title: Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse.
abstract: Laromustine is a sulfonylhdrazine alkylator with significant antileukemia activity. An international, randomized (2:1), double-blind, placebo-controlled study was conducted to compare complete remission (CR) rates and overall survival (OS) in patients with first relapse acute myeloid leukemia (AML) treated with laromustine and high-dose cytarabine (HDAC) versus HDAC/placebo. Patients received 1.5 g/m(2) per day cytarabine continuous infusion for 3 days and laromustine 600 mg/m(2) (n = 177) or placebo (n = 86) on day 2. Patients in CR received consolidation with laromustine/HDAC or HDAC/placebo as per initial randomization. After interim analysis at 50% enrollment, the Data Safety Monitoring Board (DSMB) expressed concern that any advantage in CR would be compromised by the observed on-study mortality, and enrollment was held. The CR rate was significantly higher for the laromustine/HDAC group (35% vs 19%, P = .005). However, the 30-day mortality rate and median progression-free survival were significantly worse in this group compared with HDAC/placebo (11% vs 2%; P = .016; 54 days vs 34; P = .002). OS and median response durations were similar in both groups. Laromustine/HDAC induced significantly more CR than HDAC/placebo, but OS was not improved due to mortality associated with myelosuppression and its sequelae. The DSMB subsequently approved a revised protocol with laromustine dose reduction and recombinant growth factor support. The study was registered as NCT00112554 at http://www.clinicaltrials.gov.
authors.affiliation: Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center, San Antonio, TX 78229, USA. frankgiles@aol.com
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.forename: Daniel
authors.initials: D
authors.lastname: DeAngelo
authors.forename: Karen
authors.initials: K
authors.lastname: Seiter
authors.forename: Wendy
authors.initials: W
authors.lastname: Stock
authors.forename: Robert
authors.initials: R
authors.lastname: Stuart
authors.forename: Darinka
authors.initials: D
authors.lastname: Boskovic
authors.forename: Arnaud
authors.initials: A
authors.lastname: Pigneux
authors.forename: Martin
authors.initials: M
authors.lastname: Tallman
authors.forename: Joseph
authors.initials: J
authors.lastname: Brandwein
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kell
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
authors.forename: Peter
authors.initials: P
authors.lastname: Staib
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.forename: Ann
authors.initials: A
authors.lastname: Cahill
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage*; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction; D013449:Sulfonamides / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D006834:Hydrazines; D013449:Sulfonamides; D003561:Cytarabine; C483604:laromustine