A Phase 1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 with Oral Decitabine in Subjects with Myelodysplastic Syndromes (MDS)
The goal of this clinical research study is to find the highest tolerable dose of the combination drug ASTX727 that can be given to patients with MDS. ASTX727 is a combination of the chemotherapy drug decitabine and a drug called E7727 that helps decitabine stay in your system longer. Once that highest tolerable dose is found, researchers will study the safety and effectiveness of that dose level. In Stage 3 of the study, researchers will also study how participants respond to a new method of taking the study drugs in a tablet form, as well as measure the level of the study drugs in the blood at different timepoints. In 2 earlier stages of this study, participants received decitabline by vein or capsules of E7727 and decitabine by mouth.
Treatment Location: N/A
STUDY OBJECTIVES Dose Escalation Stage - Primary Objectives Assess safety, tolerability, and pharmacokinetics (PK) of concomitant orally administered decitabine + E7727 Identify a dose of oral decitabine + E7727 that together achieve a target mean decitabine AUC comparable to that from decitabine given by IV infusion (20 mg/m2) for 1 hour Dose Escalation Stage - Secondary Objectives Determine percent change of LINE-1 demethylation in Course 1 and Course 2 Assess preliminary efficacy, as determined by response rate, duration of response, hematological improvement, rate of transfusion independence, time to AML, and overall survival Evaluate other PK parameters of decitabine, E7727, and E7727-epimer Dose Escalation Stage - Exploratory Objectives Determine change from baseline for plasma cytidine levels after treatment Assess baseline gene mutation and correlation with response Dose Confirmation Stage - Primary Objectives Confirm the dose of oral decitabine + E7727 identified in the Dose Escalation Stage administered daily x5 that achieves mean decitabine AUC (estimated from a total of 5 days of dosing) and LINE-1 DNA demethylation comparable to that of IV decitabine 20 mg/m2 daily x5. Assess response rate in all subjects Dose Confirmation Stage - Secondary Objectives Assess safety and tolerability of oral decitabine + E7727 Assess duration of response, hematological improvement, rate of transfusion independence, time to AML, and overall survival Evaluate other PK parameters of oral decitabine, E7727, and E7727-epimer (if needed) Dose Confirmation Stage - Exploratory Objective Assess baseline gene mutation and correlation with response Fixed-Dose Combination Stage - Primary Objectives Confirm the ASTX727 FDC tablet achieves mean decitabine AUC (estimated from 5 days of dosing) and LINE-1 DNA demethylation similar to that for IV decitabine 20 mg/m2 daily×5. Assess response rate in all subjects. Fixed-Dose Combination Stage - Secondary Objectives Assess safety and tolerability of ASTX727. Assess duration of response, hematological improvement, rate of transfusion independence, time to AML, and overall survival. Evaluate other PK parameters of ASTX727. Fixed-Dose Combination Stage - Exploratory Objective Assess disease-associated gene mutations and correlation with response.
IRB Review and Approval Date: 07/07/2014
Recruitment Status: Closed
Projected Accrual: N/A
Information and next steps
Phase I/Phase II
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