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

• ClinicalTrials.gov Identifier: NCT02103478
• Recruitment Status: Completed
• First Posted: April 4, 2014
• Results First Posted: October 19, 2020
• Last Update Posted: December 23, 2020
• Sponsor: Astex Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Astex Pharmaceuticals, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Myelodysplastic Syndrome; MDS	Drug: ASTX727 Dose Escalation; Drug: ASTX727 Dose Confirmation; Drug: ASTX727 Fixed-Dose Combination	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 130 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: October 28, 2014
• Actual Primary Completion Date: June 5, 2018
• Actual Study Completion Date: December 4, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1 Dose Escalation; 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).	Drug: ASTX727 Dose Escalation; Oral investigational product and approved IV decitabine; Other Names: cedazuridine (E7727); oral decitabine; IV decitabine
Experimental: Phase 2 Dose Confirmation; 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.	Drug: ASTX727 Dose Confirmation; Randomization cross over design for courses 1 and 2; Other Names: ASTX727 oral (combination of oral E7727 and oral decitabine); IV decitabine
Experimental: Phase 2 Fixed-Dose Combination; 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.	Drug: ASTX727 Fixed-Dose Combination; Fixed-dose investigational product; Other Name: ASTX727 oral (combination of oral E7727 and oral decitabine)

Outcome Measures

Primary Outcome Measures :

1. 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).
2. 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.
3. 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.
4. 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.
5. 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).

Secondary Outcome Measures :

1. 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 ]
   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.
2. Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer [ Time Frame: At specific timepoints from 0 to 24 hours post-dose ]
   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.
3. 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 ]
   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.
4. Maximum Observed Plasma Concentration (Cmax) of Decitabine [ Time Frame: At specific timepoints from 0 to 24 hours post-dose ]
   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.
5. Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2 [ Time Frame: At specific timepoints from 0 to 24 hours post-dose ]
   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.
6. Duration of Complete Response in Phase 1 [ Time Frame: Up to 32 Months ]
   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.
7. Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate [ Time Frame: Up to approximately 29 months ]
   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.
8. Mean Maximum %LINE Demethylation in Phase 1 [ Time Frame: Pre-dose to Day 28 in Course 2 (28 days per course) ]
   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.
9. Number of Participants With Overall Response in Phase 1 [ Time Frame: Up to 32 months ]
   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).
10. Number of Participants With Adverse Events [ Time Frame: Up to 5 years ]
    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.
11. Number of Participants With Hematological Improvement [ Time Frame: Up to 32 months ]
    Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria.
12. Number of Participants With Transfusion Independence [ Time Frame: Up to 32 months ]
    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.
13. Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death [ Time Frame: Up to 32 months ]
    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.
14. Number of Participants With Overall Survival [ Time Frame: Up to 32 months ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic

Phoenix, Arizona, United States, 85054

United States, California

University of Southern California

Los Angeles, California, United States, 90024

United States, Illinois

University of Chicago

Chicago, Illinois, United States, 60637

United States, Indiana

Horizon Oncology

Lafayette, Indiana, United States, 47905

United States, Maryland

Johns Hopkins

Baltimore, Maryland, United States, 21231

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, New Jersey

John Theurer Cancer Center/ Hackensack University Medical Center

Hackensack, New Jersey, United States, 07601

United States, New York

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263

Weill Cornell Medical College - New York Presbyterian Hospital

New York, New York, United States, 10021

United States, Tennessee

Vanderbilt Ingram Cancer Center

Nashville, Tennessee, United States, 37232

United States, Texas

M. D. Anderson

Houston, Texas, United States, 77030

United States, Wisconsin

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Canada, Alberta

University of Alberta Hospital

Edmonton, Alberta, Canada, T6G 2G3

Canada, Ontario

Sunnybrook Health Sciences Centre, Odette Cancer Centre

Toronto, Ontario, Canada, M4N 3M5

Princess Margaret Cancer Center

Toronto, Ontario, Canada, M5G 2M9

Canada, Quebec

Hôpital Maisonneuve-Rosemont

Montréal, Quebec, Canada, H1T 2M4

Sponsors and Collaborators

Astex Pharmaceuticals, Inc.

Investigators

• Study Director: Mohammad Azab, MD; Astex Pharmaceuticals, Inc.
• Study Chair: James Lowder, MD; Astex Pharmaceuticals, Inc.

  Study Documents (Full-Text)

Documents provided by Astex Pharmaceuticals, Inc.:

Study Protocol  [PDF] April 6, 2017

Statistical Analysis Plan  [PDF] August 8, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Astex Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02103478
• Other Study ID Numbers: ASTX727-01
• First Posted: April 4, 2014
• Results First Posted: October 19, 2020
• Last Update Posted: December 23, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Astex Pharmaceuticals, Inc.:

Myelodysplastic Syndrome; MDS

Additional relevant MeSH terms:

Preleukemia; Myelodysplastic Syndromes; Syndrome; Disease; Pathologic Processes; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Neoplasms; Decitabine; Decitabine and cedazuridine drug combination; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors