Myelodysplastic SyndromePhase 1/2NCT02103478

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

A Phase 1/2 study testing ASTX727 Dose Escalation, ASTX727 Dose Confirmation and ASTX727 Fixed-Dose Combination in people with Myelodysplastic Syndrome and MDS, run by Astex Pharmaceuticals, Inc. at 17 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

Search all trials

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. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Myelodysplastic Syndrome, MDS
What is being tested?: ASTX727 Dose Escalation, ASTX727 Dose Confirmation and ASTX727 Fixed-Dose Combination
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 130 participants
Where: 17 sitesin 2 countries
Study dates: 28 Oct 2014to 4 Dec 2019
Phase: Phase 1/2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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

Trial locations and contacts

17 sites in 2 countries.

Country

City, postcode or hospital

17 sites in 2 countries

United States13 sites

Johns Hopkins
Baltimore, Maryland, 21231
Massachusetts General Hospital
Boston, Massachusetts, 02114
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
Roswell Park Cancer Institute
Buffalo, New York, 14263
University of Chicago
Chicago, Illinois, 60637
John Theurer Cancer Center/ Hackensack University Medical Center
Hackensack, New Jersey, 07601
M. D. Anderson
Houston, Texas, 77030
Horizon Oncology
Lafayette, Indiana, 47905
University of Southern California
Los Angeles, California, 90024
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
Vanderbilt Ingram Cancer Center
Nashville, Tennessee, 37232
Weill Cornell Medical College - New York Presbyterian Hospital
New York, New York, 10021
Mayo Clinic
Phoenix, Arizona, 85054

Other trials in United States

Canada4 sites

University of Alberta Hospital
Edmonton, Alberta, T6G 2G3
Hôpital Maisonneuve-Rosemont
Montreal, Quebec, H1T 2M4
Sunnybrook Health Sciences Centre, Odette Cancer Centre
Toronto, Ontario, M4N 3M5
Princess Margaret Cancer Center
Toronto, Ontario, M5G 2M9

Other trials in Canada

About this study

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)

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.

Read the 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.

Conditions: Myelodysplastic Syndrome, MDS
Being tested: ASTX727 Dose Escalation, ASTX727 Dose Confirmation, ASTX727 Fixed-Dose Combination
Keywords: Myelodysplastic Syndrome, MDS
Medical subject headings: Myelodysplastic Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

ASTX727 Dose EscalationDrug
Also called cedazuridine (E7727), oral decitabine, IV decitabine
Oral investigational product and approved IV decitabine
ASTX727 Dose ConfirmationDrug
Also called ASTX727 oral (combination of oral E7727 and oral decitabine), IV decitabine
Randomization cross over design for courses 1 and 2
ASTX727 Fixed-Dose CombinationDrug
Also called ASTX727 oral (combination of oral E7727 and oral decitabine)
Fixed-dose investigational product

Study groups in NCT02103478
Study group	Role	What they receive
Phase 1 Dose Escalation	Experimental	Starting cohort was administered 40 mg oral cedazuridine and 20 mg oral decitabine. Participants were enrolled into successive cohorts in which either the cedazuridine or decitabine oral dose was varied in Course 1 Day 2 through Course 1 Day 5 for comparison with a single dose of IV decitabine at 20 mg/m^2 administered on Day 1 by continuous IV infusion over 1 hour (28 days per course). Receives: Drug: ASTX727 Dose Escalation
Phase 2 Dose Confirmation	Experimental	Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (E7727) (100 mg) + decitabine (35 mg) capsules Dailyx5 in Course 1 followed by IV decitabine (20 mg/m^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study. Receives: Drug: ASTX727 Dose Confirmation
Phase 2 Fixed-Dose Combination	Experimental	Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine (E7727)/35 mg decitabine) Dailyx5 in Course 1 followed by IV decitabine (20 mg/m^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, all participants received the FDC tablet Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study. Receives: Drug: ASTX727 Fixed-Dose Combination

What is being measured

The primary outcome is the main question the study is designed to answer.

