A Double Blind Placebo-Controlled Randomized Phase III Study of High Dose Continuous Infusion Cytosine Arabinoside (araC) with or without Cloretazine® in Patients with First Relapse of Acute Myeloid Leukemia (AML).
Authors: Giles Francis J. , Stock Wendy , Vey Norbert , Seiter Karen , DeAngelo Daniel J. , Boskovic Darinka , Stuart Robert K. , Johnson Bonny , Cahill Ann L. , O’Brien Susan 
Published: October 2019

Abstract
Background: AraC is considered to be the most effective single drug in the treatment of AML. For initial treatment of AML, araC is typically administered by intravenous continuous infusion for 5–7 days at doses of 100–200 mg/m2/day, usually in combination with an anthracycline. In the relapsed setting, araC remains an option for treatment and is generally administered at higher doses either alone or in combination with other agents and in a variety of schedules. Cloretazine (VNP40101M) is a novel alkylating agent that preferentially targets the O6 position of guanine. A Phase I trial of Cloretazine with araC in advanced hematologic malignancies demonstrated significant anti-leukemic activity with minimal extramedullary toxicity (Giles et al, 2005). The purpose of the current double blind randomized Phase III study is to determine if araC with Cloretazine improves outcome in AML patients (pts) in first relapse.
Methods: Eligible pts must be ≥18 years old, PS 0–2, and have AML in first relapse following a CR or CRp of 3–24 months duration. Pts are randomized using a 2:1 scheme to receive either araC 1.5 gm/m2 (d 1–3) + Cloretazine 600mg/m2 or placebo on d 2. Pts are stratified by both age and remission duration. Pts achieving CR or CRp are consolidated with araC + Cloretazine 400mg/m2, or araC + placebo according to original treatment assignment. Pts with partial response or bone marrow improvement may receive a second induction cycle. The study will accrue 420 pts, with an interim analysis for safety and efficacy at 210 pts. The primary endpoint is overall response (CR and CRp) rate. Secondary endpoints include time-to-progression, duration of response, and survival.
Results: A data safety monitoring board review of the first 32 pts was performed in 12/05. Differential toxicity between the two arms was not observed. From 03/05 to 07/06, 164 pts were enrolled by 47 sites. Median age=59 yrs (range 22–83), and 52%= male. Distribution by stratum: I = 66 (<60, CR<12mos); II= 22 (<60, CR≥12mos); III= 45 (≥60, CR<12mos); IV= 31 (≥60, CR≥12mos). Blinded data are available for 110 monitored pts: 77% were de novo AML, 23% secondary AML. 107/110 pts completed the intended treatment course. The most common reported serious adverse event was infection (50%). Importantly, of 110 pts, early deaths (≤30 days from start of treatment) occurred in only 13 (12%) pts, most of which was due to infection with neutropenia, or progressive disease.
Conclusions: A multi-site Phase III double-blind randomized trial for pts with AML in first relapse is feasible and demonstrates a recognized clinical need for new treatments across age and CR duration variables. The ability of pts to tolerate high-dose araC with or without Cloretazine as assessed by rate of SAE and early death is encouraging.