 47 courses of treatment. Complete responses were seen at cloretazine dose levels of > or =400 mg/m(2) in 10 of 37 (27%) evaluable patients, and in this patient subset, AGT activity was significantly lower in patients that responded to treatment than in patients who did not (P < or = 0.027). Dose-limiting toxicities (gastrointestinal and myelosuppression) were seen with 500 and 600 mg/m(2) of cloretazine combined with the 4-day ara-C schedule but not seen with the 3-day schedule.


CONCLUSIONS
The recommended cloretazine dose schedule for future studies is 600 mg/m(2) combined with 1.5 gm/m(2)/d continuous infusion of ara-C for 3 days. The cloretazine and ara-C regimen has significant antileukemic activity. AGT activity may be a predictor of response to cloretazine.
Giles
Francis
F
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA. frankgiles@aol.com
Verstovsek
Srdan
S
Thomas
Deborah
D
Gerson
Stanton
S
Cortes
Jorge
J
Faderl
Stefan
S
Ferrajoli
Alessandra
A
Ravandi
Farhad
F
Kornblau
Steven
S
Garcia-Manero
Guillermo
G
Jabbour
Elias
E
O'Brien
Susan
S
Karsten
Verena
V
Cahill
Ann
A
Yee
Karen
K
Albitar
Maher
M
Sznol
Mario
M
Kantarjian
Hagop
H
D000328:Adult; D000368:Aged; D000477:Alkylating Agents / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D020137:Base Pair Mismatch; D015331:Cohort Studies; D003561:Cytarabine / Q000008:administration & dosage*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004260:DNA Repair; D018450:Disease Progression; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage*; D007938:Leukemia / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage*; D013997:Time Factors
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D006834:Hydrazines; D013449:Sulfonamides; D003561:Cytarabine; C483604:laromustine; D004247:DNA; D019853:O(6)-Methylguanine-DNA Methyltransferase