Advances in Hematologic Malignancies Issue 4, Summer 2016
— David Steensma, MD
The DNA methyltransferase inhibitors azacitidine (Vidaza) and decitabine (Dacogen) are both FDA-approved for treatment of all French-American-British (FAB) Co-operative Group subtypes of
myelodysplastic syndromes (MDS), and these drugs can alter the natural history of the disease. Azacitidine, for instance, has been shown to be associated with an overall survival benefit,
while decitabine in randomized trials has delayed progression to
acute myeloid leukemia and improved blood counts.
Currently, both of these "hypomethylating" drugs are only approved for parenteral administration — intravenous for decitabine, and intravenous or subcutaneous for azacitidine — and therefore require patients to come to health care facilities for one week
of administration every month. If these agents truly work by altering DNA methylation in MDS cells and changing gene expression, as clearly occurs in vitro, then it is possible that longer schedules of administration or different schedules
from the ones that are currently used in the clinic might be associated with better responses. An oral formulation of these agents would potentially allow exploration of some of these alternate dosing schedules, as well as be more convenient for patients.
Unfortunately, neither azacitidine nor decitabine is consistently absorbed when given by mouth. Azacitidine's bioavailability varies widely after oral administration (though a newer oral formulation, CC-486, is in development), and oral decitabine is
rapidly degraded by cytosine deaminase, an enzyme expressed in liver and gut cells.
Excerpt from Abstract No. 1683 presented at ASH 2015 Annual Meeting.
E7727 is an orally-available cytosine deaminase inhibitor that in pre-clinical models dramatically increases oral bioavailability of concomitantly administered decitabine. The ASTX727-01 study is a phase 1 trial designed to characterize this combination
— specifically, to understand the pharmacological and clinical effects of oral E7727 co-administered with oral decitabine. This study has pharmacokinetic and pharmacodynamic end points, and the primary goal of this study is to determine a dose of
E7727 plus decitabine that is associated with a target mean decitabine level (i.e., area under the curve) comparable to that seen with intravenous decitabine. This study includes both a dose escalation phase, which was completed when a dose level
of E7727 closely paralleling intravenous decitabine was determined, and a dose expansion/confirmation stage, which is currently enrolling.
Eligible patients are those with International Prognostic Scoring System (IPSS) Intermediate 1, Intermediate 2, or High-risk MDS, as well as adequate hepatic and renal function and performance status, and prior treatment with no more than 1 course of
decitabine or azacitidine. The study design includes pharmacokinetic assessments of both oral and intravenous of E7727 alone, plus the combination of oral decitabine and oral E7727. A small stipend is available to help defray patients' travel expenses
to Boston. We would be grateful to see in consultation any patients with higher-risk MDS who might be eligible and willing to participate in this or other studies.
Learn more about this study.