A phase II study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, in patients with very high risk relapsed acute myeloid leukemia

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

“…26 Other grade 3/4 toxicities noted in the laromustine/HDAC arm of the current study (gastrointestinal, constitutional symptoms) are similar to those reported in previous laromustine studies. 18,20,21 The preclinical development of laromustine was focused on the synthesis of an agent that generated an alkylating species that demonstrated antitumor activity with relatively less toxicity to normal tissues. 5,[7][8][9][10]27,28 The clinical development of laromustine in AML has evolved from a consistent demonstration, in both adult and pediatric patients with a variety of refractory solid tumors or hematologic malignancies, that myelosuppression is the dose-limiting toxicity, occurring at doses that incur relatively low extramedullary toxicity.…”

“…5,[7][8][9][10]27,28 The clinical development of laromustine in AML has evolved from a consistent demonstration, in both adult and pediatric patients with a variety of refractory solid tumors or hematologic malignancies, that myelosuppression is the dose-limiting toxicity, occurring at doses that incur relatively low extramedullary toxicity. [16][17][18][19][20][21] In 2002, after analysis of 31 trials of at least 20 patients each, Leopold and Willemze concluded that no chemotherapy regimen had been shown to be more effective than another for patients with relapsed AML. 2 More recently, review of various combination chemotherapeutic regimens based on HDAC described a range of second CR of 10% to 70%.…”

“…19 In poorprognosis patients with AML in first relapse after an initial CR duration of less than 12 months, laromustine was associated with a 4% CR rate, which is within the range as an array of other myelosuppressive single agents studied in this patient population. 20 Because of the significant activity observed in the single-agent trial in patients with AML and poor risk features, 19 a phase 1 study was conducted in patients with refractory hematologic malignancies using a dose escalation of laromustine with high-dose ara-C (HDAC). 21 The MTD was 600 mg/m 2 laromustine combined with ara-C 1.5 mg/m 2 per day for 3 days, and CR was attained in 7 (22%) of 32 patients with AML.…”

Treatment and prognostic assessment of acute myeloid leukemia

“…A phase II study has revealed significant anti-leukemic activity with modest extra-medullary toxicity in elderly patients with AML. 50 However it is reported to have minimal activity in very high risk patients with relapsed AML. 48 Demethylating agents like decitabine, 5-azacytidine and zebularine and FLT3 inhibitors like SU11248 and MLN518 have been evaluated for anti-leukemic action especially in elderly.…”

Determination of Cloretazine™ (VNP40101M) and its active metabolite (VNP4090CE) in human plasma by liquid chromatography electrospray tandem mass spectrometry (LC–ESI-MS/MS)

“…The 90CE rapidly produces a chlorethylating group with an in vitro half-life of less than a minute [9]. Cloretazine TM has demonstrated its tolerability in clinical trials in adults with cancer [10][11][12][13]. A Phase I pharmacokinetic clinical trial of Cloretazine TM has been conducted in children with recurrent, progressive, or refractory brain tumors.…”