Clinical trial NCT02103478: Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral Cytidine Deaminase Inhibitor (CDAi) in Patients With Myelodysplastic Syndromes (MDS)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Myelodysplastic Syndrome
MDS
Keywords: Myelodysplastic Syndrome
MDS
Lead sponsor: Astex Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2014-04-04
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This first-in-human, 3-stage, open-label study evaluated the safety and pharmacokinetics of ASTX727, as well as determined the dose for later stages.

Detailed description: The trial was designed to define daily doses of the individual components (cedazuridine \[E7727\] or decitabine) so that decitabine exposure after oral administration would be comparable to exposure after IV decitabine at the approved daily dose of 20 mg/m\^2. The main objective of Phases 1 and 2 was to establish and confirm the doses of the 2 components to be used in the final fixed-dose combination (FDC) product (ASTX727) using mainly pharmacokinetics and pharmacodynamics as endpoints.

Eligibility criteria: Inclusion Criteria:

* International Prognostic Scoring System (IPSS) low, intermediate -1, intermediate-2, or high risk MDS (including chronic myelomonocytic leukemia; CMML) in Dose Escalation and Dose Confirmation-Randomization; only intermediate-2, or high risk MDS in Dose Confirmation-Open Label
* Eastern Cooperative Oncology Group (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 acute myeloid leukemia (AML)
* Active uncontrolled gastric or duodenal ulcer
* Known history of HIV or hepatitis C or B

Primary outcomes:
measure: Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1
timeFrame: Day 5
measure: Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2
timeFrame: Pre-dose to Day 5
measure: Number of Participants With Dose-limiting Toxicity in Phase 1
timeFrame: Up to Day 28 in Course 1 (28 days per course)
measure: Mean Maximum %LINE Demethylation in Phase 2
timeFrame: Pre-dose to Day 28 in Course 2 (28 days per course)
measure: Number of Participants With Overall Response in Phase 2
timeFrame: Up to approximately 29 months
Secondary outcomes:
measure: Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer
timeFrame: At specified timepoints from 0 to 24 hours post-dose
measure: Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer
timeFrame: At specific timepoints from 0 to 24 hours post-dose
measure: Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer
timeFrame: At specific timepoints from 0 to 24 hours post-dose
measure: Maximum Observed Plasma Concentration (Cmax) of Decitabine
timeFrame: At specific timepoints from 0 to 24 hours post-dose
measure: Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2
timeFrame: At specific timepoints from 0 to 24 hours post-dose
measure: Duration of Complete Response in Phase 1
timeFrame: Up to 32 Months
measure: Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate
timeFrame: Up to approximately 29 months
measure: Mean Maximum %LINE Demethylation in Phase 1
timeFrame: Pre-dose to Day 28 in Course 2 (28 days per course)
measure: Number of Participants With Overall Response in Phase 1
timeFrame: Up to 32 months
measure: Number of Participants With Adverse Events
timeFrame: Up to 5 years
measure: Number of Participants With Hematological Improvement
timeFrame: Up to 32 months
measure: Number of Participants With Transfusion Independence
timeFrame: Up to 32 months
measure: Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death
timeFrame: Up to 32 months
measure: Number of Participants With Overall Survival
timeFrame: Up to 32 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Lafayette
country: United States
facility: Horizon Oncology
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Hackensack
country: United States
facility: John Theurer Cancer Center/ Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College - New York Presbyterian Hospital
state: New York
city: Nashville
country: United States
facility: Vanderbilt Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: M. D. Anderson
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre, Odette Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: Montréal
country: Canada
facility: Hôpital Maisonneuve-Rosemont
state: Quebec
Study officials:
affiliation: Astex Pharmaceuticals, Inc.
name: Mohammad Azab, MD
role: STUDY_DIRECTOR
affiliation: Astex Pharmaceuticals, Inc.
name: James Lowder, MD
role: STUDY_CHAIR
References:
citation: Garcia-Manero G, Griffiths EA, Steensma DP, Roboz GJ, Wells R, McCloskey J, Odenike O, DeZern AE, Yee K, Busque L, O'Connell C, Michaelis LC, Brandwein J, Kantarjian H, Oganesian A, Azab M, Savona MR. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020 Aug 6;136(6):674-683. doi: 10.1182/blood.2019004143.
citation: Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, Faderl S, Harb W, Kantarjian H, Lowder J, Oganesian A, Azab M, Garcia-Manero G. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019 Apr;6(4):e194-e203. doi: 10.1016/S2352-3026(19)30030-4.