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).
Measured: Day 5
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.
Measured: Pre-dose to Day 5
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.
Measured: Up to Day 28 in Course 1 (28 days per course)
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.
Measured: Pre-dose to Day 28 in Course 2 (28 days per course)
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).
Measured: Up to approximately 29 months

Secondary outcomes (14)

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.
Measured: At specified timepoints from 0 to 24 hours post-dose
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.
Measured: At specific timepoints from 0 to 24 hours post-dose
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.
Measured: At specific timepoints from 0 to 24 hours post-dose
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.
Measured: At specific timepoints from 0 to 24 hours post-dose
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.
Measured: At specific timepoints from 0 to 24 hours post-dose
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.
Measured: Up to 32 Months
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.
Measured: Up to approximately 29 months
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.
Measured: Pre-dose to Day 28 in Course 2 (28 days per course)
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).
Measured: Up to 32 months
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.
Measured: Up to 5 years
Number of Participants With Hematological Improvement
Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria.
Measured: Up to 32 months
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.
Measured: Up to 32 months
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.
Measured: Up to 32 months
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.
Measured: Up to 32 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

28 Oct 20144 Dec 2019

First posted4 Apr 2014 (estimated)
Study start28 Oct 2014
Primary completion5 Jun 2018
Study completion4 Dec 2019

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Myelodysplastic SyndromeStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Sequential
Masking: None (open label)
Enrolment: 130 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02103478
Sponsor's protocol ID: ASTX727-01
Status last verified: Jul 2024
First submitted: 20 Mar 2014
Last updated: 27 Aug 2024
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
Individual data sharing: Undecided

Publications

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.
PubMed 32285126
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.
PubMed 30926081

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

RecruitingPhase 2
Testing New Therapies for Patients With Acute Myeloid Leukemia Who Are Newly Diagnosed and Have Not Yet Started Treatment (A MyeloMATCH Treatment Trial)
Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic/Myeloproliferative Neoplasm
Active, not recruitingPhase 1/2
Omacetaxine + Azacitidine in Untreated Patients With High Grade MDS
High Grade Myelodysplastic Syndromes
RecruitingPhase 1/2
Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms
Myelodysplastic Syndromes
Active, not recruitingPhase 2
Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
Adult Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Not yet recruitingPhase 1
ATRN-119 in Combination With Decitabine in Patients With TP53-Mutated AML or Higher-Risk MDS
Acute Myeloid Leukemia, High-risk Myelodysplastic Syndrome

All Myelodysplastic Syndrome trials

Study at a glance

From the registry record, last updated by the sponsor on 27 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

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)
ClinicalTrials.gov ID: NCT02103478
Acronym / sponsor ID: ASTX727-01
Conditions: Myelodysplastic Syndrome, MDS
Keywords: Myelodysplastic Syndrome, MDS
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 130 participants (actual)
Lead sponsor: Astex Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
Study start: 28 Oct 2014 (actual)
Primary completion: 5 Jun 2018 (actual)
Study completion: 4 Dec 2019 (actual)
First posted: 4 Apr 2014 (estimated)
Results: Posted 19 Oct 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Sequential
Masking: None (open label)
Number of arms: 3

Arm	Type	Receives
Phase 1 Dose Escalation	Experimental	Drug: ASTX727 Dose EscalationStarting cohort was administered 40 mg oral cedazuridine and 20 mg oral decitabine. Participants were enrolled into successive cohorts in which either the cedazuridine or decitabine oral dose was varied in Course 1 Day 2 through Course 1 Day 5 for comparison with a single dose of IV decitabine at 20 mg/m^2 administered on Day 1 by continuous IV infusion over 1 hour (28 days per course).
Phase 2 Dose Confirmation	Experimental	Drug: ASTX727 Dose ConfirmationParticipants were randomized in a 1:1 ratio to receive either oral cedazuridine (E7727) (100 mg) + decitabine (35 mg) capsules Dailyx5 in Course 1 followed by IV decitabine (20 mg/m^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Phase 2 Fixed-Dose Combination	Experimental	Drug: ASTX727 Fixed-Dose CombinationParticipants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine (E7727)/35 mg decitabine) Dailyx5 in Course 1 followed by IV decitabine (20 mg/m^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, all participants received the FDC tablet Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

