PS1029 CLINICAL BENEFIT OF GLASDEGIB PLUS LOW-DOSE CYTARABINE IN PATIENTS WITH DE NOVO AND SECONDARY ACUTE MYELOID LEUKEMIA: LONG-TERM ANALYSIS OF A PHASE 2 RANDOMIZED TRIAL
Authors: M. Heuser, W. Fiedler, M.A. Sekeres, P. Montesinos, B. Leber, A. Merchant, C. Papayannidis, J.A. Pérez-Simón, C.J. Hoang, W.W. Ma, M. Zeremski, A. O’Connell, G. Chan, J.E. Cortes
Journal: HemaSphere (2019)

Background: The combination of all-trans retinoic acid (ATRA) and intravenous arsenic trioxide (IV ATO) cures most patients with acute promyelocytic leukemia (APL). However, daily 2-hour infusions of ATO over several months constitute a significant burden for hospitals and patients. A novel encapsulated formulation of oral ATO (Phebra Pty Ltd, Australia) has the potential to significantly simplify treatment delivery and improve the overall treatment experience of patients with APL. Aims: To characterize the bioavailability of encapsulated oral ATO in patients with APL by comparing the AUC0–24 and Cmax of total arsenic in whole blood (WB) and plasma (PL) after oral and IV ATO administration. Methods: ALLG APML5 (ACTRN12616001022459) is a bioavailability study embedded within a standard-of-care consolidation regimen. Eligibility required documented hematological complete remission following induction with ATRA + IV ATO (+ idarubicin for patients with initial WBC count > 10x109/l). Registered patients were consolidated with 7 cycles of ATRA 45 mg/m2/d (7d/week for 2 weeks, with 2 weeks between cycles), and 4 cycles of IV ATO 0.15 mg/kg/d (5d/week for 4 weeks, with 4 weeks between cycles). Pharmacokinetic (PK) sampling was performed on days 1 and 4 in week 1 of each ATO cycle. Oral ATO 0.15 mg/kg/d (administered 1 hour before food as 10 mg and/or 1 mg capsules rounded up to the nearest 1 mg) was substituted for IV ATO in week 1 of cycle 2, and again in week 1 of cycle 4 (with PK-directed dose modification if required). Total arsenic was quantitated by inductively coupled plasma mass spectrometry. Point estimates of mean oral/IV arsenic ratios ± 90% confidence intervals (CI) for AUC0–24 and Cmax in WB and PL were calculated by linear mixed model analysis incorporating fixed and random effects, and the results were compared with conventional bioequivalence limits (0.80, 1.25). Results: This preliminary analysis encompasses 53 evaluable PK profiles from 9 patients: 4 males, 5 females, median age 52 years (range 20–66). Both formulations were associated with significant increases in all PK parameters from day 1 to day 4 (p < 0.001 for WB AUC0–24, PL AUC0–24, WB Cmax and PL Cmax; Figure 1), indicative of short-term arsenic accumulation within each cycle. However there was no accumulation of arsenic between sequential cycles. No significant PK differences between the oral and IV formulations were identified (Figure 1). Estimates of the geometric mean of the oral/IV ratio for each PK parameter closely approximate unity (Table 1), and the 90% CIs fall within (or just upon) the bioequivalence limits (0.80, 1.25). Although exposure to encapsulated oral ATO was restricted to 10 days, its use was not associated with any increase in the frequencies of grade 3–4 adverse events, gastrointestinal toxicity or QTc prolongation. No patient required dose adjustment of oral ATO in cycle 4 based on PK or toxicity criteria.Summary/Conclusion: The data demonstrate promising evidence of average bioequivalence for the oral and IV arsenic formulations with low inter- and intra-patient variability, and indicate encapsulated oral ATO 0.15 mg/kg/d and IV ATO 0.15 mg/kg/d provide comparable arsenic exposure over repeated cycles of consolidation.