Overview

Conditions myelodysplastic syndrome, mds
Treatments astx727 dose escalation, astx727 dose confirmation
Phase phase 1/phase 2
Sponsor Astex Pharmaceuticals
Start date May 2014
End date April 2017
Trial size 120 participants
Trial identifier NCT02103478, ASTX727-01

Summary

This 2-stage, open-label study will evaluate safety and pharmacokinetics of ASTX727, as well as determine the dose for the study's second stage. In the second stage the selected dose will be confirmed and evaluated for clinical activity, including response rate.

Recruiting in the following locations…

United States Arizona, Maryland, Massachusetts, New Jersey, New York, and Wisconsin
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification pharmacokinetics study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
ASTX727 is given by mouth daily X 5 consecutive days. Dosing details will vary in the first 3 courses of therapy for pharmacokinetic measurements. Based on safety and pharmacokinetic results the dose will be modified for subsequent cohorts. Dose escalation will continue until target pharmacokinetics are achieved or until a safe dose is exceeded. This dose will be carried forward into Phase 2.
astx727 dose escalation E7727
Oral investigational product and approved IV decitabine
(Active Comparator)
Subjects will compare one cycle of daily x 5 IV decitabine vs. one cycle of daily x 5 oral decitabine and E7727 for PK and PD. They will be randomized 1:1 as to the order the cycles are administered. In cycle 3 or greater the oral combination will be administered.
astx727 dose confirmation ASTX727 oral (combination of oral E7727 and oral decitabine)
Randomization cross over design for courses 1 and 2

Primary Outcomes

Measure
Pharmacokinetics: plasma decitabine after oral decitabine and E7727 area under the plasma concentration versus time curve (AUC) by cohort.
time frame: (Phase 1) Days -3,1,2 and 5 of Cycle 1 and Day -3 of cycle 2. (Phase 2) Cycle 1 vs. Cycle 2 (Day 1 IV decitabine vs Day 1-5 oral decitabine)
Incidence of Dose limiting toxicities by cohort
time frame: Phase 1 in Cycle 1 (28 days)
Pharmacodynamics: Maximum %LINE-1 demethylation of ASTX727 compared to 20mg/m2 IV decitabine
time frame: (Phase 1 and 2) Days 1,8,15 and 22 for Cycles 1 and 2. Day 1 for cycles 3 and above.
Overall Response Rate
time frame: Phase 1 and 2 through study completion

Secondary Outcomes

Measure
Pharmacokinetics: area under the plasma concentration versus time curve (AUC) of oral decitabine, E7727 and E7727-epimer
time frame: (Phase 1) Days -3,1,2 and 5 of Cycle 1 and Day -3 of cycle 2. (Phase 2) Cycle 1 vs. Cycle 2 (Day 1 IV decitabine vs Day 1-5 oral decitabine)
Pharmacodynamics: Mean maximum % demethylation of the LINE-1 elements in peripheral blood will be reported by cohort
time frame: (Phase 1 and 2) Days 1,8,15 and 22 for Cycles 1 and 2. Day 1 for cycles 3 and above.
Number and proportion of subjects with adverse events by type and grade
time frame: Phase 1 and 2 , through study completion, an average of one year
Pharmacokinetics: Maximum Plasma Concentration (Cmax) of oral decitabine, E7727 and E7727-epimer
time frame: (Phase 1) Days -3,1,2 and 5 of Cycle 1 and Day -3 of cycle 2. (Phase 2) Cycle 1 vs. Cycle 2 (Day 1 IV decitabine vs Day 1-5 oral decitabine)
Pharmacokinetics: Minimum Plasma Concentration (Cmin) of oral decitabine, E7727 and E7727-epimer
time frame: (Phase 1) Days -3,1,2 and 5 of Cycle 1 and Day -3 of cycle 2. (Phase 2) Cycle 1 vs. Cycle 2 (Day 1 IV decitabine vs Day 1-5 oral decitabine)

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: - IPSS low, intermediate -1, intermediate-2, or high risk MDS (including CMML) in Dose Escalation and Dose Confirmation-Randomization; only intermediate-2, or high risk MDS in Dose Confirmation-Open Label - ECOG 0 to 2 - No major surgery within 2 weeks of starting study treatment - No cytotoxic chemotherapy within 2 weeks of starting study treatment - Able to swallow pills Exclusion Criteria: - Previous treatment with 2 or more courses of decitabine (all stages) or azacitidine (Dose Confirmation stage only) - Treatment with investigational therapy within 2 weeks of study treatment - Uncontrolled medical disease(s) or active, uncontrolled infection - Diagnosed with AML - Active uncontrolled gastric or duodenal ulcer - Known history of HIV or hepatitis C or B

Additional Information

Official title A Phase1-2 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)
Description Dose levels for the study's second stage will be based on safety and pharmacokinetics.
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by Astex Pharmaceuticals.