Phase II Study of VNP40101M (Cloretazine®) in Elderly Patients with De Novo Poor Risk Acute Myelogenous Leukemia (AML).

VNP40101M (Cloretazine®) is a novel sulfonylhydrazine alkylating agent which preferentially targets the O₆ position of guanine resulting in DNA cross-links. Data from a previously reported phase II multi-center single agent study (CLI-033) in patients ≥60 years old with newly diagnosed AML or high risk MDS showed an overall response rate of 31% after VNP40101M induction (Giles, 2007). Subgroup analysis showed significant activity in 54 elderly patients with de novo AML with 24 patients (45%) achieving a complete response (CR) or CRp (CI: 30.9;58.6). Subsequently a confirmatory phase II study of single agent VNP40101M was conducted in elderly patients with poor risk de novo AML (CLI-043). Patients received induction therapy with 600 mg/m² VNP40101M as a 60-minute infusion on day 1. A second induction cycle could be administered to patients with a partial response or hematologic improvement. Patients with CR or CRp received consolidation with cytarabine 400mg/m²/day CIV for 5 days. Patients were eligible if they were ≥60 yrs and had one of the following poor risk factors: age ≥70 yrs, ECOG PS 2, unfavorable cytogenetics, or cardiac, pulmonary or hepatic dysfunction. Patients with a prior diagnosis of MDS or favorable cytogenetics were excluded. A 2-stage optimal minimax design was employed with a target response rate of 35%. The study proceeded to the 2nd stage when >8 responses were confirmed. At least 22 responses in 77 patients are required to accept the hypothesis of a 35% target response rate. Eighty-five patients were treated as of August 14, 2007. Median age (range): 73 yrs (61– 86 y); male: 59%. The majority of patients (79%) had 2 or more risk factors. The most common risk factors were age ≥70 (78%), unfavorable cytogenetics (45%, half with complex karyotype), ECOG PS 2 (41%) and cardiac dysfunction (38%). Thirty VNP40101M-related serious adverse events (SAE) have been reported to date in 22 of 85 patients. The most common SAEs are myelosuppression or complications thereof (pancytopenia (10%), infection (47%)). Non-hematologic SAEs consist of the following gr.3 events: left ventricular dysfunction (1), transaminitis (1), confusion (1), seizure (1), rash (1), hypokalemia (1), weakness (1) and hypoxia/pleural effusion (2). Seventy-nine patients are currently evaluable for early death analysis. Of these, 12 patients (15%) and 16 patients (20%) died at ≤30 days and ≤42 days from first induction therapy, respectively. The most common causes of induction death were progression of disease (6) and infection (6). Other causes were tumor lysis syndrome (1), acute renal failure (1), and respiratory failure (2). A confirmatory Phase II single-agent study of VNP40101M shows anti-leukemia activity in elderly patients with de novo AML and multiple poor-risk features. Major toxicities include myelosuppression. Severe drug-related non-hematological toxicity is uncommon. Patients continue in follow up, and additional safety and response data is pending.