Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral Cytidine Deaminase Inhibitor (CDAi) in Patients With Myelodysplastic Syndromes (MDS)

Myelodysplastic Syndrome Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02103478
• Other study ID #: ASTX727-01
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: October 28, 2014
• Est. completion date: December 4, 2019

Study information

• Verified date: December 2020
• Source: Astex Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 130
• Est. completion date: December 4, 2019
• Est. primary completion date: June 5, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• MDS
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• ASTX727 Dose Escalation
Oral investigational product and approved IV decitabine
• ASTX727 Dose Confirmation
Randomization cross over design for courses 1 and 2
• ASTX727 Fixed-Dose Combination
Fixed-dose investigational product

Locations

Country	Name	City	State
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Hôpital Maisonneuve-Rosemont	Montréal	Quebec
Canada	Princess Margaret Cancer Center	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre, Odette Cancer Centre	Toronto	Ontario
United States	Johns Hopkins	Baltimore	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Chicago	Chicago	Illinois
United States	John Theurer Cancer Center/ Hackensack University Medical Center	Hackensack	New Jersey
United States	M. D. Anderson	Houston	Texas
United States	Horizon Oncology	Lafayette	Indiana
United States	University of Southern California	Los Angeles	California
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Vanderbilt Ingram Cancer Center	Nashville	Tennessee
United States	Weill Cornell Medical College - New York Presbyterian Hospital	New York	New York
United States	Mayo Clinic	Phoenix	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Astex Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1	Mean AUC0-t of oral decitabine given with cedazuridine (E7727) following IV decitabine 20 mg/m^2 infusion on Day 5. AUCs were calculated by the linear up/log down method using the measured concentration-time values above the BQL (below the limit of quantification).	Day 5
Primary	Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2	Decitabine 5-day AUC ratio following IV decitabine 20 mg/m^2 infusion versus concomitant oral administration of decitabine + cedazuridine (E7727) or ASTX727 in the dose combination and fixed-dose combination stages, respectively. AUC0-t (the area under the concentration-time curve from time zero to the time of the last (tlast) quantifiable concentration (Ct)) by dose/cohort and course/days was used for estimating decitabine cumulative 5-day AUC0-t exposures.	Pre-dose to Day 5
Primary	Number of Participants With Dose-limiting Toxicity in Phase 1	Number of participants with protocol-specified dose-limiting toxicities (DLTs) in the dose escalation stage. DLTs were defined using the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAEv4.0), specifically = Grade 3 non-hematologic toxicity (except Grade 3 nausea, vomiting, or diarrhea that is controllable by anti-emetics or optimal therapy or related to underlying disease or disease progression), specific Grade 3 laboratory tests, related prolonged Grade 4 thrombocytopenia or neutropenia that was not present prior to dosing, does not resolve within 14 days, and is not related to underlying disease, or any toxicity related to study treatment that results in treatment delays of >4 weeks after Day 28.	Up to Day 28 in Course 1 (28 days per course)
Primary	Mean Maximum %LINE Demethylation in Phase 2	Mean maximum % long interspread nuclear element-1 (LINE-1) demethylation after oral decitabine + cedazuridine (E7727) or ASTX727 (Course 1 or Course 2 - Treatment) compared with IV decitabine 20 mg/m^2 (Course 1 or Course 2 - IV Decitabine) in the dose confirmation and fixed-dose combination stages, respectively. Least squares mean of maximum %LINE-1 methylation change from baseline.	Pre-dose to Day 28 in Course 2 (28 days per course)
Primary	Number of Participants With Overall Response in Phase 2	The evaluation of response was based on International Working Group (IWG) 2006 MDS Response Criteria, with overall response calculated as number of participants with complete response+partial response+marrow complete response+hematological improvement (CR+PR+mCR+HI).	Up to approximately 29 months
Secondary	Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer	AUC is a measure of the plasma concentration of the drug over time (AUC0-8). PK parameters are reported for the dose escalation stage by cohort in Phase 1 and dose confirmation and fixed-dose combination stages in Phase 2.	At specified timepoints from 0 to 24 hours post-dose
Secondary	Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer	Cmax is the maximum observed plasma concentration. PK parameters are reported for the dose escalation stage by cohort in Phase 1 and dose confirmation and fixed-dose combination stages in Phase 2.	At specific timepoints from 0 to 24 hours post-dose
Secondary	Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer	Tmax is the time to maximum observed plasma concentration. PK parameters are reported for the dose escalation stage by cohort in Phase 1 and the dose confirmation and fixed-dose combination stages in Phase 2.	At specific timepoints from 0 to 24 hours post-dose
Secondary	Maximum Observed Plasma Concentration (Cmax) of Decitabine	Cmax is the maximum observed plasma concentration. PK parameters for plasma decitabine are reported for the dose escalation stage by cohort in Phase 1 and dose confirmation and fixed-dose combination stages in Phase 2.	At specific timepoints from 0 to 24 hours post-dose
Secondary	Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2	Tmax is the time to reach maximum plasma concentration for decitabine. PK parameters for plasma decitabine are reported for the dose confirmation and fixed-dose combination stages.	At specific timepoints from 0 to 24 hours post-dose
Secondary	Duration of Complete Response in Phase 1	Duration of response (in number of days) was calculated from the first time the response was observed to time of relapse or last time point in the study.	Up to 32 Months
Secondary	Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate	Duration of response (in number of days) was calculated from the first time the response was observed to time of relapse or last time point in the study. Kaplan-Meier estimate for complete response is shown.	Up to approximately 29 months
Secondary	Mean Maximum %LINE Demethylation in Phase 1	Mean maximum % long interspread nuclear element-1 (LINE-1) demethylation decrease from baseline after oral decitabine + cedazuridine (E7727) or ASTX727 compared with IV decitabine 20 mg/m^2 in the dose escalation stage.	Pre-dose to Day 28 in Course 2 (28 days per course)
Secondary	Number of Participants With Overall Response in Phase 1	The evaluation of response was based on International Working Group 2006 MDS Response Criteria, with overall response calculated as number of participants with complete response+partial response+marrow complete response+hematological improvement (CR+PR+mCR+HI).	Up to 32 months
Secondary	Number of Participants With Adverse Events	Number of participants with any treatment-emergent adverse event (AE) and any AE graded =3 using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.	Up to 5 years
Secondary	Number of Participants With Hematological Improvement	Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria.	Up to 32 months
Secondary	Number of Participants With Transfusion Independence	Transfusion independence was calculated based on the number of transfusion-dependent participants at baseline who had no red blood cell or platelet transfusions for 56 consecutive days or more after treatment.	Up to 32 months
Secondary	Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death	Number of participants to reach the event (AML or death), where time to reach AML was calculated as the number of days from the day the participant received the first dose of IV decitabine, oral decitabine + E7727, or the FDC tablet to the date of death or the date of MDS progression to AML as defined by =20% blasts in bone marrow or peripheral blood using the World Health Organization classification. Time to AML or death was censored on the last date of contact if a participant was lost to follow up prior to reaching a time-to-event endpoint.	Up to 32 months
Secondary	Number of Participants With Overall Survival	Overall survival was defined as the number of days from the day the participant received the first dose of IV decitabine, oral decitabine + E7727, or the FDC tablet to the date of death, regardless of cause.	Up to 32 months