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

Key exclusion criteria (6 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
ASTX727 Dose EscalationAlso: cedazuridine (E7727), oral decitabine, IV decitabineOral investigational product and approved IV decitabine	Drug	Phase 1 Dose Escalation
ASTX727 Dose ConfirmationAlso: ASTX727 oral (combination of oral E7727 and oral decitabine), IV decitabineRandomization cross over design for courses 1 and 2	Drug	Phase 2 Dose Confirmation
ASTX727 Fixed-Dose CombinationAlso: ASTX727 oral (combination of oral E7727 and oral decitabine)Fixed-dose investigational product	Drug	Phase 2 Fixed-Dose Combination

Primary outcome

Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1
Time frame: Day 5
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).
Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2
Time frame: Pre-dose to Day 5
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.
Number of Participants With Dose-limiting Toxicity in Phase 1
Time frame: Up to Day 28 in Course 1 (28 days per course)
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.
Mean Maximum %LINE Demethylation in Phase 2
Time frame: Pre-dose to Day 28 in Course 2 (28 days per course)
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.
Number of Participants With Overall Response in Phase 2
Time frame: Up to approximately 29 months
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).

14 secondary outcomes

Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer
Time frame: At specified timepoints from 0 to 24 hours post-dose
Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer
Time frame: At specific timepoints from 0 to 24 hours post-dose
Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer
Time frame: At specific timepoints from 0 to 24 hours post-dose
Maximum Observed Plasma Concentration (Cmax) of Decitabine
Time frame: At specific timepoints from 0 to 24 hours post-dose
Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2
Time frame: At specific timepoints from 0 to 24 hours post-dose
Duration of Complete Response in Phase 1
Time frame: Up to 32 Months
Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate
Time frame: Up to approximately 29 months
Mean Maximum %LINE Demethylation in Phase 1
Time frame: Pre-dose to Day 28 in Course 2 (28 days per course)
Number of Participants With Overall Response in Phase 1
Time frame: Up to 32 months
Number of Participants With Adverse Events
Time frame: Up to 5 years
Number of Participants With Hematological Improvement
Time frame: Up to 32 months
Number of Participants With Transfusion Independence
Time frame: Up to 32 months
Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death
Time frame: Up to 32 months
Number of Participants With Overall Survival
Time frame: Up to 32 months

Results and safety

Results posted to the registry on 19 Oct 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Phase 1 Dose Escalation Cohort 1	7	0
Phase 1 Dose Escalation Cohort 2	6	0
Phase 1 Dose Escalation Cohort 3	6	0
Phase 1 Dose Escalation Cohort 4	6	0
Phase 1 Dose Escalation Cohort 5	19	0
Phase 2 Dose Confirmation Sequence A	25	0
Phase 2 Dose Confirmation Sequence B	25	0
Phase 2 Fixed-Dose Combination Sequence A	16	0
Phase 2 Fixed-Dose Combination Sequence B	14	0

Primary outcome: Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1

Time frame: Day 5. Geometric mean (Geometric Coefficient of Variation). Unit: ng*h/mL

Measure	Phase 1 Dose Escalation Cohort 1 n = 5	Phase 1 Dose Escalation Cohort 2 n = 6	Phase 1 Dose Escalation Cohort 3 n = 6	Phase 1 Dose Escalation Cohort 4 n = 6	Phase 1 Dose Escalation Cohort 5 n = 19
Value	53.6 (40)	68.9 (44)	94.8 (46)	221 (74)	146 (50)

Population analysed: Participants who were successfully dosed according to criteria for both ASTX727 and IV decitabine dosing and with evaluable pharmacokinetic (PK) measurements are included.

Primary outcome: Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2

Time frame: Pre-dose to Day 5. Geometric least squares mean (80% Confidence Interval). Unit: Ratio of Geometric LSM

Measure	Phase 2 Dose Confirmation n = 40	Phase 2 Fixed-Dose Combination n = 24
Value	93.52 (82.10 to 106.50)	97.59 (80.48 to 118.30)

Population analysed: Participants with evaluable PK measurements are included. Phase 2 crossover design was used to compare AUC ratio for oral and IV administration.

Primary outcome: Number of Participants With Dose-limiting Toxicity in Phase 1

Time frame: Up to Day 28 in Course 1 (28 days per course). Count of participants. Unit: Participants

Measure	Phase 1 Dose Escalation Cohort 1 n = 7	Phase 1 Dose Escalation Cohort 2 n = 6	Phase 1 Dose Escalation Cohort 3 n = 6	Phase 1 Dose Escalation Cohort 4 n = 6	Phase 1 Dose Escalation Cohort 5 n = 19
Value	0	0	0	0	1

Population analysed: The safety population includes participants in Phase 1 who received at least one dose of study drug.

Primary outcome: Mean Maximum %LINE Demethylation in Phase 2

Time frame: Pre-dose to Day 28 in Course 2 (28 days per course). Least squares mean (95% Confidence Interval). Unit: Percent

Measure	Phase 2 Dose Confirmation n = 48	Phase 2 Fixed-Dose Combination n = 30
Course 1 - Treatment	11.159 (9.023 to 13.294)	10.077 (7.696 to 12.459)
Course 1 - IV Decitabine	11.303 (9.167 to 13.439)	12.665 (10.12 to 15.211)
Course 2 - Treatment	9.833 (7.446 to 12.219)	8.134 (4.438 to 11.830)
Course 2 - IV Decitabine	9.920 (7.534 to 12.307)	8.230 (4.887 to 11.574)

Phase 2 Dose Confirmation: Mean Difference (Final Values): -0.144 (95% CI -3.165 to 2.876)
Phase 2 Dose Confirmation: Mean Difference (Final Values): -0.087 (95% CI -3.463 to 3.288)
Phase 2 Fixed-Dose Combination: Mean Difference (Final Values): -2.588 (95% CI -6.074 to 0.899)

Population analysed: The pharmacodynamic population includes all participants with evaluable data who received at least one dose of investigational product.

14 secondary outcomes are reported in the full results.

Adverse events

Time frame: Up to 5 years. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Phase 1 Dose Escalation Cohort 1	2 of 7 (28.6%)	6 of 7 (85.7%)	2 of 7
Phase 1 Dose Escalation Cohort 2	4 of 6 (66.7%)	6 of 6 (100%)	2 of 6
Phase 1 Dose Escalation Cohort 3	2 of 6 (33.3%)	6 of 6 (100%)	1 of 6
Phase 1 Dose Escalation Cohort 4	6 of 6 (100%)	6 of 6 (100%)	1 of 6
Phase 1 Dose Escalation Cohort 5	14 of 19 (73.7%)	18 of 19 (94.7%)	5 of 19
Phase 2 Dose Confirmation	39 of 50 (78%)	48 of 50 (96%)	29 of 50
Phase 2 Fixed-Dose Combination	25 of 30 (83.3%)	30 of 30 (100%)	21 of 30

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 27 Aug 2024.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 32285126Garcia-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.
Derived from this study: PubMed 30926081Savona 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.
Individual participant dataSharing planned: Undecided

Related trials for Myelodysplastic Syndrome

RecruitingPhase 2
Testing New Therapies for Patients With Acute Myeloid Leukemia Who Are Newly Diagnosed and Have Not Yet Started Treatment (A MyeloMATCH Treatment Trial)
Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic/Myeloproliferative Neoplasm
Active, not recruitingPhase 1/2
Omacetaxine + Azacitidine in Untreated Patients With High Grade MDS
High Grade Myelodysplastic Syndromes
RecruitingPhase 1/2
Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms
Myelodysplastic Syndromes
Active, not recruitingPhase 2
Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
Adult Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Not yet recruitingPhase 1
ATRN-119 in Combination With Decitabine in Patients With TP53-Mutated AML or Higher-Risk MDS
Acute Myeloid Leukemia, High-risk Myelodysplastic Syndrome

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Mohammad Azab, MD study director

Astex Pharmaceuticals, Inc.

James Lowder, MD study chair

Astex Pharmaceuticals, Inc.

17 sites in 2 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 17 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Oct 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1 (time frame: Day 5). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02103478, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Aug 2024.